CORT
Cortistatin precursor [Contains: Cortistatin-29; Cortistatin-17] [UNQ307/PRO350]
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Aging affects the body composition and balance of energy metabolism. Here, we collected in a single work several physiological parameters to show how aging and sex differences can influence energy homeostasis. Body mass index (BMI), Lee index, glucose tolerance, glycemia, and lipidogram in fasting were measured in male and female Wistar rats at the ages of 2, 6, 9, 12, and 18 months. We also measured the lipid profile, free fatty acids, glycerol, glycemia, leptin, adiponectin, insulin, corticosterone (CORT), prolactin (PRL), thyroid stimulated hormone, and triiodothyronine (T3) in 3- and 18-month-old rats of both sexes, fed ad libitum. Animals were classified as obese beginning at 2 months in males and 6 months in females. Aged male rats showed hyperglycemia and glucose intolerance compared to young males and old females. In the ad libitum condition, the 18-month males presented higher serum levels of triglycerides, total cholesterol, and free fatty acids than females. The 18-month-old females had higher PRL and CORT concentration than males, but insulin and T3 were higher in 18-month-old males than females. Our work demonstrated that aging processes on energy metabolism in rats is sex specific, with a better lipid profile and glucose tolerance in aged females.
Keywords
- aging
- body composition
- energy metabolism
- metabolism-related hormone
- sex differences
Social isolation (SI) is a major health risk in older people leading to cognitive decline. This study examined how SI and age influence performance in the novel object recognition (NOR) and elevated plus maze (EPM) tasks in C57BL/6 mice aged 3 or 24 months. Mice were group-housed (groups of 2-3) or isolated for 2 weeks prior to experimentation. Following NOR and EPM testing hippocampal norepinephrine (NE), 5, hydroxytryptamine (5-HT), 5, hydroxyindole acetic acid (5-HIAA), corticosterone (CORT) and interleukin-6 (IL-6) were determined and serum collected for basal CORT analysis. A separate set of mice were exposed to the forced swim test (FST), sacrificed immediately and serum CORT determined. SI impaired performance in the NOR and the FST, reduced hippocampal 5-HT, increased hippocampal IL-6 and increased serum CORT post-FST in young mice. Aged mice either failed to respond significantly to SI (NOR, FST, hippocampal 5-HT, serum CORT post FST) or SI had synergistic effects with age (hippocampal NE, 5-HIAA:5-HT). In conclusion, the lack of response to SI in the aged mice may affect health by preventing them adapting to new stressors, while the synergistic effects of SI with age would increase allostatic load and enhance the deleterious effects of the ageing process.
Keywords
- Aging
- Hippocampus
- Inflammation
- Memory
- Serotonin
- Social isolation
- Stress
Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter allopregnanolone (AlloP) levels, an important neurosteroid in the brain. We assessed the levels and regulation of AlloP and the effects of AlloP supplementation on cognitive function in 4-month-old and 24-month-old male C57BL/6 mice. With age, the expression of enzymes involved in the AlloP synthetic pathway was decreased and corticosterone (CORT) synthesis increased. Supplementation of AlloP improved cognitive function. Interestingly, interleukin 6 (IL-6) infusion in young animals significantly reduced the production of AlloP compared with controls. It is notable that inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein 130, significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of AlloP and increases CORT levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in AlloP levels and an increase in CORT. Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.
Keywords
- Alzheimer’s disease
- aging
- cognitive function
- enzyme regulation
- inflammation
- neurosteroid
- progesterone
- steroid hormones
Maintenance of the volume and osmolality of body fluids is important, and the adaptive responses recruited to protect against osmotic stress are crucial for survival. The objective of this work was to compare the responses that occur in aging male and female rats during water deprivation. For this purpose, groups of male and female Wistar rats aged 3 mo (adults) or 18 mo (old) were submitted to water deprivation (WD) for 48 h. The water and sodium (0.15 M NaCl) intake, plasma concentrations of oxytocin (OT), arginine vasopressin (AVP), corticosterone (CORT), atrial natriuretic peptide (ANP), and angiotensin II (ANG II) were determined in hydrated and water-deprived animals. In response to WD, old male and female rats drank less water and saline than adults, and both adult and old females drank more water and saline than respective males. Dehydrated old animals displayed lower ANG II plasma concentration and CORT response compared with the respective normohydrated rats. Dehydrated adult males had higher plasma ANP and AVP as well as lower CORT concentrations than dehydrated adult females. Moreover, plasma OT and CORT levels of old female rats were higher than those in the dehydrated old male rats. Relative expression of ANG II type 1 receptor mRNA was decreased in the subfornical organ of adult and old male rats as well as adult female rats in response to WD. In conclusion, the study elucidated the effect of sex and age on responses induced by WD, altering the degree of dehydration induced by 48 h of WD.
MeSH Terms
- Age Factors
- Animals
- Arginine Vasopressin
- Behavior, Animal
- Dehydration
- Drinking
- Female
- Male
- Rats, Wistar
- Sex Factors
- Sodium Chloride
- Subfornical Organ
- Water Deprivation
Keywords
- aging
- hormonal response
- sex differences
- sodium appetite
- thirst
Life history theory predicts that physiological and behavioral responsiveness to stress should be delayed in development until the benefits of heightened reactivity outweigh the costs of potentially chronic glucocorticoid levels. Birds often acquire stress-responsiveness at locomotor independence, however, both stress-responsiveness and locomotor ability are delayed in birds with altricial developmental strategies. Parrots (Psittacidae) are extremely altricial, but it is not known whether they also postpone physiological responsiveness to stress until locomotor independence. We quantified individual variation in baseline and stress-induced plasma corticosterone (CORT) concentrations, the main avian glucocorticoid, in wild green-rumped parrotlets (Forpus passerinus) of Venezuela at four stages of nestling development. Parrotlet neonates are very underdeveloped and compete for parental care among extreme sibling size hierarchies, a competitive scenario that might benefit from early hypothalamic-pituitary-adrenal (HPA) functionality. Nestlings that underwent a standardized restraint stress-treatment showed higher average CORT concentrations compared to baseline in all age groups sampled, and exhibited no evidence of age-related changes in the stress response. This is 2 weeks before locomotor independence and earlier than previously documented for altricial species. Results suggest that precocity of HPA function may be advantageous to growth and survivorship in extremely altricial birds.
MeSH Terms
- Adrenal Glands
- Aging
- Animals
- Corticosterone
- Female
- Hypothalamo-Hypophyseal System
- Male
- Parrots
- Restraint, Physical
- Stress, Physiological
Keywords
- Venezuela
- adrenocortical
- altricial
- birds
- corticosterone
- glucocorticoid
- hypothalamic-pituitary-adrenal axis
- ontogeny
- parrots
- stress
Our previous finding demonstrated that chronic corticosterone (CORT) may be involved in mediating the pathophysiology of premature aging in rats. Frequent jet lag increases the risk for many diseases, including obesity and type 2 diabetes, and is associated with the aging processes. However, the effect of jet lag on CORT-induced depression and its association with aging phenotypes remain unclear. In this study, the rats were exposed to both CORT and jet lag treatment, and the differences were analyzed and compared to rats with single CORT treatment. Our results showed that jet lag treatment aggravated CORT-induced depression-like behavior evidenced by sucrose intake test, forced swimming test, and open field test. Additionally, this treatment aggravated the shortening of telomeres, which possibly resulted in decreased telomerase activity, and downregulated the expression of telomere-binding factor 2 (TRF2) and telomerase reverse transcriptase compared to that in CORT rats, as revealed by quantitative real-time-polymerase chain reaction and western blot analysis, respectively. The shortening of telomeres may have been caused by increased oxidative stress, which was associated with the inhibition of sirtuin 3. Exposure to jet lag also aggravated the degeneration of mitochondrial functions, as shown by the decreases in the mRNA expression of COX1, ND1, and Tfam. Our findings provide physiological evidence that jet lag exposure may worsen stress-induced depression and age-related abnormalities.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- Corticosterone
- Cyclooxygenase 1
- Depression
- Jet Lag Syndrome
- Liver
- Male
- Membrane Proteins
- NADH Dehydrogenase
- Oxidative Stress
- Phenotype
- Rats
- Rats, Wistar
- Sirtuin 3
- TATA Box Binding Protein-Like Proteins
- Transcription Factors
Keywords
- age-related phenotypes
- depression
- jet lag
- oxidative stress
- telomere length
Calorie restriction (CR), which lengthens lifespan in many species, is associated with moderate hyperadrenocorticism and attenuated inflammation. Given the anti-inflammatory action of glucocorticoids, we tested the hypothesis that the hyperadrenocorticism of CR contributes to its attenuated inflammatory response. We used a corticotropin-releasing-hormone knockout (CRHKO) mouse, which is glucocorticoid insufficient. There were four controls groups: CRHKO mice and wild-type (WT) littermates fed either ad libitum (AL) or CR (60% of AL food intake), and three experimental groups: (a) AL-fed CRHKO mice given corticosterone (CORT) in their drinking water titrated to match the integrated 24-hr plasma CORT levels of AL-fed WT mice, (b) CR-fed CRHKO mice given CORT to match the 24-hr CORT levels of AL-fed WT mice, and (c) CR-fed CHRKO mice given CORT to match the 24-hr CORT levels of CR-fed WT mice. Inflammation was measured volumetrically as footpad edema induced by carrageenan injection. As previously observed, CR attenuated footpad edema in WT mice. This attenuation was significantly blocked in CORT-deficient CR-fed CRHKO mice. Replacement of CORT in CR-fed CRHKO mice to the elevated levels observed in CR-fed WT mice, but not to the levels observed in AL-fed WT mice, restored the anti-inflammatory effect of CR. These results indicate that the hyperadrenocorticism of CR contributes to the anti-inflammatory action of CR, which may in turn contribute to its life-extending actions.
MeSH Terms
- Adrenocortical Hyperfunction
- Animals
- Anti-Inflammatory Agents
- Caloric Restriction
- Carrageenan
- Corticosterone
- Corticotropin-Releasing Hormone
- Edema
- Inflammation
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
Keywords
- CRH
- aging
- calorie restriction
- corticosterone
- inflammation
- mouse
Disrupted circadian rhythms are a recognized effect of depression, and our previous article demonstrated an association between depression and premature aging, but the underlying mechanisms are not well understood. In the present study, we used a mouse model of chronic corticosterone (CORT)-treated depression to elucidate a mechanism by which depression may be associated with the circadian clock and mediate age-related phenotypes. Mice received a daily injection of 20 mg/kg CORT for 21 consecutive days, and the depression-like behaviors of mice were identified by the sucrose intake test, tail suspension test and open field test. Our findings indicated that CORT injection may be correlated with the circadian clock by impairing circadian rhythms or shifting the phase values of clock genes. We also showed that CORT-treated mice exhibited a significant gradual reduction in body weight gain with increased oxidative stress, including reduced activity of antioxidant-related enzymes, reduced glutathione:glutathione disulfide ratio and cytochrome (Cyt)-C level, and elevated reactive oxygen species content. Moreover, chronic CORT injection affected inflammatory responses, the production of mitochondrial ATP and telomere shortening, which may be associated with the Sirtuin 3 (SIRT3) signaling pathway. Additionally, chronic CORT injection disrupted the circadian rhythms of some indexes of aging phenotypes and altered the phase values of these indexes. Our findings suggest that psychologically stressful conditions such as depression are linked to changes in circadian rhythms and age-related phenotypes.
MeSH Terms
- Age Factors
- Aging
- Animals
- Behavior, Animal
- Circadian Clocks
- Circadian Rhythm
- Corticosterone
- Depression
- Gene Expression
- Inflammation
- Male
- Mice, Inbred C57BL
- Phenotype
- Reactive Oxygen Species
- Telomere Shortening
- Weight Gain
Stress exposure during development can impact both the expression of individual traits and associations between traits, but whether stress results in stronger or weaker associations between traits is unclear. In this study, we examined within- and among-trait associations for morphological and physiological traits in zebra finches (Taeniopygia guttata) exposed to corticosterone (CORT) during the nestling and fledging stages as well as in control birds. Birds exposed to CORT exhibited stronger within-trait correlations over time and stronger associations among traits. We found preliminary evidence that birds that died before the median age of death had stronger within- and among-trait correlations independent of treatment, and among CORT-treated birds, smaller birds were more likely to survive beyond the median age than larger birds. These findings suggest that stress hormone exposure in early life can result in reduced developmental flexibility, with potential fitness ramifications, and that these costs may be greater for larger offspring. Furthermore, our results provide experimental evidence for pleiotropic effects of hormones during development through altered patterns of phenotypic correlation.
MeSH Terms
- Animals
- Animals, Newborn
- Bacteria
- Body Size
- Corticosterone
- Female
- Finches
- Lipopolysaccharides
- Longevity
- Male
- Phenotype
- Stress, Physiological
- Stress, Psychological
Keywords
- corticosterone
- development
- morphometrics
- mortality
- phenotypic programming
- zebra finch
The hypothalamus-pituitary-adrenal axis (HPA) is the main regulator of the stress response. The key of the HPA is the parvocellular paraventricular nucleus of the hypothalamus (pPVN) controlled by higher-order limbic stress centers. The reactivity of the HPA axis is considered to be a function of age, but to date, little is known about the background of this age-dependency. Sporadic literature data suggest that the stress sensitivity as assessed by semi-quantitation of the neuronal activity marker c-Fos may also be influenced by age. Here, we aimed at investigating the HPA activity and c-Fos immunoreactivity 2 h after the beginning of a single 60 min acute restraint stress in eight age groups of male Wistar rats. We hypothesized that the function of the HPA axis (i.e., pPVN c-Fos and blood corticosterone (CORT) level), the neuronal activity of nine stress-related limbic areas (i.e., magnocellular PVN (mPVN), medial (MeA), central (CeA), basolateral nuclei of the amygdala, the oval (ovBNST), dorsolateral (dlBNST), dorsomedial (dmBNST), ventral and fusiform (fuBNST) divisions of the bed nucleus of the stria terminalis (BNST)), and two brainstem stress centers such as the centrally projecting Edinger-Westphal nucleus (cpEW) and dorsal raphe nucleus (DR) show age dependency in their c-Fos response. The somatosensory barrel cortex area (S1) was evaluated to test whether the age dependency is specific for stress-centers. Our results indicate that the stress-induced rise in blood CORT titer was lower in young age reflecting relatively low HPA activity. All 12 stress-related brain areas showed c-Fos response that peaked at 2 months of age. The magnitude of c-Fos immunoreactivity correlated negatively with age in seven regions (MeA, CeA, ovBNST, dlBNST, dmBNST, fuBNST and pPVN). Unexpectedly, the CeA, ovBNST and cpEW showed a considerable basal c-Fos expression in 1-month-old rats which decreased with age. The S1 showed a U-shaped age-related dynamics in contrast to the decline observed in stress centers. We conclude that the age- and brain area dependent dynamics in stress-induced neuronal activity pattern may contribute to the age dependance of the stress reactivity. Further studies are in progress to determine the neurochemical identity of neurons showing age-dependent basal and/or stress-induced c-Fos expression.
Keywords
- Edinger-Westphal nucleus
- aging
- amygdala
- bed nucleus of stria terminalis
- corticosterone
- dorsal raphe nucleus
- restraint stress
- stress response
A substantial literature details the relationship between age-related changes to the hypothalamic-pituitary-adrenal axis and deterioration of mnemonic functions that depend on the hippocampus. The relationship between adrenocortical status and other forms of memory that depend on the prefrontal cortex is less well understood in the context of advanced age. Here, we characterized performance of young adult and aged F344 rats on a prefrontal cortex-dependent working memory task and subsequently measured corticosterone (CORT) levels over the diurnal cycle and during exposure to an acute stressor. Our analyses revealed that aged rats with better working memory mounted a greater CORT response during acute stress exposure than either young adults or age-matched rats with impaired working memory. We also observed that age-related elevation of basal CORT levels is not associated with working memory performance. Jointly, these data reveal that the hypothalamic-pituitary-adrenal axis-mediated response to acute stress is positively associated with working memory in aging.
MeSH Terms
- Aging
- Animals
- Choice Behavior
- Corticosterone
- Hypothalamo-Hypophyseal System
- Male
- Memory, Short-Term
- Pituitary-Adrenal System
- Prefrontal Cortex
- Rats, Inbred F344
- Restraint, Physical
- Stress, Psychological
Keywords
- Circadian
- Corticosterone
- Glucocorticoids
- Hypothalamic-pituitary-adrenal axis
- Normal aging
- Prefrontal cortex
- Stress
- Working memory
Stress exposure has been implicated in the development of mood disorders, although little is known about the lasting effects of repeated stress during the adolescent period on sex-specific differences in endocrine and plasticity-signaling responses in adulthood. Using a 10-day combinatory stress paradigm (postnatal day (PND) 26 to 35), we examined sex-specific impact of adolescent stress and inhibition of tyrosine-related kinase B (TrkB) receptor (ANA-12; 0.5 mg/kg, i.p.) on 1) adolescent blood corticosterone levels, 2) adult locomotion and anxiety-like behavior, and 3) region-specific differences in endogenous TrkB full-length (TrkB.FL) and truncated (TrkB.T1) receptor isoforms. Blood collected on days 1, 5 and 10 revealed elevated basal and stress-induced CORT secretion in females compared to males, while ANA-12 attenuated CORT elevations post stress in both sexes. As adults, all females exhibited higher locomotor and exploratory activity than males in the open field test and elevated plus maze, and differences were comparable in the forced swim within stress-naïve and stress groups. Biochemically, vehicle-treated males showed elevated TrkB.T1 and TrkB.FL compared to vehicle-treated females in the PFC, hippocampus and NAc, and levels were consistently attenuated by ANA-12 treatment in non-stress males. With regards to stress exposure, expression of both isoforms was strongly down-regulated in the NAc of males only and was associated with increased TrkB.T1 in the PFC. ANA-12 enhanced expression in females, independent of stress exposure, compared to vehicle-treated counterparts, expression being increased for TrkB.T1 versus TrkB.FL and magnitude of the changes being region-specific. In contrast, ANA-12 effects in stressed males were restricted to inhibition of both isoforms in the hippocampus. Together, our findings support that TrkB activation, contingent on stress exposure, differentially affects TrkB isoform regulation during adulthood. Sex-specific biochemical responses at delayed intervals following adolescent stress exposure further support the need to include the sex variable in animal models.
MeSH Terms
- Aging
- Animals
- Azepines
- Benzamides
- Corticosterone
- Exploratory Behavior
- Female
- Hippocampus
- Immobility Response, Tonic
- Locomotion
- Male
- Maze Learning
- Nucleus Accumbens
- Phenotype
- Prefrontal Cortex
- Protein Isoforms
- Protein Kinase Inhibitors
- Rats
- Receptor, trkB
- Sex Characteristics
- Stress, Psychological
Keywords
- ANA-12
- Adolescence
- Behavior
- Combinatory stress
- Corticosterone
- Sex-specific differences
- TrkB.FL
- TrkB.T1
The aim of this study was to analyze the effects of lifelong aerobic exercise (AE) on the adaptive response of the stress system in rats. It is well known that hypothalamic-pituitary-adrenal axis (HPA) activity differs when triggered by voluntary or forced exercise models. Male Wistar rats belonging to exercise (E) or control (C) groups were subjected to chronic AE, and two cutoff points were established at 8 (middle age) and 18 months (old age). Behavioral, biochemical and histopathological studies were performed on the main components/targets of the stress system. AE increased adrenal sensitivity (AS), brain corticosterone (CORT) and corticotropin-releasing factor (CRF), but had no effect on the thymus, adrenal glands (AGs) weight or plasma CORT. In addition, AE exerted no effect on the sympathetic tone, but significantly reduced anxiety-related behavior and emotionality. Aging decreased AS and deregulated neuroendocrine feedback, leading to an anxiogenic state which was mitigated by AE. Histopathological and morphometric analysis of AGs showed no alterations in middle-aged rats but adrenal vacuolization in approximately 20% old rats. In conclusion, lifelong AE did not produce adverse effects related to a chronic stress state. On the contrary, while AE upregulated some components of the HPA axis, it generated an adaptive response to cumulative changes, possibly through different compensatory and/or super compensatory mechanisms, modulated by age. The long-term practice of AE had a strong positive impact on stress resilience so that it could be recommended as a complementary therapy in stress and depression disease.
MeSH Terms
- Adrenal Glands
- Aging
- Animals
- Anxiety
- Brain
- Catecholamines
- Corticosterone
- Male
- Random Allocation
- Rats, Wistar
- Resilience, Psychological
- Running
- Stress, Psychological
Keywords
- HPA axis
- aging
- anxiety
- exercise
- stress
- treadmill running
This study investigated whether sst2 gene deletion interacts with age and chronic stress exposure to produce exacerbated emotional and cognitive ageing. Middle-aged (10-12 month) sst2 knockout (sst2KO) and wild-type (WT) mice underwent an unpredictable chronic mild stress (UCMS) procedure for 6 weeks or no stress for control groups. This was followed by a battery of tests to assess emotional and cognitive functions and neuroendocrine status (CORT level). A re-evaluation was performed 6 months later (i.e. with 18-month-old mice). UCMS reproduced neuroendocrine and behavioral features of stress-related disorders such as elevated circulating CORT levels, physical deteriorations, increased anxiety- and depressive-like behaviors and working memory impairments. sst2KO mice displayed behavioral alterations which were similar to stressed WT and exhibited exacerbated changes following UCMS exposure. The evaluations performed in the older mice showed significant long-term effects of UCMS exposure. Old sst2KO mice previously exposed to UCMS exhibited spatial learning and memory accuracy impairments and high levels of anxiety-like behaviors which drastically added to the effects of normal ageing. Spatial abilities and emotionality scores (mean z-scores) measured both at the UCMS outcome and 6 months later were correlated with the initially measured CORT levels in middle-age. The present findings indicate that the deletion of the sst2 receptor gene produces chronic hypercorticosteronemia and exacerbates sensitivity to stressors which over time, have consequences on ageing brain function processes.
MeSH Terms
- Aging
- Animals
- Anxiety
- Chronic Disease
- Cognition
- Cognitive Dysfunction
- Corticosterone
- Depression
- Disease Models, Animal
- Emotions
- Gene Deletion
- Memory Disorders
- Memory, Short-Term
- Mice, Inbred C57BL
- Mice, Knockout
- Receptors, Somatostatin
- Stress, Psychological
Keywords
- Anxiety
- Corticosterone
- Depression
- Memory
- Mice
- Somatostatin
Stress hormones such as corticosterone (CORT) play an essential role in the development of depression. Chronic CORT administration has been shown to induce dysfunction in the hypothalamic-pituitary-adrenal axis leading to depression, which was in turn associated with accelerated aging. However, the effect of CORT administration on aging remains unclear. Rats were acclimatized for 1 week and then injected daily with CORT (40mg/kg) or vehicle (n = 10 each) for 21 consecutive days. Age-related indexes were then compared between CORT-treated rats and control rats. CORT induced affective behaviors indicative of depressive-like symptoms in rats, including reduced sucrose preference and increased immobility time in the forced swimming test. CORT-treated rats exhibited telomere shortening, possibly contributing to decreased telomerase activity and down-regulated expression of telomere-binding factor 2, correlated with enhanced oxidative damage. This was associated with inhibition of sirtuin 3 leading to reduced activities of superoxide dismutase 2 and glutathione reductase. CORT-treated rats showed degenerated mitochondrial functions represented by decreased adenosine triphosphate production, decreased nicotinamide adenine dinucleotide content, and decreased activity of nicotinamide phosphoribosyltransferase. The group sample sizes were small, and only male rats and a single dose level of CORT were used. These findings demonstrate that CORT-induced depression may be involved in mediating the pathophysiology of premature aging in rats.
MeSH Terms
- Aging, Premature
- Animals
- Anti-Inflammatory Agents
- Antioxidants
- Chronic Disease
- Corticosterone
- Depressive Disorder
- Disease Models, Animal
- Hypothalamo-Hypophyseal System
- Male
- Oxidative Stress
- Pituitary-Adrenal System
- Rats
- Rats, Wistar
- Reactive Oxygen Species
- Stress, Psychological
- Telomere
Keywords
- Corticosterone
- Depression
- Premature aging
- SIRT3 signaling pathway
- Telomere length
Developmental conditions in early life frequently have long-term consequences on the adult phenotype, but the adult environment can modulate such long-term effects. Glucocorticoid hormones may be instrumental in mediating developmental effects, but the permanency of such endocrine changes is still debated. Here, we manipulated environmental conditions during development (small vs. large brood size, and hence sibling competition) and in adulthood (easy vs. hard foraging conditions) in a full factorial design in zebra finches, and studied effects on baseline (Bas-CORT) and stress-induced (SI-CORT) corticosterone in adulthood. Treatments affected Bas-CORT in females, but not in males. Females reared in small broods had intermediate Bas-CORT levels as adults, regardless of foraging conditions in adulthood, while females reared in large broods showed higher Bas-CORT levels in hard foraging conditions and lower levels in easy foraging conditions. Female Bas-CORT was also more susceptible than male Bas-CORT to non-biological variables, such as ambient temperature. In line with these results, repeatability of Bas-CORT was higher in males (up to 51%) than in females (25%). SI-CORT was not responsive to the experimental manipulations in either sex and its repeatability was high in both sexes. We conclude that Bas-CORT responsiveness to intrinsic and extrinsic conditions is higher in females than in males, and that the expression of developmental conditions may depend on the adult environment. The latter finding illustrates the critical importance of studying of causes and consequences of long-term developmental effects in other environments in addition to standard laboratory conditions.
MeSH Terms
- Aging
- Animals
- Clutch Size
- Competitive Behavior
- Exploratory Behavior
- Feeding Behavior
- Female
- Finches
- Glucocorticoids
- Growth and Development
- Male
- Sex Factors
- Sibling Relations
- Social Environment
- Stress, Psychological
Keywords
- Corticosterone
- Developmental effects
- Environmental responsiveness
- Environmental stress
- Foraging conditions
- Glucocorticoids
- Sex differences
- Taenopygia guttata
The environment can affect individual performance directly via resource availability or indirectly through resource allocation among competing fitness components, such as body growth and maintenance activities related to short-term survival. Corticosterone (CORT), the main glucocorticoid in birds, may be an important mediator of energy allocation to different organismal functions, but its effect on the plasticity of fitness-related traits has rarely been investigated at different ontogenetic stages. Here, we evaluated the role of baseline and stress-induced CORT on nestling development of wild great tits (Parus major) under different growth conditions and at different developmental stages. We found that nestling mass and condition were positively related to stress-induced levels of total CORT and free CORT in the middle of nestling stage but negatively related at the prefledging stage. Our results also showed that stress-induced levels of total CORT can be used as a proxy for bioavailable free CORT. No significant relationship of body mass or condition in either stage was shown with levels of baseline CORT or stress-induced CORT-binding globulin capacity. None of these age-specific relationships depend on brood size manipulation. We conclude that the effects of glucocorticoids on nestling performance are stage specific. The ability to secrete CORT may have beneficial effects on nestling development in the middle of the nestling stage, while it can be adaptive to keep CORT levels at optimal ranges before fledging to give priority to growth-related processes that are important for long-term fitness.
MeSH Terms
- Aging
- Animals
- Body Weight
- Corticosterone
- Passeriformes
Keywords
- fitness
- free corticosterone
- glucocorticoids
- great tit
- growth
- trade-off
The aim of this study was to assess the interaction effect of transportation duration and parental age on physiological stress responses and quality in day-old chicks. After hatch, 3240 chicks from either 29-week old (young) or 60-week old (old) broiler breeders were transported for 1.5h (short) or 11h (long). Thereafter, 228 chicks were assessed for quality and blood plasma was assayed for corticosterone (CORT), lactate, glucose, and thiobarbituric acid-reactive substances (TBARS, increased concentrations can indicate oxidative stress). No interaction effects of parental age and transportation duration were found (all P>0.10). Chicks from young breeders showed higher CORT levels (P=0.007) and were of higher quality (Tona method, P<0.001) than those from old breeders. After long transportation, chicks showed increased CORT (P<0.001) and lower TBARS levels (P<0.001) compared to after short transportation. No evidence was provided that long transportation differently affected the quality or stress responses of chicks from breeder flocks of two ages.
MeSH Terms
- Aging
- Animals
- Chickens
- Corticosterone
- Oxidative Stress
- Stress, Physiological
- Thiobarbituric Acid Reactive Substances
- Time Factors
- Transportation
Keywords
- Animal welfare
- Day-old broiler chick
- Parental flock age
- Physiology
- Stress
- Transportation
Experiencing stress during adolescence can increase neophobic behaviors in adulthood, but most tests have been conducted in the absence of conspecifics. Conspecifics can modulate responses to stressors, for example by acting as 'social buffers' to attenuate the aversive appraisal of stressors. Here, we investigate the long-term effects of adolescent stress on the behavioral responses to novel stimuli (a mild stressor) across social contexts in an affiliative passerine bird, the zebra finch. During early (days 40-60) or late (days 65-85) adolescence the birds (n=66) were dosed with either saline or the hormone corticosterone (CORT). CORT was given in order to mimic a physiological stress response and saline was given as a control. In adulthood, the birds' behavioral responses to a novel environment were recorded in both the presence and absence of conspecifics. An acute CORT response was also quantified in adolescence and adulthood. Our findings show clear evidence of social context mediating any long-term effects of adolescent stress. In the presence of familiar conspecifics no treatment effects were detected. Individually, birds dosed with CORT in early adolescence were slower to enter a novel environment, spent more time perching in the same novel environment, and, if female, engaged in more risk assessment. Birds dosed in late adolescence were unaffected. No treatment effects were detected on CORT, but adolescents had a higher CORT concentration than adults. Our results are the first to suggest that familiar conspecifics in adulthood can buffer the long-term effects of stress that occurred during early adolescence.
MeSH Terms
- Adaptation, Psychological
- Aging
- Animals
- Behavior, Animal
- Corticosterone
- Female
- Finches
- Male
- Sexual Maturation
- Social Environment
- Stress, Physiological
- Stress, Psychological
- Time
Keywords
- Adolescence
- Corticosterone
- Developmental stress
- HPA axis
- Novel environment
- Plasticity
- Programming
- Social buffering
Stress and depression are associated with an acceleration of brain and bodily aging; effects which have been attributed to chronic elevations of glucocorticoids. We tested the hypothesis that a three week administration of stress-associated levels of corticosterone (CORT, the principal rodent glucocorticoid) would increase systemic and CNS DNA and RNA damage from oxidation; a phenomenon known to be centrally involved in the aging process. We also hypothesized that older individuals would be more sensitive to this effect and that the chronic CORT administration would exacerbate age-related memory decline. Young and old male Sprague-Dawley rats were non-invasively administered CORT by voluntary ingestion of nut paste containing either CORT (25mg/kg) or vehicle for a total of 22 days. CORT increased the 24h urinary excretion of the hormone to the levels previously observed after experimental psychological stress and caused a downregulation of the glucocorticoid receptor in the CA1 area of the hippocampus. Contrary to our hypothesis, 24h excretion of 8-oxodG/8-oxoGuo (markers of DNA/RNA damage from oxidation) was reduced in CORT-treated young animals, whereas old animals showed no significant differences. In old animals, CORT caused a borderline significant reduction of RNA oxidation in CNS, which was paralleled by a normalization of performance in an object location memory test. To our knowledge, this is the first demonstration that chronic stress-associated levels of CORT can reduce nucleic acid damage from oxidation. These findings contradict the notion of elevated CORT as a mediator of the accelerated aging observed in stress and depression.
MeSH Terms
- 8-Hydroxy-2'-Deoxyguanosine
- Aging
- Animals
- Corticosterone
- DNA Damage
- Deoxyguanosine
- Hippocampus
- Humans
- Memory
- Oxidative Stress
- Rats
Keywords
- Aging
- Depression
- Glucocorticoids
- Oxidatively generated nucleic acid damage
- Stress
Sterol 27-hydroxylase (CYP27A1) plays an important role in cholesterol homeostasis by degrading cholesterol to bile acids. Betaine can alleviate high-fat diet-induced hepatic cholesterol accumulation and maternal betaine treatment programs the hepatic expression of CYP27A1 in offspring. Excessive corticosterone (CORT) exposure causes hepatic cholesterol deposition in chickens, yet it remains unknown whether prenatal betaine modulates CORT-induced cholesterol accumulation in chicken liver later in life and whether it involves epigenetic gene regulation of CYP27A1. In this study, fertilized eggs were injected with saline or betaine at 2.5mg/egg before incubation, and the hatchlings were raised under the same condition till 56days of age followed by 7days of subcutaneous CORT injection. Plasma concentrations of total cholesterol (Tch), HDL- and LDL-cholesterol were significantly increased (P<0.05), after CORT challenge, in both control and betaine groups. However, prenatal betaine exposure prevented CORT-induced increase (P<0.05) in hepatic Tch content. Hepatic expression of cholesterol biosynthesis genes and ACAT1 protein that esterifies cholesterol for storage, were activated in both control and betaine groups upon CORT challenge. However, betaine-treated chickens were protected from CORT-induced repression (P<0.05) in LXR and CYP27A1 expression in the liver. CORT-induced down-regulation of LXR and CYP27A1 coincided with significantly increased (P<0.05) CpG methylation on their promoters, which was significantly ameliorated in betaine-treated chickens. These results suggest that in ovo betaine injection alleviates CORT-induced hepatic cholesterol deposition most probably through epigenetic regulation of CYP27A1 and LXR genes in juvenile chickens.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Anti-Inflammatory Agents
- Betaine
- Blotting, Western
- Chickens
- Cholestanetriol 26-Monooxygenase
- Cholesterol
- Corticosterone
- DNA Methylation
- Epigenesis, Genetic
- Female
- Gastrointestinal Agents
- Gene Expression Regulation, Enzymologic
- Immunoprecipitation
- Lipid Metabolism
- Liver
- Pregnancy
- Prenatal Exposure Delayed Effects
- Promoter Regions, Genetic
- RNA, Messenger
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
Keywords
- Betaine
- CYP27A1
- Cholesterol
- Corticosterone
- DNA methylation
Exposure to stressors can affect an organism's physiology and behavior as well as that of its descendants (e.g. through maternal effects, epigenetics, and/or selection). We examined the relative influence of early life vs. transgenerational stress exposure on adult stress physiology in a species that has populations with and without ancestral exposure to an invasive predator. We raised offspring of eastern fence lizards (Sceloporus undulatus) from sites historically invaded (high stress) or uninvaded (low stress) by predatory fire ants (Solenopsis invicta) and determined how this different transgenerational exposure to stress interacted with the effects of early life stress exposure to influence the physiological stress response in adulthood. Offspring from these high- and low-stress populations were exposed weekly to either sub-lethal attack by fire ants (an ecologically relevant stressor), topical treatment with a physiologically-appropriate dose of the stress-relevant hormone, corticosterone (CORT), or a control treatment from 2 to 43weeks of age. Several months after treatments ended, we quantified plasma CORT concentrations at baseline and following restraint, exposure to fire ants, and adrenocorticotropic hormone (ACTH) injection. Exposure to fire ants or CORT during early life did not affect lizard stress physiology in adulthood. However, offspring of lizards from populations that had experienced multiple generations of fire ant-invasion exhibited more robust adult CORT responses to restraint and ACTH-injection compared to offspring from uninvaded populations. Together, these results indicate that transgenerational stress history may be at least as important, if not more important, than early life stress in affecting adult physiological stress responses.
MeSH Terms
- Aging
- Animals
- Ants
- Corticosterone
- Female
- Food Chain
- Lizards
- Maternal Exposure
- Maternal Inheritance
- Stress, Physiological
- Stress, Psychological
Keywords
- Corticosterone
- Early life stress
- Evolutionary history
- Fire ant
- Invasive species
- Lizard
- Predation
- Stress response
- Transgenerational stress
Withdrawal and avoidance behavior are common symptoms of depression and can appear as a consequence of absence of reward, i.e. extinction-induced depression (EID). This is particularly relevant for the aged organism subjected to pronounced loss of former rewards. Avoidance of the former site of reward and increased withdrawal into a distant compartment accompany extinction of food-rewarded behavior in rodent models. During extinction, behavioral markers for re-learning dissociate from indicators of extinction-induced depression. Here we examined the effect of a chronic treatment with corticosterone (CORT), a well-known inducer of depression-related behavior, on EID in adult and aged rats. Adult (3-4months) and aged (18months) male rats were treated with CORT via drinking water for 3weeks prior to extinction of a cued food-reward task. CORT treatment increased the distance from the site of reward and decreased goal tracking behavior during extinction, especially in the aged rats. Plasma hormone levels measured before and after restraint stress showed a decline in basal ACTH- and CORT-levels after chronic CORT treatment in aged animals. The treatment significantly impaired the HPA-axis activation after acute stress in both, adult and aged animals, alike. Altogether, these findings show an enhancement of EID after chronic CORT treatment in the aged organism, which may be mediated by an impaired HPA-axis sensitivity. These findings may have special relevance for the investigation of human geriatric depression.
MeSH Terms
- Aging
- Animals
- Corticosterone
- Cues
- Depression
- Extinction, Psychological
- Humans
- Hypothalamo-Hypophyseal System
- Male
- Pituitary-Adrenal System
- Rats
- Rats, Wistar
- Reward
Keywords
- ACTH
- Chronic stress
- Corticosterone
- Depression model
- Despair
- Extinction
- Goal tracking
We examined whether hypothalamic-pituitary-adrenal axis activity in the nestlings of a semialtricial raptor, the black kite (Milvus migrans), varied with advancing age, throughout the day, and in response to a number of socioecological factors presumed to affect allostatic load. Both baseline corticosterone (CORT) titers and maximum CORT levels during 30 min of handling and restraint augmented across all sampled ages, suggesting that nestlings' energetic demands and capacity to respond to perturbations increase progressively throughout development. CORT secretion also peaked in the early morning, reached minimum levels in the central hours of the day, and increased again before dusk, suggesting a possible role of CORT in the regulation of activity-inactivity patterns. Finally, nestlings raised in a year of low marsh inundation, implying lower food availability and heightened allostatic loads, exhibited higher adrenocortical responsiveness to stress than nestlings raised in years of intermediate or high flooding. The nondetectable effect of other socioecological variables, such as territory quality, temperature, or brood order, suggests that parents may be able to buffer their nestlings from adverse environmental conditions or that the effect of such factors may have been obscured by selective mortality operating before sampling. We propose that future studies increase the simultaneous use of complementary techniques (fecal sampling, feather analysis) to reach firmer and more comprehensive conclusions, especially for planning the management and conservation of sensitive species.
MeSH Terms
- Adrenal Cortex
- Aging
- Animals
- Circadian Rhythm
- Corticosterone
- Environment
- Falconiformes
- Hypothalamo-Hypophyseal System
- Pituitary-Adrenal System
Keywords
- allostatic load
- corticosterone
- developmental hypothesis
- marshland inundation levels
We previously observed lasting and sex-specific detrimental consequences of early adolescent intermittent ethanol exposure (AIE), with male, but not female, rats showing social anxiety-like alterations when tested as adults. The present study used Sprague Dawley rats to assess whether social alterations induced by AIE (3.5g/kg, intragastrically, every other day, between postnatal days [P] 25-45) are further exacerbated by stressors later in life. Another aim was to determine whether AIE alone or in combination with stress influenced intake of a sweetened ethanol solution (Experiment 1) or a sweetened solution ("supersac") alone (Experiment 2) under social circumstances. Animals were exposed to restraint on P66-P70 (90min/day) or left nonstressed, with corticosterone (CORT) levels assessed on day 1 and day 5 in Experiment 2. Social anxiety-like behavior emerged after AIE in non-stressed males, but not females, whereas stress-induced social anxiety was evident only in water-exposed males and females. Adult-typical habituation of the CORT response to repeated restraint was not evident in adult animals after AIE, a lack of habituation reminiscent of that normally evident in adolescents. Neither AIE nor stress affected ethanol intake under social circumstances, although AIE and restraint independently increased adolescent-typical play fighting in males during social drinking. Among males, the combination of AIE and restraint suppressed "supersac" intake; this index of depression-like behavior was not seen in females. The results provide experimental evidence associating adolescent alcohol exposure, later stress, anxiety, and depression, with young adolescent males being particularly vulnerable to long-lasting adverse effects of repeated ethanol. This article is part of a Special Issue entitled SI: Adolescent plasticity.
MeSH Terms
- Aging
- Alcohol Drinking
- Animals
- Anxiety
- Binge Drinking
- Central Nervous System Depressants
- Corticosterone
- Depression
- Disease Models, Animal
- Ethanol
- Female
- Habituation, Psychophysiologic
- Male
- Motor Activity
- Random Allocation
- Rats, Sprague-Dawley
- Resilience, Psychological
- Restraint, Physical
- Sex Characteristics
- Sexual Maturation
- Social Behavior
- Stress, Psychological
Keywords
- Adolescence
- Anhedonia
- Anxiety
- Ethanol
- Sex differences
- Social facilitation
- Stress
Caffeine is a commonly used psychoactive substance and consumption by children and adolescents continues to rise. Here, we examine the lasting effects of adolescent caffeine consumption on anxiety-related behaviors and several neuroendocrine measures in adulthood. Adolescent male Sprague-Dawley rats consumed caffeine (0.3g/L) for 28 consecutive days from postnatal day 28 (P28) to P55. Age-matched control rats consumed water. Behavioral testing for anxiety-related behavior began in adulthood (P62) 7 days after removal of caffeine. Adolescent caffeine consumption enhanced anxiety-related behavior in an open field, social interaction test, and elevated plus maze. Similar caffeine consumption in adult rats did not alter anxiety-related behavior after caffeine removal. Characterization of neuroendocrine measures was next assessed to determine whether the changes in anxiety were associated with modifications in the HPA axis. Blood plasma levels of corticosterone (CORT) were assessed throughout the caffeine consumption procedure in adolescent rats. Adolescent caffeine consumption elevated plasma CORT 24h after initiation of caffeine consumption that normalized over the course of the 28-day consumption procedure. CORT levels were also elevated 24h after caffeine removal and remained elevated for 7 days. Despite elevated basal CORT in adult rats that consumed caffeine during adolescence, the adrenocorticotropic hormone (ACTH) and CORT response to placement on an elevated pedestal (a mild stressor) was significantly blunted. Lastly, we assessed changes in basal and stress-induced c-fos and corticotropin-releasing factor (Crf) mRNA expression in brain tissue collected at 7 days withdrawal from adolescent caffeine. Adolescent caffeine consumption increased basal c-fos mRNA in the paraventricular nucleus of the hypothalamus. Adolescent caffeine consumption had no other effects on the basal or stress-induced c-fos mRNA changes. Caffeine consumption during adolescence increased basal Crf mRNA in the central nucleus of the amygdala, but no additional effects of stress or caffeine consumption were observed in other brain regions. Together these findings suggest that adolescent caffeine consumption may increase vulnerability to psychiatric disorders including anxiety-related disorders, and this vulnerability may result from dysregulation of the neuroendocrine stress response system.
MeSH Terms
- Adrenocorticotropic Hormone
- Aging
- Amygdala
- Animals
- Anxiety
- Behavior, Animal
- Caffeine
- Corticosterone
- Corticotropin-Releasing Hormone
- Hypothalamo-Hypophyseal System
- Male
- Paraventricular Hypothalamic Nucleus
- Pituitary-Adrenal System
- Rats
- Stress, Psychological
Keywords
- Adolescence
- Corticotropin-releasing hormone
- Glucocorticoid
- Hypothalamic–pituitary–adrenal axis
- Immediate early gene
The seasonality of depressive symptoms is prevalent in children and adolescents. However, the mechanisms that underlie such susceptibility to seasonal influences on mood disorders are unclear. We examined the effects of a short photoperiod condition on the susceptibility to subchronic unpredictable mild stress (SCUS) and rhythmic alterations of plasma corticosterone (CORT), melatonin, and neuropeptide Y (NPY) in adolescent male rats. Compared with the 12h/12h light/dark photoperiod control (CON) rats, the 8h/16h photoperiod SCUS rats exhibited significant anhedonia, a core symptom of human depression, together with a blunted diurnal rhythm and elevation of 24h CORT, melatonin, and NPY levels. The 8h/16h photoperiod condition also blunted the rhythmicity of CORT, caused a phase inversion of melatonin, and caused a phase delay of NPY compared with 12h/12h CON rats. Such abnormalities of plasma CORT, NPY, and melatonin might cause adolescent individuals to present higher stress reactivity and greater vulnerability to stress over their lifetimes. The present study provides evidence of the susceptibility to the seasonality of stress-related disorders in adolescence.
MeSH Terms
- Aging
- Anhedonia
- Animals
- Circadian Rhythm
- Corticosterone
- Disease Models, Animal
- Disease Susceptibility
- Male
- Melatonin
- Neuropeptide Y
- Photoperiod
- Rats, Sprague-Dawley
- Resilience, Psychological
- Seasonal Affective Disorder
- Seasons
- Stress, Psychological
- Uncertainty
Keywords
- Adolescence
- Diurnal rhythm
- Short photoperiod
- Stress
- Susceptibility
Exposure to an immune challenge during peripuberty/adolescence, but not in adulthood, can cause enduring alterations in reproductive and non-reproductive behaviors. This suggests that the peripubertal/adolescent brain might respond differently to a stressor, like an immune challenge, than the adult brain. The goal of this study was to examine whether there are age and sex differences in the acute response to an immune challenge. To examine this research question, we investigated c-Fos expression in various brain regions. Corticosterone (CORT) concentration in the serum was quantified to examine hypothalamic-pituitary-adrenal axis (HPA-axis) responsiveness. Results showed that lipopolysaccharide (LPS; a bacterial endotoxin) treatment, induced a significant increase in the number of c-Fos immunoreactive cells in adult male and female mice compared to their saline controls. However, in peripubertal/adolescent mice, LPS treatment failed to increase the number of c-Fos immunoreactive cells in both male and female mice compared to their saline controls. LPS treatment also significantly increased serum CORT concentration in all mice regardless of sex and age. However, adult female mice treated with LPS showed significantly greater serum CORT concentration compared to adult and peripubertal/adolescent males and peripubertal/adolescent females treated with LPS. These findings support our hypothesis and suggest that there are important age and sex differences in acute immune response, which may allude to mechanisms for the enduring behavioral alterations, observed previously in mice exposed to an immune challenge during puberty but not in adulthood.
MeSH Terms
- Age Factors
- Aging
- Analysis of Variance
- Animals
- Brain
- Corticosterone
- Female
- Lipopolysaccharides
- Male
- Mice
- Neurons
- Proto-Oncogene Proteins c-fos
- Sex Characteristics
Keywords
- LPS
- adolescence
- c-Fos
- puberty
- sex differences
- stress
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) locally regenerates active glucocorticoids from their inert forms thereby amplifying intracellular levels within target tissues including the brain. We previously showed greater increases in intra-hippocampal corticosterone (CORT) levels upon Y-maze testing in aged wild-type than in 11β-HSD1(-/-) mice coinciding with impaired and intact spatial memory, respectively. Here we examined whether ageing influences 11β-HSD1 regulation of CORT in the dorsal hippocampus under basal conditions during the diurnal cycle and following stress. Intra-hippocampal CORT levels measured by in vivo microdialysis in freely behaving wild-type mice displayed a diurnal variation with peak levels in the evening that were significantly elevated with ageing. In contrast, the diurnal rise in intra-hippocampal CORT levels was greatly diminished in 11β-HSD1(-/-) mice and there was no rise with ageing; basal intra-hippocampal CORT levels were similar to wild-type controls. Furthermore, a short (3 min) swim stress induced a longer lasting increase in intra-hippocampal CORT levels in wild-type mice than in 11β-HSD1(-/-) mice despite no genotypic differences in elevation of plasma CORT. These data indicate that 11β-HSD1 activity contributes substantially to diurnal and stress-induced increases in hippocampal CORT levels. This contribution is even greater with ageing. Thus, 11β-HSD1 inhibition may be an attractive target for treating cognitive impairments associated with stress or ageing.
MeSH Terms
- 11-beta-Hydroxysteroid Dehydrogenase Type 1
- Aging
- Animals
- Circadian Rhythm
- Corticosterone
- Hippocampus
- Male
- Mice
- Mice, Knockout
- Microdialysis
- Stress, Psychological
Keywords
- ageing
- glucocorticoids
- hippocampus
- hypothalamic-pituitary-adrenal axis
Human and nonhuman adolescents have impaired retention of extinction of learned fear, relative to juveniles and adults. It is unknown whether exposure to stress affects extinction differently in adolescents versus adults. These experiments compared the short- and long-term effects of exposure to the stress-related hormone corticosterone (CORT) on the extinction of learned fear in adolescent and adult rats. Across all experiments, adolescent and adult rats were trained to exhibit good extinction retention by giving extinction training across 2 consecutive days. Despite this extra training, adolescents exposed to 1 week of CORT (200 μg/ml) in their drinking water showed impaired extinction retention when trained shortly after the CORT was removed (Experiment 1a). In contrast, adult rats exposed to CORT (200 μg/ml) for the same duration did not exhibit deficits in extinction retention (Experiment 1b). Exposing adolescents to half the amount of CORT (100 μg/ml; Experiment 1c) for 1 week similarly disrupted extinction retention. Extinction impairments in adult rats were only observed after 3 weeks, rather than 1 week, of CORT (200 μg/ml; Experiment 1d). Remarkably, however, adult rats showed impaired extinction retention if they had been exposed to 1 week of CORT (200 μg/ml) during adolescence (Experiment 2). Finally, exposure to 3 weeks of CORT (200 μg/ml) in adulthood led to long-lasting extinction deficits after a 6-week drug-free period (Experiment 3). These findings suggest that although CORT disrupts both short- and long-term extinction retention in adolescents and adults, adolescents may be more vulnerable to these effects because of the maturation of stress-sensitive brain regions. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
MeSH Terms
- Age Factors
- Aging
- Animals
- Anti-Inflammatory Agents
- Conditioning, Classical
- Corticosterone
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Extinction, Psychological
- Learning Disabilities
- Male
- Rats
- Rats, Sprague-Dawley
- Time Factors
Physiological mechanisms underlying migration remain poorly understood, but recent attention has focused on the role of the glucocorticoid hormone corticosterone (CORT) as a key endocrine regulator of migration. The migration-modulation hypothesis (MMH) proposes that baseline plasma CORT levels are elevated in migratory birds to facilitate hyperphagia and lipogenesis and that further elevation of CORT in response to acute stress is suppressed. Consequently, CORT may be a poor indicator of individual condition or environmental variation in migratory birds. We tested the MMH by measuring baseline and stress-induced CORT in common yellowthroats (Geothlypis trichas) during fall migration over 2 consecutive years in the Revelstoke Reach drawdown zone, a migratory stopover site affected by local hydroelectric operations. Birds had low baseline CORT at initial capture (<5 ng/mL) and then showed a robust stress response, with CORT increasing to ca. 50 ng/mL within 10-20 min. Our data therefore do not support the MMH. Baseline CORT did not vary with body mass, time of capture, Julian day, or year, suggesting that variable flooding regimes did not affect baseline CORT. Individual variation in the rate of increase in CORT was correlated with Julian day, being higher later in the migration period. Our data suggest that plasma CORT can be a useful metric in migration studies.
MeSH Terms
- Animal Migration
- Animals
- Body Weight
- British Columbia
- Corticosterone
- Environment
- Female
- Longevity
- Male
- Seasons
- Sex Characteristics
- Songbirds
Early life events, such as calorie restriction (CR) and elevated glucocorticoids, can calibrate the lifelong behavioural and physiological profile of an individual. Stress reactivity in adulthood is particularly sensitive to early life events; however, the consequence to fear and anxiety-like behaviour is less clear. Consequently, the current study sought to examine the effects of post-natal CR and glucocorticoid elevation, long considered powerful programming stimuli, on the subsequent fear and anxiety behaviour of the adult offspring. Rat dams received either corticosterone (200 μg/ml) supplementation in drinking water (CORT) or a 25% CR from post-natal day (PND) 1 to 11. Responses to the elevated plus maze (EPM), open field and a predator odour (TMT; 2,5-dihydro-2,4,5-trimethylthiazoline) were characterised in the adult male offspring. Both treatment conditions resulted in enhanced fear responses to TMT, characterised by heightened risk assessment and increased avoidance of TMT. CORT nursed offspring further demonstrated an anxiogenic profile in the open field. Basal hypothalamic-pituitary-adrenal function was unchanged in CORT adult offspring, whilst corticosterone concentration was elevated by post-natal CR. CR and CORT treated dams both exhibited greater anxiety-like behaviour in the EPM. A modest and temporary enhancement of maternal care was observed in CR and CORT treated dams, with CR dams further exhibiting rapid pup retrieval latencies. The results indicate enhanced emotionality in the adult male progeny of dams exposed to CR and corticosterone supplementation during the post-natal period. The modest enhancement of maternal care observed by both treatments is unlikely to have influenced the behavioural profile of the offspring.
MeSH Terms
- Aging
- Animals
- Animals, Suckling
- Anxiety
- Behavior, Animal
- Caloric Restriction
- Corticosterone
- Exploratory Behavior
- Fear
- Female
- Glucocorticoids
- Lactation
- Male
- Rats
- Rats, Wistar
Keywords
- Anxiety-like behaviour
- Calorie restriction
- Early stress
- Fear behaviour
- Maternal behaviour
- Maternal corticosterone
- Maternal programming
- Post-natal period
Cholesterol is an essential component of brain and nerve cells and is essential for maintaining the function of the nervous system. Epidemiological studies showed that patients suffering from anxiety disorders have higher serum cholesterol levels. In this study, we investigated the influence of high cholesterol diet on anxiety-like behavior in elevated plus maze in animal model and explored the relationship between cholesterol and anxiety-like behavior from the aspect of central neurochemical changes. Young (3 weeks old) and adult (20 weeks old) rats were given a high cholesterol diet for 8 weeks. The anxiety-like behavior in elevated plus maze test and changes of central neurochemical implicated in anxiety were measured. In young rats, high cholesterol diet induced anxiolytic-like behavior, decreased serum corticosterone (CORT), increased hippocampal brain-derived neurotrophic factor (BDNF), increased hippocampal mineralocorticoid receptor (MR) and decreased glucocorticoid receptor (GR). In adult rats, high cholesterol diet induced anxiety-like behavior and increase of serum CORT and decrease of hippocampal BDNF comparing with their respective control group that fed the regular diet. High cholesterol diet induced age-dependent effects on anxiety-like behavior and central neurochemical changes. High cholesterol diet might affect the central nervous system (CNS) function differently, and resulting in different behavior performance of anxiety in different age period.
MeSH Terms
- Aging
- Animals
- Anxiety
- Brain Chemistry
- Brain-Derived Neurotrophic Factor
- Cholesterol, Dietary
- Diet
- Hippocampus
- Hydrocortisone
- Male
- Motor Activity
- Neurotransmitter Agents
- Rats
- Rats, Sprague-Dawley
11Beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) locally amplifies active glucocorticoids within specific tissues including in brain. In the hippocampus, 11β-HSD1 messenger RNA increases with aging. Here, we report significantly greater increases in intrahippocampal corticosterone (CORT) levels in aged wild-type (WT) mice during the acquisition and retrieval trials in a Y-maze than age-matched 11β-HSD1(-/-) mice, corresponding to impaired and intact spatial memory, respectively. Acute stress applied to young WT mice led to increases in intrahippocampal CORT levels similar to the effects of aging and impaired retrieval of spatial memory. 11β-HSD1(-/-) mice resisted the stress-induced memory impairment. Pharmacologic inhibition of 11β-HSD1 abolished increases in intrahippocampal CORT levels during the Y-maze trials and prevented spatial memory impairments in aged WT mice. These data provide the first in vivo evidence that dynamic increases in hippocampal 11β-HSD1 regenerated CORT levels during learning and retrieval play a key role in age- and stress-associated impairments of spatial memory.
MeSH Terms
- 11-beta-Hydroxysteroid Dehydrogenase Type 1
- Aging
- Animals
- Glucocorticoids
- Hippocampus
- Male
- Maze Learning
- Memory Disorders
- Mice, Inbred C57BL
- Molecular Targeted Therapy
- Pyrazoles
- RNA, Messenger
- Spatial Memory
- Stress, Psychological
- Thiophenes
Keywords
- 11β-HSD1
- Aging
- Corticosterone
- Hippocampus
- Spatial memory
- Stress
Experiences of severe trauma during childhood are thought to be risk factors for developing mental disorders, such as anxiety and mood disorders, later in life. Correspondingly, exposure of rodents to early-life stress has been shown to affect neuronal circuitry and emotional behavior in adulthood, indicating a significant impact of stress on brain development. One current hypothesis proposes that the developing central nervous system is more sensitive to environmental influences, such as stress, than the adult. To test this hypothesis, we compared long-lasting effects of systemic corticosterone (CORT) administrations in two distinct early developmental periods. Mice exposed to early-neonatal CORT treatment on postnatal days (PD) 2-4 exhibited strongly enhanced excitability of neurons of the basolateral nucleus of the amygdala (BLA) in early adolescence and displayed impaired extinction of contextually conditioned fear memory, a type of behavior in which the BLA plays an important role. Furthermore, gene-expression of NMDA receptor subunits as well as calcium-activated K( )-channels was reduced in the amygdala. In contrast, exposure to the same CORT concentrations in a late-neonatal period (PD17-19) did not significantly affect BLA electrophysiology or extinction learning in adolescence. These results suggest age-dependent consequences of neonatal CORT exposure in amygdala neurons and provide evidence for a detrimental influence of early-neonatal stress on adolescent fear-memory processing.
MeSH Terms
- Aging
- Amygdala
- Animals
- Animals, Newborn
- Fear
- Female
- Glucocorticoids
- In Vitro Techniques
- Mice
- Mice, Inbred C57BL
- Neurons
- Patch-Clamp Techniques
- Potassium Channels, Calcium-Activated
- Pregnancy
- Receptors, N-Methyl-D-Aspartate
Keywords
- Basolateral amygdala
- Corticosterone
- Fear extinction
- Neuronal excitability
- Postnatal development
- Stress
Maternal effects provide a mechanism to adapt offspring phenotype and optimize the mother's fitness to current environmental conditions. Transferring steroids to the yolk is one way mothers can translate environmental information into potential adaptive signals for offspring. However, maternally-derived hormones might also have adverse effects for offspring. For example, recent data in zebra finch chicks suggested that ageing related-processes (i.e. oxidative stress and telomere loss) were increased after egg-injection of corticosterone (CORT). Still, we have few experimental data describing the effect of maternal effects on the growth-ageing trade-off in offspring. Here, we chronically treated pre-laying zebra finch females (Taeniopygia guttata) with 17-β-estradiol (E2) or CORT, and followed offspring growth and cellular ageing rates (oxidative stress and telomere loss). CORT treatment decreased growth rate in male chicks and increased rate of telomere loss in mothers and female offspring. E2 increased body mass gain in male offspring, while reducing oxidative stress in both sexes but without affecting telomere loss. Since shorter telomeres were previously found to be a proxy of individual lifespan in zebra finches, maternal effects may, through pleiotropic effects, be important determinants of offspring life-expectancy by modulating ageing rate during embryo and post-natal growth.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Body Weight
- Corticosterone
- Estradiol
- Female
- Finches
- Longevity
- Male
- Oxidative Stress
- Telomere Homeostasis
The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD.
MeSH Terms
- Adult
- Aged
- Aging
- Animals
- Circadian Rhythm
- Corticosterone
- Female
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Middle Aged
- Nervous System
- Pulmonary Disease, Chronic Obstructive
- Serotonin
- Smoking
Although glucocorticoids (GCs) are known to exert numerous effects in the hippocampus, their chronic regulatory functions remain poorly understood. Moreover, evidence is inconsistent regarding the long-standing hypothesis that chronic GC exposure promotes brain aging/Alzheimer disease. Here, we adrenalectomized male F344 rats at 15 months of age, maintained them for 3 months with implanted corticosterone (CORT) pellets producing low or intermediate (glucocorticoid receptor-activating) blood levels of CORT, and performed microarray/pathway analyses in hippocampal CA1. We defined the chronic GC-dependent transcriptome as 393 genes that exhibited differential expression between intermediate and low CORT groups. Short-term CORT (4 days) did not recapitulate this transcriptome. Functional processes/pathways overrepresented by chronic CORT-up-regulated genes included learning/plasticity, differentiation, glucose metabolism, and cholesterol biosynthesis, whereas processes overrepresented by CORT-down-regulated genes included inflammatory/immune/glial responses and extracellular structure. These profiles indicate that GCs chronically activate neuronal/metabolic processes while coordinately repressing a glial axis of reactivity/inflammation. We then compared the GC transcriptome with a previously defined hippocampal aging transcriptome, revealing a high proportion of common genes. Although CORT and aging moved expression of some common genes in the same direction, the majority were shifted in opposite directions by CORT and aging (eg, glial inflammatory genes down-regulated by CORT are up-regulated with aging). These results contradict the hypothesis that GCs simply promote brain aging and also suggest that the opposite direction shifts during aging reflect resistance to CORT regulation. Therefore, we propose a new model in which aging-related GC resistance develops in some target pathways, whereas GC overstimulation develops in others, together generating much of the brain aging phenotype.
MeSH Terms
- Adrenalectomy
- Aging
- Animals
- Body Weight
- CA1 Region, Hippocampal
- Corticosterone
- Drinking
- Drug Implants
- Eating
- Glial Fibrillary Acidic Protein
- Glucocorticoids
- Immunohistochemistry
- Male
- Oligonucleotide Array Sequence Analysis
- Rats
- Rats, Inbred F344
- Receptors, Glucocorticoid
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
- Transcriptome
Amphibian tadpoles display extensive anti-predator phenotypic plasticity, reducing locomotory activity and, with chronic predator exposure, developing relatively smaller trunks and larger tails. In many vertebrates, predator exposure alters activity of the neuroendocrine stress axis. We investigated predator-induced effects on stress hormone production and the mechanistic link to anti-predator defences in Rana sylvatica tadpoles. Whole-body corticosterone (CORT) content was positively correlated with predator biomass in natural ponds. Exposure to caged predators in mesocosms caused a reduction in CORT by 4 hours, but increased CORT after 4 days. Tadpoles chronically exposed to exogenous CORT developed larger tails relative to their trunks, matching morphological changes induced by predator chemical cue; this predator effect was blocked by the corticosteroid biosynthesis inhibitor metyrapone. Tadpole tail explants treated in vitro with CORT increased tissue weight, suggesting that CORT acts directly on the tail. Short-term treatment of tadpoles with CORT increased predation mortality, likely due to increased locomotory activity. However, long-term CORT treatment enhanced survivorship, likely due to induced morphology. Our findings support the hypothesis that tadpole physiological and behavioural/morphological responses to predation are causally interrelated. Tadpoles initially suppress CORT and behaviour to avoid capture, but increase CORT with longer exposure, inducing adaptive phenotypic changes.
MeSH Terms
- Animals
- Antimetabolites
- Corticosterone
- Cues
- Food Chain
- Genetic Fitness
- Larva
- Longevity
- Metyrapone
- Michigan
- Neurosecretory Systems
- Ranidae
- Time Factors
Fearfulness of an individual can affect its sensitivity to stress, while at the same time the social situation in which an animal lives can affect its fear level. It is however unknown what the long-term effects of high fearfulness on sensitivity to stress are, on individual or group level in laying hens. We hypothesize that increased fearfulness at a young age results in increased sensitivity to stress at an adult age, and that this relation can differ between groups, due to differences in group composition. Therefore, we studied the relation between fearfulness in an Open Field (OF) test at six weeks of age and plasma-corticosterone (CORT) levels after a 5-min Manual Restraint test (MR) at 33 weeks of age, and assessed behavior in the home pen. We used birds from a low mortality line, selected for four generations on low mortality due to feather pecking and cannibalism and a control line (n=153 in total, eight pens/line). These lines are known to differ in fearfulness and stress physiology. Chicks from the low mortality line were more active in the OF compared to chicks from the control line. Chicks that showed a fearful response (no walking, no vocalizing) in the OF test had higher CORT at 33 weeks of age than chicks that walked and/or vocalized in the OF test and had higher activity in the home pen as adults. On group level, a passive response in the OF was related to high CORT levels after MR. Presence of at least one fearful bird in a group led to higher CORT in the other group mates compared to birds from groups with no fearful birds present. Birds from groups in which more than 50% of birds had severe comb lesions had higher CORT levels compared to birds from groups with less than 50% of birds affected. High fearfulness of laying hen chicks can on individual level have a long-term effect on stress sensitivity. The presence of fearful birds in a group as well as signs of social instability in a group, indicated by comb lesions, can affect sensitivity to stress of birds from the same group. The mechanism by which this occurs can lie in social transmission of (fear related) behavior, but this suggestion needs further investigation.
MeSH Terms
- Aging
- Animals
- Chickens
- Corticosterone
- Exploratory Behavior
- Fear
- Female
- Freezing Reaction, Cataleptic
- Homing Behavior
- Linear Models
- Reaction Time
- Reproduction
- Restraint, Physical
- Social Environment
- Vocalization, Animal
Variation in the prenatal and postnatal environments can have long-term effects on adult phenotype. In humans and other animals, exposure to stressors can lead to long-term changes in physiology. These changes may predispose individuals to disease, especially disorders involving energy metabolism. In addition, by permanently altering metabolic rates and energy requirements, such effects could have important fitness consequences. We determined the effects of early-life food restriction and corticosterone (CORT) treatment on growth and adult body size, body composition (assessed via quantitative magnetic resonance) and metabolic rates in the song sparrow, Melospiza melodia. Nestlings were hand-raised in captivity from 3 days of age. Treatments (ad libitum food, food restriction or CORT treatment) lasted from day 7 to day 60. Both experimental treatments had sex-specific effects on growth. In the nestling period, CORT-treated males weighed more than controls, whereas CORT-treated females weighed less than controls. Food-restricted males weighed the same as controls, whereas food-restricted females weighed less than controls. Both experimental treatments also had sex-specific effects on standard metabolic rate (SMR). Females exposed to food restriction or CORT treatment during development had higher SMRs in adulthood than control females, but neither stressor affected SMR in males. There were no effects of either treatment on adult body size, body composition (lean or fat mass) or peak metabolic rate. Therefore, early-life stress may have sex-specific programming effects on metabolic rates and energy expenditure in song sparrows. In addition, both treatments affected nestling growth in a manner that exaggerated the typical sex difference in nestling mass, which could provide male nestlings with a competitive advantage over their sisters when developing in a poor-quality environment.
MeSH Terms
- Aging
- Animals
- Basal Metabolism
- Body Composition
- Body Size
- Body Weight
- Cortisone
- Feeding Behavior
- Female
- Food Deprivation
- Linear Models
- Male
- Nesting Behavior
- Principal Component Analysis
- Sex Characteristics
- Sparrows
- Stress, Physiological
- Vocalization, Animal
The widespread use of mobile phones raises the question of the effects of electromagnetic fields (EMF, 900 MHz) on the brain. Previous studies reported increased levels of the glial fibrillary acidic protein (GFAP) in the rat's brain after a single exposure to 900 MHz global system for mobile (GSM) signal, suggesting a potential inflammatory process. While this result was obtained in adult rats, no data is currently available in older animals. Since the transition from middle-age to senescence is highly dependent on environment and lifestyle, we studied the reactivity of middle-aged brains to EMF exposure. We assessed the effects of a single 15 min GSM exposure (900 MHz; specific absorption rate (SAR)=6 W/kg) on GFAP expression in young adults (6 week-old) and middle-aged rats (12 month-old). Brain interleukin (IL)-1β and IL-6, plasmatic levels of corticosterone (CORT), and emotional memory were also assessed. Our data indicated that, in contrast to previously published work, acute GSM exposure did not induce astrocyte activation. Our results showed an IL-1β increase in the olfactory bulb and enhanced contextual emotional memory in GSM-exposed middle-aged rats, and increased plasmatic levels of CORT in GSM-exposed young adults. Altogether, our data showed an age dependency of reactivity to GSM exposure in neuro-immunity, stress and behavioral parameters. Reproducing these effects and studying their mechanisms may allow a better understanding of mobile phone EMF effects on neurobiological parameters.
MeSH Terms
- Aging
- Animals
- Brain
- Cell Phone
- Conditioning, Classical
- Corticosterone
- Glial Fibrillary Acidic Protein
- Interleukin-1beta
- Interleukin-6
- Male
- Memory
- Neurogenic Inflammation
- Neuroimmunomodulation
- Radiation Injuries
- Radio Waves
- Rats
- Rats, Sprague-Dawley
Healthy aged individuals are more likely to suffer profound memory impairments following a challenging life event such as a severe bacterial infection, surgery, or an intense psychological stressor, than are younger adults. Importantly, these peripheral challenges are capable of producing a neuroinflammatory response, (e.g., increased pro-inflammatory cytokines). In this review we will present the literature demonstrating that in the healthy aged brain this response is exaggerated and prolonged. Normal aging primes or sensitizes microglia and this appears to be the source of this amplified response. We will review the growing literature suggesting that a dysregulated neuroendocrine response in the aged organism is skewed toward higher brain CORT levels, and that this may play a critical role in priming microglia. Among the outcomes of an exaggerated neuroinflammatory response are impairments in synaptic plasticity, and reductions in key downstream mediators such as Arc and BDNF. We will show that each of these mechanisms is important for long-term memory formation, and is compromised by elevated pro-inflammatory cytokines.
MeSH Terms
- Aging
- Cognition
- Hippocampus
- Humans
- Hypothalamo-Hypophyseal System
- Immune System
- Microglia
Breeding individuals enter an emergency life-history stage when their body reserves reach a minimum threshold. Consequently, they redirect current activity toward survival, leading to egg abandonment in birds. Corticosterone (CORT) is known to promote this stage. How and to what extent CORT triggers egg abandonment when breeding is associated with prolonged fasting, however, requires further investigation. We manipulated free-living male Adélie penguins with CORT-pellets before their laying period. We then examined their behavioral response with respect to nest abandonment in parallel with their prolactin levels (regulating parental care), and the subsequent effects of treatment on breeding success in relieved birds. Exogenous CORT triggered nest abandonment in 60% of the treated penguins ~14 days after treatment and induced a concomitant decline in prolactin levels. Interestingly, prolactin levels in treated penguins that did not abandon their nest were higher at the point of implantation and also after being relieved by females, when compared with abandoning penguins. Among successful birds, the treatment did not affect the number of chicks, nor the brood mass. Our results show the involvement of CORT in the decision-making process regarding egg abandonment in Adélie penguins when incubation is associated with a natural long fast. However, we suggest that CORT alone is not sufficient to trigger nest abandonment but that 1) prolactin levels need to reach a low threshold value, and 2) a rise in proteolysis (i.e. utilization of protein as main energy substrate) seems also to be required.
MeSH Terms
- Algorithms
- Animals
- Behavior, Animal
- Corticosterone
- Exploratory Behavior
- Feeding Behavior
- Female
- Longevity
- Longitudinal Studies
- Male
- Models, Biological
- Nesting Behavior
- Prolactin
- Sexual Behavior, Animal
- Spheniscidae
- Uric Acid
Behavioral and brain development is influenced by both maternal and non-maternal aspects of the postnatal environment and the precise nature of their interaction is the topic of an ongoing debate. Here, we consider the joint influence of neonatal environmental novelty and maternal self-stress regulation on the development of acoustic startle reflex (ASR), an extensively investigated model system for learning and neural plasticity. We test the hypothesis in the rat that brief repeated neonatal exposures to novelty can affect ASR in late adulthood and that this influence is sensitive to postnatal context of maternal self-stress regulation. We carried out the neonatal and early adulthood novelty exposure (PND 1-21 and PND 54-63 respectively), obtained measures of maternal self-stress regulation after weaning (PND 25-26), and evaluated in the male rats, ASR and ASR plasticity at adulthood (ASR1 and ASR2, one week apart, at 13.5 months of age). During ASR1, offspring, whose mothers had poor self-stress regulation as indexed by a high circulating basal corticosterone (CORT) concentration, showed a novelty-induced decrease of ASR latency. Offspring whose mothers had good self regulation as indexed by a low CORT, showed a novelty-induced increase in ASR latency. From ASR1 to ASR2, offspring whose mothers had poor self-stress regulation, showed a novelty-induced ASR latency habituation (increase in latency) while offspring whose mothers had good self regulation showed no novelty effect. These findings support a novel framework in which maternal and non-maternal postnatal environments exert interacting influences on the neonates, with maternal individual differences in self-stress regulation providing a critical context to enable bidirectional novelty-induced influence across different rat families.
MeSH Terms
- Acoustic Stimulation
- Aging
- Animals
- Animals, Newborn
- Corticosterone
- Exploratory Behavior
- Female
- Habituation, Psychophysiologic
- Male
- Maternal Behavior
- Rats
- Rats, Long-Evans
- Reaction Time
- Reflex, Startle
- Stress, Psychological
There is evidence that depression may have a different neural basis at different ages. Although chronic stress and elevated glucocorticoid levels have been demonstrated to lead to the emergence of mood disorders, it remains unclear how moderate elevation of glucocorticoid levels in young animals influences depression-like behaviors and brain functions. To address this issue, the present study examines how chronic corticosterone (CORT) administration during adolescence and early adulthood influences depression-like behaviors, hypothalamic-pituitary-adrenal (HPA) axis response and hippocampal cell proliferation. Male mice were chronically administrated with CORT drinking water (20mg/L) during adolescence. After two months of treatment, serum CORT levels were measured using enzyme immunoassay. Hippocampal glucocorticoid and mineralocorticoid receptors were characterized using Western blot. Tail suspension and forced swim tests were used to assess depression-related behaviors in mice. Immunohistochemistry was performed to measure bromodeoxyuridine (BrdU) incorporation in order to assess cell proliferation in the hippocampus. Our results suggest that chronic CORT administration induced a mild but not significant elevation in basal CORT levels and attenuated the physiological responses to stress. Chronic CORT administration also reduced expression of the hippocampal mineralocorticoid receptor and decreased immobility time in both the tail suspension test and the forced swim test. Moreover, chronic CORT administration increased the BrdU immunoreactivities in the hippocampus. Taken together, these findings suggest that chronic mild elevation by CORT administration during the adolescence and early adulthood attenuates depression-like behaviors.
MeSH Terms
- Aging
- Animals
- Blotting, Western
- Cell Proliferation
- Corticosterone
- Depression
- Hippocampus
- Hypothalamo-Hypophyseal System
- Male
- Mice
- Mice, Inbred C57BL
- Motor Activity
- Pituitary-Adrenal System
- Receptors, Glucocorticoid
- Receptors, Mineralocorticoid
Food restriction (FR) has a beneficial effect on aging process and exerts a significant effect on the responses of rodents to standard behavioral tasks. The aim of this study was to assess the cumulative influence of FR on the behavioral and biochemical parameters in Wistar rats. Six-month-old rats were subjected to restrictive feeding (50% of the daily food intake, every-other-day feeding regimen) for one month or for six months until ages of 7 and 12months, respectively. We examined the habituation of exploratory movement, amphetamine (AMPH)-induced motor activity, as well as changes in serum corticosterone (CORT) and glucose levels. The results obtained from FR animals were compared with ad libitum (AL)-fed age-matched control rats. Habituation of motor activity was only affected by six months of restrictive feeding. The sensitization of the motor response to AMPH that was observed in animals exposed to FR for one month was not observed in animals that were exposed to the same feeding regimen for six months. Serum CORT was increased and serum glucose was decreased in both FR groups. These results clearly show that despite the similarity of the biochemical changes that were induced by one and six months of FR, the nature of the changes in motor activities in these two groups of animals during habituation and after AMPH treatment was different. Our findings indicate that long-term FR has complex behavioral consequences that need to be carefully evaluated with respect to animal age, duration of FR and severity of the diet.
MeSH Terms
- Aging
- Amphetamine
- Analysis of Variance
- Animals
- Behavior, Animal
- Blood Glucose
- Central Nervous System Stimulants
- Corticosterone
- Exploratory Behavior
- Food Deprivation
- Habituation, Psychophysiologic
- Male
- Motor Activity
- Rats
- Rats, Wistar
Here we review the neurobiology of infant odor learning in rats, and discuss the unique role of the stress hormone corticosterone (CORT) in the learning necessary for the developing rat. During the first 9 postnatal (PN) days, infants readily learn odor preferences, while aversion and fear learning are attenuated. Such restricted learning may ensure that pups only approach their mother. This sensitive period of preference learning overlaps with the stress hyporesponsive period (SHRP, PN4-14) when pups have a reduced CORT response to most stressors. Neural underpinnings responsible for sensitive-period learning include increased activity within the olfactory bulb and piriform "olfactory" cortex due to heightened release of norepinephrine from the locus coeruleus. After PN10 and with the decline of the SHRP, stress-induced CORT release permits amygdala activation and facilitates learned odor aversions and fear. Remarkably, odor preference and attenuated fear learning can be reestablished in PN10-15 pups if the mother is present, an effect due to her ability to suppress pups' CORT and amygdala activity. Together, these data indicate that functional changes in infant learning are modified by a unique interaction between the developing CORT system, the amygdala, and maternal presence, providing a learning system that becomes more flexible as pups mature.
MeSH Terms
- Aging
- Amygdala
- Animals
- Animals, Newborn
- Association Learning
- Corticosterone
- Fear
- Locus Coeruleus
- Maternal Behavior
- Motor Activity
- Norepinephrine
- Object Attachment
- Odorants
- Olfactory Bulb
- Rats
- Stress, Psychological
The main purpose of this study was to evaluate the effect of aging on plasma and free corticosterone (CORT) levels in the brain in basal conditions and in response to an acute stressor. Microdialysis experiments were performed in the hippocampus (HC) and the prefrontal cortex (PFC) of young adult (6 months) and aged (24 months) male Wistar rats. Basal free levels of CORT in the HC and the PFC were higher in aged animals. Restraint stress increased plasma CORT and free CORT levels in the HC and the PFC both in young and aged animals. However, while the increase of plasma CORT was higher in aged rats compared with young rats, the increases of free CORT in the HC and the PFC were not different between these two groups of rats. These results suggest that the changes produced by aging in the brain may be related to the enhanced basal levels of free CORT and not to the CORT increases in response to stress.
MeSH Terms
- Aging
- Animals
- Corticosterone
- Hippocampus
- Male
- Prefrontal Cortex
- Rats
- Rats, Wistar
- Stress, Psychological
- Tissue Distribution
- Up-Regulation
- Wakefulness
Fledging is a major life transition for birds, when juveniles move from the safety of a nest into an environment where they must find food and avoid predators. The timing of fledging within a season can have significant effects on future survival and breeding success. Proximate triggers of fledging are unknown: though wing development is likely a primary factor, other physiological changes, such as elevated plasma corticosterone (CORT), may affect fledging behavior. Laysan Albatross (Phoebastria immutabilis) chicks have an extended post-hatching period during which they reach 150% of adult mass. However, approaching fledging, chicks fast for days to weeks and lose mass while still putting energy into feather growth. We evaluated chick morphology and physiology to elucidate proximate triggers of fledging. As in some other species, CORT increased as chicks fasted and lost body mass. At the same time, corticosteroid binding globulin (CBG) declined, thus amplifying free CORT prior to fledging. Once chicks reached a morphological threshold, free CORT levels predicted how long they stayed at the colony: chicks with higher free CORT fledged sooner. To perturb the relationship between body condition, endocrine physiology, and fledging behavior, we supplementally fed chicks for the month before fledging. Fed birds had a slower decrease in body mass, slower decrease in CBG, slower increase in free CORT, and stayed at the colony longer after reaching a morphological threshold. Our study suggests that as chicks lose mass, free CORT acts as a signal of energetic or nutritional state to adjust the timing of fledging.
MeSH Terms
- Aging
- Animals
- Animals, Wild
- Behavior, Animal
- Birds
- Body Weight
- Corticosterone
- Fasting
- Glucocorticoids
- Time Factors
- Transcortin
Ferulic acid (4-hydroxy-3-methoxycinnamic acid; FA) is a plant constituent and is contained in several medicinal plants for clinical use. In this paper, we investigated the effects of FA on the proliferation of neural stem/progenitor cells (NSC/NPCs) in vitro and in vivo. FA significantly increased the proliferation of NSC/NPCs cultured from the telencephalon of embryonic day-14 rats, and increased the number and size of secondary formed neurospheres. An in vitro differentiation assay showed that FA did not affect the percentage of either neuron-specific class III beta-tubulin (Tuj-1)-positive cells or glial fibrillary acidic protein (GFAP)-positive cells in the total cell population. Oral administration of FA increased the number of newly generated cells in the dentate gyrus (DG) of the hippocampus of corticosterone (CORT)-treated mice, indicating that FA enhances the proliferation of adult NSC/NPCs in vivo. We also found that oral administration of FA increased cAMP response element binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) mRNA level in the hippocampus of CORT-treated mice, and ameliorated the stress-induced depression-like behavior of mice. These novel pharmacological effects of FA may be useful for the treatment of mood disorders such as depression.
MeSH Terms
- Aging
- Animals
- Cell Differentiation
- Cell Proliferation
- Cells, Cultured
- Central Nervous System Agents
- Corticosterone
- Coumaric Acids
- Dentate Gyrus
- Depression
- Hippocampus
- Male
- Mice
- Neurogenesis
- Neurons
- Rats
- Rats, Wistar
- Stem Cells
- Stress, Psychological
- Telencephalon
The use of the club drugs 3,4-methylenedioxymethamphetamine (MDMA) and 5-methoxy-n,n-diisopropyltryptamine (Foxy) is of growing concern, especially as many of the effects, particularly during development, are unknown. The effects of these drugs upon homeostasis may be important since both are known to stimulate the hypothalamic-pituitary-adrenal axis. The purpose of this experiment was to examine alterations in rats in corticosterone and glucose following an acute exposure to these drugs at different stages of development: preweaning, juvenile, and adulthood. Both MDMA and Foxy increased corticosterone levels significantly at all ages examined, while glucose was elevated at all stages except at the juvenile time point (postnatal day 28). For both measures, there were no differences between the sexes with either drug. The data indicate that an acute exposure to these drugs alters CORT and glucose levels, raising the possibility that these changes may have effects on behavioral and cognitive function, as we and others have previously demonstrated.
MeSH Terms
- 5-Methoxytryptamine
- Age Factors
- Aging
- Animals
- Corticosterone
- Female
- Glucose
- Hypothalamo-Hypophyseal System
- Male
- N-Methyl-3,4-methylenedioxyamphetamine
- Pituitary-Adrenal System
- Rats
- Rats, Sprague-Dawley
- Serotonin Agents
- Up-Regulation
Adolescence is associated with potentially stressful challenges, and adolescents may differ from adults in their stress responsivity. To investigate possible age-related differences in stress responsiveness, the consequences of repeated restraint stress (90 min/day for 5 days) on anxiety, as indexed using the elevated plus-maze (EPM) and modified social interaction (SI) tests, were assessed in adolescent and adult Sprague-Dawley male and female rats. Control groups at each age included non-stressed and socially deprived animals, with plasma corticosterone (CORT) levels also measured in another group of rats on days 1 and 5 of stress (sampled 0, 30, 60, 90, and 120 min following restraint onset). While repeatedly restrained animals exhibited similar anxiety levels compared to non-stressed controls in the EPM, restraint stress increased anxiety at both ages in the SI test (as indexed by reduced social investigation and social preference). Daily weight gain measurements, however, revealed more marked stress-related suppression of body weight in adolescents versus adults. Analysis of stress-induced increases in CORT likewise showed that adolescents demonstrated less habituation than adults, embedded within typical sex differences in CORT magnitude (females greater than males) and age differences in CORT recovery (adolescents slower than adults). Despite no observable age-related differences in the behavioral response to restraint, adolescents were more sensitive to the repeated stressor in terms of physiological indices of attenuated weight gain and habituation of stress-induced CORT.
MeSH Terms
- Age Factors
- Aging
- Analysis of Variance
- Animals
- Animals, Newborn
- Anxiety
- Behavior, Animal
- Body Weight
- Corticosterone
- Female
- Male
- Maze Learning
- Rats
- Rats, Sprague-Dawley
- Restraint, Physical
- Sex Factors
- Social Behavior
- Time Factors
Potential interactions between age and endocrinological functioning have been understudied in wild ape populations. Therefore, we examined the relationship between age and the secretion of androgens and glucocorticoids in 15 juvenile, subadult, and adult male chimpanzees (Pan troglodytes schweinfurthii) free ranging in the Budongo Forest of Uganda. One hundred and nine fecal samples were opportunistically collected, between 07:30 and 13:30 hr, during the wet season. Fecal samples were preserved, by oven drying, and steroid content extracted before radioimmunoassay for dehydroepiandrosterone-sulfate (DHEA-S), testosterone (TEST), cortisol (CORT), and corticosterone (CCT). Employing indexes of age as predictive factors, linear mixed-effects modeling and non-parametric statistical comparisons of fecal steroid levels were conducted. Age was observed to significantly influence the production of both glucocorticoids and androgens in male Budongo Forest chimpanzees. Basically, whereas TEST and CORT increased, DHEA-S and CCT levels slightly declined as animals matured.
MeSH Terms
- Aging
- Animals
- Feces
- Female
- Gonadal Steroid Hormones
- Male
- Pan troglodytes
- Uganda
In response to stressors, most vertebrates elevate secretion of glucocorticoids (CORT) to produce a 'stress response' that enhances survival, but simultaneously inhibits reproduction. Circumstances in which the value of current reproduction is high relative to the value of future reproduction and survival, often lead to suppression of the stress response thus ensuring that critical resources are not diverted away from reproduction. Consistent with this expectation, we have previously reported that the magnitude of the stress response (maximum levels of CORT) declines with age in breeding adults of a long-lived seabird, the common tern (Sterna hirundo). While age-related changes in the stress response may be common in vertebrates, the mechanisms that underlie them are poorly understood. The glucocorticoid stress response is regulated by the hypothalamic-pituitary-adrenal (HPA) axis, and one mechanism that may contribute to an age-related decline in the stress response is changes in adrenal capacity (adrenal sensitivity to ACTH and/or an ability to secrete CORT in response to ACTH). To test this hypothesis, we captured and injected 92 known-aged adult common terns (Sterna hirundo) ranging in age from 3 to 29 years with either a control saline or an experimental adrenocorticotropin (ACTH) solution and measured the effects on stress-induced CORT after 30 min of restraint. In both treatment groups, stress-induced CORT significantly declined with age, suggesting that a decrease in adrenal capacity contributes to a reduction in the stress response in older adults.
MeSH Terms
- Adrenal Glands
- Adrenocorticotropic Hormone
- Aging
- Animals
- Charadriiformes
- Female
- Hydrocortisone
- Hypothalamus
- Male
- Pituitary Gland
- Restraint, Physical
- Stress, Psychological
Ethanol's effects on the developing brain include alterations in morphology and biochemistry of the hypothalamus. To examine the potential functional consequences of ethanol's interference with hypothalamic differentiation, we studied the long-term effects of prenatal ethanol exposure on basal circadian rhythms of core body temperature (CBT) and heart rate (HR). We also examined the late afternoon surge in corticosterone (CORT). Core body temperature and HR rhythms were studied in separate groups of animals at 4, 8, and 20 months of age. The normal late afternoon rise in plasma CORT was examined in freely moving male rats at 6 months of age via an indwelling right atrial cannula. Results showed that the CBT circadian rhythm exhibited an earlier rise after the nadir of the rhythm in fetal alcohol-exposed (FAE) males at all ages compared to controls. At 8 months of age, the amplitude of the CBT circadian rhythm in FAE males was significantly reduced to the level observed in controls at 20 months. No significant effects of prenatal ethanol exposure were observed on basal HR rhythm at any age. The diurnal rise in CORT secretion was blunted and prolonged in 6-month-old FAE males compared to controls. Both control groups exhibited a robust surge in CORT secretion around the onset of the dark phase of the light cycle, which peaked at 7:30 p.m. Whereas FAE males exhibited a linear rise beginning in mid afternoon, which peaked at 9:30 p.m. These results indicate that exposure to ethanol during the period of hypothalamic development can alter the long-term regulation of circadian rhythms in specific physiological systems.
MeSH Terms
- Age Factors
- Aging
- Animals
- Body Temperature
- Central Nervous System Depressants
- Circadian Rhythm
- Corticosterone
- Ethanol
- Female
- Heart Rate
- Hypothalamus
- Male
- Pregnancy
- Prenatal Exposure Delayed Effects
- Rats
In order to evaluate the metabolic responses of laying hens induced by high temperature at later laying stage, nine 60-wk-old laying hens (Gallus gallus domesticus) were employed in the present study. The hens were exposed to 32 degrees C for 21 d and blood samples were obtained before and at 1, 7, 14 and 21 d of heat exposure. The reactive oxygen species (ROS) formed in blood during heat exposure were estimated by the ex vivo spin-trapping method. Body temperature and plasma concentrations of glucose, urate, creatine kinase (CK), triiodothyronine (T(3)), thyroxine (T(4)), corticosterone (CORT), thiobarbituric acid reacting substances (TBARS), ferric/reducing antioxidant power (FRAP) and superoxide dismutase (SOD) activity were measured. Plasma levels of glucose, CK and CORT were not significantly influenced by heat exposure at any time point. The circulating concentrations of T(3) were decreased while plasma T(4) levels changed in the opposite way. The formation of ROS was significantly augmented by heat exposure in laying hens though the body temperature was not significantly altered. The enhanced enzymatic and non-enzymatic antioxidant systems acted in concert to alleviate the heat stress evoked oxidative damage.
MeSH Terms
- Acute Disease
- Age Factors
- Aging
- Animals
- Antioxidants
- Biomarkers
- Blood Glucose
- Body Temperature
- Chickens
- Chronic Disease
- Corticosterone
- Creatine Kinase
- Female
- Heat Stress Disorders
- Oviposition
- Oxidation-Reduction
- Oxidative Stress
- Reactive Oxygen Species
- Superoxide Dismutase
- Thiobarbituric Acid Reactive Substances
- Thyroxine
- Time Factors
- Triiodothyronine
- Uric Acid
Neonatal manipulations are known to alter the activity of the immune system and the hypothalamus-pituitary-adrenal (HPA) axis. This study was performed in order to examine whether brief and long maternal separations (BMS and LMS, respectively) interfere with the onset and development of murine lupus in NZB/NZWF1 females, and to determine whether the pattern of corticosterone (CORT) secretion throughout life is associated to the expression of the disease. Maternal separation was performed daily during postnatal days 1-14, lasting 15 min in the BMS group and 3h in the LMS group. Blood was sampled from the retro-orbital plexus on the 9th week, and every other week, from 10th to 34th weeks of life, for detection of anti-nuclear antibodies (ANA) and anti-double-strand DNA (anti-dsDNA) antibodies, and for determination of CORT serum levels. Urine samples were collected on the 21st, 27th, 33rd and 37th weeks of life. There were no group differences in regard to disease-related parameters, but LMS females presented a tendency for late onset of anti-dsDNA antibodies. BMS and LMS mice exhibited reduced CORT levels compared to non-manipulated (NM) animals. There was a strong negative correlation between total mean CORT concentration and onset of ANA, and a strong positive correlation between total mean CORT concentration and life span only in the NM group. Neonatal manipulations appeared to eliminate these correlations; hence, both BMS and LMS modified basal CORT secretion and the association between glucocorticoids and immune activity in the NZB/NZWF1 mouse strain.
MeSH Terms
- Animals
- Animals, Newborn
- Antibodies, Antinuclear
- Corticosterone
- DNA
- Female
- Genetic Predisposition to Disease
- Longevity
- Lupus Erythematosus, Systemic
- Male
- Maternal Deprivation
- Mice
- Mice, Inbred NZB
- Mice, Inbred Strains
- Proteinuria
- Time Factors
Effects of glucocorticoids (GCs) on maze-learning performances and hippocampal morphology were observed in male C57BL/6Cr mice. Correlations between aging, GCs and maze-learning performances were also studied. (2) Eight-arm radial maze was used in maze-learning tests. Learning performance was assessed by the parameters of time of getting all the bait, number of reentry errors into the already-entered arm with bait, and number of missed entries into an unbaited arm. Brain sections, 8 mum thick, were Nissl-stained with cresyl violet or stained immunocytochemically with antibodies against neurofilaments. (3) With aging, normal pyramidal cells decreased gradually in amount, and degenerating cells increased since the age of 18 months, accompanied with the maze-learning deficit. Here we have suggested that these changes were associated with the age-related deficits in adaptation tolerance of neurons to stress. In addition, the age-related deficits in plasticity of hippocampal neurons to GCs in young mice (3 months of age) resulted in an increase in plasma corticosterone (CORT) concentrations, degeneration of hippocampal pyramidal cells, as well as maze-learning deficits. (4) In conclusion, our data indicated that CORT caused the degeneration of hippocampal pyramidal cells and the impairment of memory.
MeSH Terms
- Aging
- Animals
- Anti-Inflammatory Agents
- Corticosterone
- Glucocorticoids
- Hippocampus
- Male
- Maze Learning
- Memory Disorders
- Mice
- Mice, Inbred C57BL
- Pyramidal Cells
Glucocorticosteroids (GCs) of the hypothalam-pituitary-adrenal axis play a role in association with both stressful events and daily life processes. However, relatively little is known about the role of GCs in relation to daily and seasonal life processes in animals in the wild. In this paper, we present data on basal levels of plasma corticosterone CORT in chicks of a pelagic seabird, the thin-billed prion, Pachyptila belcheri, during two predictable changes in demands, the daily activity pattern and the preparation for fledging. By comparing chicks fed recently with unfed chicks, we test how GC levels are modified according to nutritional condition. In accordance with their nocturnal feeding rhythm, chicks had a clear daily rhythm with increased CORT secretion at night, but CORT levels during the active phase were also highly elevated in unfed chicks compared with fed chicks. Close to fledging, chicks rapidly increased basal CORT levels, and again unfed chicks had higher levels than fed chicks, although the age effect here was stronger than the effect of recent feeding. The present data thus support the hypothesis that GC levels are adjusted to life stages with predictable changes in demands, but food availability and/or internal energy stores also affect the level to which GCs increase.
MeSH Terms
- Aging
- Animals
- Antarctic Regions
- Birds
- Circadian Rhythm
- Corticosterone
- Female
- Life Cycle Stages
- Oviposition
- Periodicity
A rapid elevation in the level of endogenous corticosterone (CORT) functions in the stress response associated with the hypothalamus-pituitary-adrenal axis, and it has been well documented that high levels of CORT play neurotoxic roles in the hippocampus. Both aging and the circadian rhythm possibly affect the sensitivity to CORT, although their endogenous modifications in the CORT-mediated events remain unclear. To explore the influence of age or circadian time on hippocampal vulnerability to excess CORT, we examined the relative mRNA expression of bcl-2 and bax in the dentate gyrus (DG) and the CA1 subfield, compared with the CA3 as an internal standard, after acute CORT administration using in situ RT-PCR. Male rats aged 10 weeks (young) or 6 months (adult) were treated with CORT at 0800 or 2000 h. The bcl-2 to bax mRNA ratio in the dentate gyrus (DG) was significantly decreased 2h after CORT exposure in the young rats treated at 0800 or 2000 h. In the adult rats, the treatment with CORT at 0800 h significantly decreased the bcl-2 to bax ratio, whereas the treatment at 2000 h was ineffective; the discrepancy between the treatment time points was apparent in adult rats, but not in young rats. Our results emphasize the importance of circadian time as well as age as a factor influencing the stress paradigm.
MeSH Terms
- Age Factors
- Aging
- Animals
- Biological Clocks
- Circadian Rhythm
- Corticosterone
- Hippocampus
- Male
- Proto-Oncogene Proteins c-bcl-2
- RNA, Messenger
- Rats
- Rats, Wistar
- bcl-2-Associated X Protein
This study investigated whether chronic stress-induced spatial memory deficits were caused by changes in the hypothalamic-pituitary-adrenal axis, such as corticosterone (CORT) elevations on the day of memory assessment, rather than the consequence of structural changes in the hippocampus. Male Sprague-Dawley rats were restrained for 6 h/day/21 days, and spatial memory was assessed on the Y-maze on day 22. Ninety minutes before training, rats received a subcutaneous injection of vehicle or metyrapone, a CORT synthesis inhibitor, and then spatial memory was determined 4-h later. The highest dose of metyrapone (75 mg/kg, s.c.) was most effective at preventing stress-induced spatial memory deficits. Chronic stress increased total CORT levels following Y-maze exposure, while acute metyrapone treatment dose-dependently attenuated total and free (unbound) CORT levels in both stress and control conditions. Blood samples taken from a separate subset of chronically stressed rats showed that baseline CORT levels were similar across the restraint period. Finally, chronic stress down-regulated glucocorticoid, but not mineralocorticoid, receptor mRNA expression within the hippocampus (dentate gyrus, CA1, CA2, CA3). These findings suggest that chronic stress-induced spatial memory deficits may be mediated by hypothalamic-pituitary-adrenal axis dysregulation. Specifically, CORT elevations and reductions in hippocampal glucocorticoid receptor expression, at the time of behavioural assessment may be involved, as opposed to a direct effect that is solely dependent upon hippocampal structural changes. These results have significance for treating cognitive decline in conditions associated with elevated glucocorticoids that include subpopulations in ageing, depression, Cushing's disease and Alzheimer's disease.
MeSH Terms
- Aging
- Animals
- Chronic Disease
- Corticosterone
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Down-Regulation
- Hippocampus
- Hypothalamo-Hypophyseal System
- Male
- Maze Learning
- Memory Disorders
- Neuropsychological Tests
- Pituitary-Adrenal System
- Pyridines
- RNA, Messenger
- Rats
- Rats, Sprague-Dawley
- Receptors, Glucocorticoid
- Stress, Psychological
Estrogen has been shown to suppress neural inflammation in vivo in response to intracerebral LPS injections or by intraparenchymal injections of NMDA. Using the latter approach, we have shown that estrogen suppresses inflammatory cytokine expression in lesioned ovariectomized young adult females but not reproductive senescent animals. However, in cultured microglia derived from either young or senescent animals, estrogen fails to suppress LPS-induced cytokine expression. These data suggest that estrogen's effects on the neural inflammatory response may result from its actions on blood-borne immune cells or its actions at the blood brain barrier or both. This hypothesis was directly tested here using a systemic injury model and comparing the neural inflammatory response in the olfactory bulb, which is protected by the blood brain barrier, and in the pituitary gland, which is incompletely protected by the blood brain barrier. Young and senescent Sprague-Dawley female rats were ovariectomized and replaced with either an estrogen or placebo pellet. Three weeks later, animals received a single i.p. injection of LPS (or vehicle) and were terminated 0.5, 2 or 3h later. Systemic injections of LPS increased IL-1beta expression in the liver in a time-dependent manner in young and senescent females. In young adults, LPS increased cytokine expression in both the bulb and the pituitary gland. However, estrogen treatment attenuated IL-1beta expression in the olfactory bulb but not in the pituitary gland. In senescent animals, estrogen completely suppressed IL-1beta expression in the bulb and the pituitary gland, while placebo-replaced animals responded normally. This age-related difference in cytokine induction by LPS was also seen in mRNA regulation, such that LPS induced IL-1beta mRNA in the olfactory bulb of young adults but not in the senescent female. Age and hormone effects on pituitary cytokines were also mirrored in plasma corticosterone (CORT) levels, such that estrogen treatment to senescent females attenuated LPS-induced CORT. These data suggest that the central inflammatory response to a systemic insult can be modulated by estrogen although the mechanism underlying the initiation of this response varies with reproductive age.
MeSH Terms
- Aging
- Analysis of Variance
- Animals
- Brain
- Corticosterone
- Cytokines
- Drug Interactions
- Estrogen Replacement Therapy
- Estrogens
- Female
- Gene Expression
- Interleukin-1
- Lipopolysaccharides
- Liver
- Ovariectomy
- RNA, Messenger
- Rats
- Rats, Sprague-Dawley
- Reverse Transcriptase Polymerase Chain Reaction
- Time
Concentrations of hormones related to energy homeostasis may differ between populations with varied body compositions, acting as signals to increase or decrease energy intake and/or expenditure. How these parameters correlate with body composition in horses and how they vary in fit (F) versus unfit (UF) Standardbred racehorses is unclear. The purpose of this study was to test the hypothesis that plasma concentrations of glucose (GLU), insulin (INS), cortisol (CORT), ghrelin (GHRL), adiponectin (ADIP) and leptin (LEP) would be correlated with body composition and differ in fit (F) versus unfit (UF) horses. Fasting plasma samples were taken from 12 unfit (11 /- 2 years, 521 /- 77 kg; mean /- SD) and 34 fit (4 /- 2 years, 475 /- 83 kg) Standardbred horses. GHRL, LEP, ADIP, INS and CORT concentrations were measured using radioimmunoassay. GLU concentration was measured using colorometric kits. Body composition data included body weight, body condition score (BCS), and percent fat (�t) calculated using rump fat thickness measured ultrasonically and the Westervelt equation. Data were analyzed using Pearson Product moment and Student's t tests. There were no differences (P>0.05) between F and UF horses for the plasma concentrations of CORT (69 /- 14 versus 76 /- 23 microg/dL), INS (7.2 /- 3.5 versus 7.1 /- 1.8 microIU/mL) or GLU (90 /- 6 versus 86 /- 7 mg/dL). Plasma GHRL and ADIP concentrations were greater (P<0.05) in F versus UF horses (54 /- 27 versus 33 /- 17 pg/mL and 1820 /- 276 versus 1333 /- 249 ng/mL, respectively), while plasma LEP was lower in F versus UF (1.0 /- 0.6 versus 4.4 /- 2.4 ng/mL, P<0.001). BCS and �t were lower in F versus UF horses (4.8 /- 0.3 versus 6.7 /- 0.5 and 11.9 /- 1.6 versus 15.4 /- 2.5%, respectively), with no correlation between �t and GHRL (-0.12, P>0.05), although there was a positive correlation between �t and LEP ( 0.72, P<0.05), and a negative correlation between �t and ADIP (-0.40, P<0.05). The data show that in comparing fit and unfit horses, there are variations in body composition as well as concurrent and substantial differences in the concentrations of hormones, cytokines, and other parameters related to the control of appetite and feed intake.
MeSH Terms
- Adiponectin
- Aging
- Animals
- Body Composition
- Energy Metabolism
- Female
- Ghrelin
- Horses
- Leptin
- Male
- Peptide Hormones
- Physical Conditioning, Animal
Neuropeptide Y (NPY) and agouti-related protein (AgRP), potent stimulants of feeding, have been linked in adult rats to both corticosterone (CORT) and dietary carbohydrate. To understand the significance of this relationship early in life, measurements were taken of these parameters at different ages around weaning, in rats given a choice of macronutrient diets or maintained on a carbohydrate-rich diet. The results demonstrate that, in both male and female rat pups, the expression and production of NPY and AgRP in the arcuate nucleus (ARC) peak on postnatal day 21 (P21), compared to P15 before weaning and P27 after weaning. These elevated levels of peptide were associated with peak levels of CORT and glucose and also a strong, natural preference for carbohydrate at weaning, which accounted for 55-65% of the pups' total diet. In subgroups defined by their body weight at these stages, rats with as little as 4% lower body weight (compared to higher weight pups) had 30-60% greater expression of NPY and AgRP in the ARC and elevated levels of CORT, with no difference in leptin or insulin. This response was significantly more pronounced at P21 than at P15 or P27. The importance of carbohydrate during this stage was suggested by additional results showing elevated NPY expression, CORT levels, body weight and inguinal fat pad weights in P27 pups raised on a 65% carbohydrate diet vs. 45% carbohydrate. These results suggest that hypothalamic NPY and AgRP, together with CORT, have glucoregulatory as well as feeding stimulatory functions that help mediate the transition from suckling of a fat-rich diet to independent feeding of a carbohydrate-rich diet. During this critical period, the carbohydrate together with the peptides and CORT provide the important signals, including elevated glucose, that promote de novo lipogenesis and enable weanling animals to survive periods of food deprivation.
MeSH Terms
- Aging
- Agouti-Related Protein
- Animals
- Appetite Regulation
- Body Weight
- Corticosterone
- Dietary Carbohydrates
- Feeding Behavior
- Female
- Glucose
- Hypothalamus
- Intercellular Signaling Peptides and Proteins
- Male
- Neuropeptide Y
- Neurosecretory Systems
- Proteins
- Rats
- Rats, Sprague-Dawley
- Sex Factors
- Signal Transduction
- Up-Regulation
- Weaning
Corticosteroids synergize with the thyroid hormone (TH) at late metamorphic stages and might have a role in the hormonal regulation of amphibian metamorphosis. This role could be influenced by diel fluctuations, particularly if the peak of the plasma corticoids changed in relation to the TH peaks. Diel variation in plasma corticosteroids was studied in Rana catesbeiana prometamorphic and climax tadpoles on 18:6, 12:12 and 6:18 light:dark (LD) cycles. Cortisol (hydrocortisone; HC) and aldosterone (ALDO) exhibited different, but LD cycle-specific, circadian fluctuations at prometamorphosis, whereas corticosterone (CORT) was undetectable (less than 1.18 ng/ml). HC, ALDO and CORT rhythms became synchronous at early metamorphic climax on all LD cycles, although the cosinor-derived acrophases, which occurred around the time of the dark:light transition, shifted approximately 6 h earlier from 18L:6D to 6L:18D. On both 18L:6D and 12L:12D, the acrophase of HC changed little from prometamorphosis to climax, whereas that of ALDO underwent a major phase shift. On 6L:18D, both the ALDO and the HC acrophases shifted at climax. These LD cycle-specific phase shifts of the diel rhythms placed the acrophases of the corticoids in different phase relationships to that of the previously determined thyroxine (T(4)) acrophase at climax, and may partially explain the influence of the light regimen on metamorphic timing. The pronounced diel variations in the corticoid concentrations from the troughs to the peaks show that hormone levels are a function of the time of day and the environmental lighting regimen, which need to be taken into account in measuring the level of plasma hormones in amphibians. The 24-h means calculated from the data of all the sampling times showed that only plasma ALDO and CORT, but not HC, rose markedly at climax, although there were significant LD cycle-related differences in the mean levels of both HC and ALDO at prometamorphosis, and in HC at climax. Additional work sampling at mid-light showed that plasma CORT peaked at Stage XXIII, decreased at the end of climax, and remained low in the postmetamorphic froglet at 2.1 ng/ml. In the adult bullfrog, CORT was clearly the predominant corticosteroid at 34.3 ng/ml, whereas HC and ALDO levels were only approximately 1.3 ng/ml.
MeSH Terms
- Adrenal Cortex Hormones
- Aging
- Aldosterone
- Animals
- Corticosterone
- Hydrocortisone
- Larva
- Osmolar Concentration
- Photoperiod
- Rana catesbeiana
We studied the long-term effect of neonatal treatment with the synthetic glucocorticoid dexamethasone (DEX) on stress responsivity later in life. It was found that the plasma adrenocorticotropin hormone (ACTH) and corticosterone (CORT) responses induced by novelty or conditioned fear stress were markedly attenuated in adult rats that had been neonatally treated with DEX as compared with saline (SAL)-treated controls. Since there were no differences in the heart rate, body temperature, plasma noradrenaline, plasma adrenaline and behavioral responses to these stressors, this points to a deficit within the hypothalamic-pituitary-adrenal (HPA) axis of DEX rats. We found no differences between DEX and SAL rats in basal plasma CORT concentrations measured throughout the circadian cycle, nor in the fraction unbound of CORT circulating under resting conditions, indicating normal tonic regulation of the HPA axis in DEX rats. Since we also found no differences in the hormonal responses induced by intravenous injection of graded doses of ACTH or corticotropin-releasing hormone (CRH), we investigated the sensitivity of the HPA response to stress for inhibition by glucocorticoids. Pretreatment with a low dose of CORT that did not affect the HPA response of SAL rats markedly inhibited the ACTH and CORT responses induced by novelty stress in DEX rats. This strongly suggests that an enhanced corticosteroid feedback underlies the blunted HPA response to stress in DEX rats. Finally, using quantitative immunocytochemistry, we found an increase in arginine-vasopressin (AVP) but not CRH stores in the external zone of the median eminence, suggesting an altered AVP/CRH ratio in the secretory output of the hypophysiotropic paraventricular nucleus. Taken together, our results show that exposure to DEX during early life leads to hyporesponsivity of the HPA axis to stress most likely due to hypersensitivity of the axis for negative feedback by corticosteroids at the suprapituitary level.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Arginine Vasopressin
- Circadian Rhythm
- Conditioning, Psychological
- Corticosterone
- Corticotropin-Releasing Hormone
- Cosyntropin
- Dexamethasone
- Exploratory Behavior
- Fear
- Feedback
- Glucocorticoids
- Hypothalamo-Hypophyseal System
- Pituitary-Adrenal System
- Rats
- Rats, Wistar
- Stress, Psychological
In the rat, relative to pup nonhandling (NH), early handling (EH) leads to old-adult offspring with a hyporesponsive HPA axis, superior spatial cognition, and greater hippocampal (HIPP) neuronal density. The present study compared the effects of EH and repeated maternal separation (MS), in the form of 6-hr separation on each of 4 days beginning at day 12, on spatial cognition, corticosterone (CORT) levels, and HIPP characteristics, in aged rats. Male Wistar rat pups were exposed to EH, MS, NH or our normal in-house husbandry (CON) and tested at 18-20 months. Relative to NH and CON, EH demonstrated superior spatial cognition, reduced CORT stress response, reduced CA-field volume and no change in HIPP neuronal number. MS demonstrated a trend to superior spatial cognition, an unaffected CORT stress response, reduced CA-field volume and no change in HIPP neuronal number. These findings are important in terms of the life-span mechanisms via which postnatal manipulations induce neurobehavioral effects, and the mechanisms via which CORT and HIPP structure relate to HIPP function.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Behavior, Animal
- Cell Count
- Corticosterone
- Female
- Handling, Psychological
- Hippocampus
- Male
- Maternal Deprivation
- Maze Learning
- Neurons
- Organ Size
- Rats
- Rats, Wistar
- Reaction Time
- Stereotaxic Techniques
- Stress, Psychological
Although final brain size and the number of available neurons and axons appear to be established early in infancy, plasticity of the brain continues during adolescence through an integrated process of overproduction and elimination of synapses and receptors. In addition, hormonal levels change dramatically during this period, as a result of the onset of puberty. This age-specific condition has been suggested to serve as a permissive factor for the emergence of a number of early-onset neuropsychiatric disorders, including schizophrenia, attention-deficit hyperactivity disorder (ADHD), and perhaps substance abuse. However, relatively few investigations have focused on animal models of this developmental phase. The periadolescent rodent (similar30-45-day-old), has been proposed as a useful model. Periadolescent rats and mice are generally associated with a peculiar behavioral profile, consisting of basal hyperactivity, high attraction towards novel stimuli and a marked involvement in affiliative and playful behaviors. Moreover, a unique profile of psychopharmacological responsivity characterizes rodents around this age. Recent experiments by our group investigated age-related discontinuities in the response of the hypothalamic-pituitary-adrenal axis (HPA) to both stress and psychostimulants. The latter are often administered as therapeutic drugs to children with ADHD, which have been also associated with an impaired response to stress and abnormalities in HPA axis function. Indeed, an altered functioning of the HPA axis has been proposed as a possible risk factor and a potential marker for such a behavioral vulnerability. Animals were studied at adulthood (> pnd 70) or during periadolescence. Experiment I characterized basal corticosterone (CORT) levels in naive mice kept undisturbed in standard social conditions from weaning to sacrifice. Periadolescent male mice showed higher basal CORT levels than adult subjects, suggesting that the set up of the HPA axis is physiologically elevated during adolescence. In experiment II, we investigated age-related differences in the response to both acute and chronic stress conditions. Periadolescent and adult mice were housed either in a standard (three animals per cage) or in a crowding condition (nine animals per cage). The latter has been indeed reported to potentiate the subsequent reaction to acute stress in adult rodents. At the end of this period and following 24 h individual housing, mice were injected with either saline (SAL) or a standard amphetamine (AMPH) dose (2 mg/kg), and faced with a mild acute psychological stress, namely removal of sawdust from the home cage. Important sex differences emerged in animals of the two ages. Periadolescent females showed a reduced CORT response to acute stress. Within the adult male group, the chronic crowding condition produced a prominent potentiation of CORT response to the acute stress challenge. Conversely, this profile was not evidenced in periadolescents. These results indicate a strong role for gender and social variables in the response of periadolescent subjects to the various aspects of stress. As for AMPH effects, in the absence of significant changes in adult subjects, the drug produced a marked CORT release in periadolescent mice. A better understanding of neuroendocrine-related AMPH effects as a function of social and environmental risk factors during adolescence, might deepen our knowledge on the neurobiological bases of genetically determined neuropsichiatric disorders and possibly improve the therapeutical efficacy of psychostimulant drugs.
MeSH Terms
- Acute Disease
- Aging
- Amphetamine
- Animals
- Central Nervous System Stimulants
- Chronic Disease
- Corticosterone
- Crowding
- Female
- Male
- Mice
- Sex Characteristics
- Stress, Psychological
Despite extensive research on the relationship between acute stress and hippocampal function in adults, little is known about the short- and long-term effects of prolonged juvenile stress on learning, memory, and other hippocampal functions. This experiment investigated whether spatial learning would be altered in juvenile and adult rats previously exposed to a chronic stressor: 6 h of social isolation (SI) daily at 15-21 days of age. SI was found to increase circulating plasma levels of corticosterone (CORT) and allopregnanolone (3-alpha,5-alpha-pregnan-20-one; 3,5-THP) at 1 h after separation on the fourth day, indicating that the isolation was an effective stressor. When tested as juveniles (post-natal (PN) 22-24), spatial learning was impaired on the Morris water maze in the previously isolated subjects compared to non-isolated controls. However, when tested as adults (PN 92-94), subjects previously exposed to SI during the third week of life demonstrated more rapid learning of the task than controls. These results are discussed in light of research on the effects of CORT on the developing hippocampus.
MeSH Terms
- Aging
- Animals
- Body Weight
- Female
- Hydrocortisone
- Male
- Maze Learning
- Memory, Short-Term
- Pregnanolone
- Rats
- Rats, Long-Evans
- Social Isolation
- Stress, Psychological
Plasma corticosterone (CORT) levels were measured after short periods of sleep deprivation in rats at postnatal days 12, 16, 20, and 24. There was an age-dependent increase in basal CORT levels and sleep deprivation significantly elevated CORT at all ages compared to non-sleep deprived controls. The levels of CORT after sleep deprivation in P16, P20 and P24 animals were similar, resulting in an age-dependent decrease of the magnitude of the response. Sleep deprived P12 animals had lower levels of CORT. However, the observed response to sleep deprivation suggests that sleep loss is a significant stressor at this age. These observations suggest that younger animals are more sensitive to the effects of mild sleep deprivation than older ones.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Corticosterone
- Electroencephalography
- Radioimmunoassay
- Rats
- Rats, Long-Evans
- Sleep Deprivation
- Stress, Psychological
Considering age-related changes in serotonin (5HT) function, we examined normative data of prolactin (PRL) and cortisol (CORT) responses to D-fenfluramine (D-FEN) in healthy elderly subjects. Twenty-three healthy male and female volunteers aged 60-86 participated in a single-blind, placebo-controlled, fixed-order, crossover-design challenge test. Two baseline PRL and CORT values and the responses of these hormones to 30 mg of oral D-FEN and placebo over a 4 h period were measured on two separate sessions. PRL and CORT responses were significantly greater following D-FEN than after placebo. Peak PRL responses (maximum change from baseline following D-FEN) were relatively robust compared to peak CORT responses. Peak PRL concentration was positively correlated with plasma D-nor-FEN concentration. Gender and aging had no effect on hormonal responses in the elderly. Although the weight adjusted dose used in this study was higher than the therapeutic dose of D-FEN, PRL responses were modest and only two participants experienced side effects. D-FEN is a safe serotonergic probe and PRL responsivity to D-FEN is a reliable index of central 5HT function in the elderly. An age-related decline in serotonergic function must be considered in determining the dose requirement for maximal hormonal responses to D-FEN challenge tests in the elderly.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Behavior
- Body Weight
- Female
- Fenfluramine
- Hemodynamics
- Humans
- Hydrocortisone
- Male
- Middle Aged
- Neurotransmitter Agents
- Prolactin
- Serotonin
- Serotonin Uptake Inhibitors
- Sex Characteristics
The psychostimulant D-amphetamine (AMPH) increases generalised activity in adult subjects, while exerting a paradoxical "calming effect" in children with Attention-deficit Hyperactivity Disorder (AD/HD). A number of animal models have been developed to characterise the neurobiological basis of this AMPH action. In this line, the present review summarises recent work on the effects of AMPH on behavioural and physiological parameters in developing mice with a special emphasis on the role of gender and environmental risk factors. Behavioural and neuroendocrine responses to AMPH administration (0, 1, or 3 mg/kg, IP) and their relation to changes in the environment, represented by social stimuli, were studied in infant CD-1 mouse pups of both sexes at three different developmental ages (3, 8, or 18 postnatal (pnd) days). Mouse pups were assessed either in baseline condition or following 24 h maternal deprivation. AMPH exerted a paradoxical effect on CORT secretion only in maternally deprived subjects while affecting behaviour mainly in deprived female subjects, which showed a generalised shift to the left in the dose-response curve to this drug. Unwanted perseverative motor effects and possible dependence states represent side effects of AMPH administration. Further knowledge on these aspects comes from another set of studies where a shortened conditioned place preference (CPP) paradigm was employed to assess the reinforcing properties of AMPH (0, 1, 3.3, or 10 mg/kg) in developing mice on 14-17, 21-24, and 28-31 pnd. Data indicate that AMPH-CPP develops early, mice being able, already at two weeks of age, to acquire a place preference that relies on adult-like sensory, motor, and associative capacities. AMPH-CPP appears earlier in females, compared to males. A detailed analysis of acute D-amphetamine effects evidenced that the drug produces a dose-dependent increase in locomotor activity and in several responses (including stereotypes). These effects appear much larger at both post weaning stages than in preweanlings and are significantly more pronounced in females than in males. Overall these data suggest that AMPH action is dependent on the baseline level of activity and indicate a strong role of gender in the effects of this drug measured early on during development, with females showing greater sensitivity to this drug. A better understanding of AMPH action during the early ontogenetic phases, particularly its interaction with environmental factors, might extend our knowledge on the neurobiological basis of AD/HD, possibly improving the clinical efficacy of psychostimulant drugs.
MeSH Terms
- Aging
- Animals
- Attention Deficit Disorder with Hyperactivity
- Central Nervous System Stimulants
- Dextroamphetamine
- Environment
- Female
- Male
- Mice
- Risk Factors
- Sex Characteristics
Aging is associated with a disturbance in the regulation of the hypothalamic-pituitary-adrenal axis (HPA) and reduced levels of glucocorticoid receptors (GR) in the hippocampus. To compensate for these effects, we have investigated whether estrogen therapy normalized the HPA response to stress and GR in hippocampus and paraventricular (PVN) nucleus. Young (3-4 months) and old (20 months) male Sprague-Dawley rats were bled by tail cut in the basal state and following ether stress. While basal and ether-stimulated levels of plasma corticosterone (CORT) were similar in the two groups, old animals presented a delayed termination of the response to ether stress. A dexamethasone inhibition test carried out in old animals, showed a failure to completely block plasma CORT after ether stimulation. Furthermore, in old rats GR-immunoreactive levels were reduced in CA1-CA2 hippocampal subfields and subiculum, while normal levels were obtained in CA3-CA4 and PVN. We observed that prolonged estrogen treatment (6 weeks) of old rats normalized the termination of the stress response, restored dexamethasone inhibition of plasma CORT, and increased GR immunoreactivity in CA1 and CA2 hippocampal subfields and subiculum. The results suggest that estrogen treatment enhanced the glucocorticoid feedback signal by increasing GR in hippocampus, and corrected the disturbances in HPA axis regulation. These animal experiments may be important to elucidate the effects of estrogenic on the hippocampal and HPA dysfunction associated with aging and Alzheimer's disease in humans.
MeSH Terms
- Adrenal Glands
- Aging
- Animals
- Corticosterone
- Estradiol
- Ether
- Hippocampus
- Hypothalamus
- Kinetics
- Male
- Organ Size
- Pituitary Gland
- Rats
- Rats, Sprague-Dawley
- Receptors, Glucocorticoid
- Stress, Physiological
Repeated isolation of neonatal rats produces persistent changes in physiology and behavior. In Experiment 1, we examined changes in plasma corticosterone (CORT) levels as a possible mechanism for the effects of isolation. Pups that were isolated from their mother and the nest for 1 h per day on postnatal days (PND) 2-9 were compared to control litters of pups that were either nonhandled or handled but not isolated. On PND 2, compared to nonhandled pups, handled pups had elevated CORT levels that returned to baseline levels within 30 to 60 min of return to the home cage. No significant elevation of CORT levels were found in handled pups on PND 9. The CORT levels of isolated pups were over twice those of nonhandled pups on PND 2 and four times those of nonhandled pups on PND 9. In Experiment 2, we investigated whether the increased CORT release in response to isolation on PND 9 was the result of the pups' treatment on the previous six days as against an effect of maturation. Plasma CORT levels were measured in rat pups that were either isolated, handled or nonhandled on PNDs 2-8 during the conditions of isolation, handling and nonhandling on PND 9. There were no differences among the groups in basal plasma levels of CORT. Handling on PND 9 did not result in elevated CORT levels in any of the groups. All three groups showed a significant increase in plasma CORT levels after isolation on PND 9. However, the CORT response to isolation of pups previously isolated on PND 2-8 were significantly higher than pups that were either handled or nonhandled on PNDs 2-8. Thus, daily episodes of isolation potentiate the hypothalamic-pituitary-adrenal response to stress.
MeSH Terms
- Aging
- Analysis of Variance
- Animals
- Animals, Newborn
- Corticosterone
- Female
- Handling, Psychological
- Rats
- Rats, Sprague-Dawley
- Social Isolation
- Time Factors
Individual differences arise from both genetic and epigenetic factors. The aim of this study was to test whether pups raised in distinct socio-sexual conditions would show different behavioural and neuroendocrine responses to d-amphetamine (AMPH) administration upon placement in a novel environment. This issue was addressed by testing infant CD-1 mouse pups of both sexes at three different developmental ages [3, 8, or 18 postnatal (PND) days]. These pups were raised from birth in all-male, all-female, or mixed-sex litters. AMPH effects were assessed as a function of the hypothalamic-pituitary-adrenal (HPA) axis activational state using litters that were either maternally deprived for 24 h (DEP) or normally kept with the dam (NDEP). A concomitant maternal behaviour score carried out on selected postpartum days showed that mothers taking care of all-male litters were more often involved in Active nursing than those rearing the mixed-sex ones, whereas the latter were found more often Laying still out of the nest. Basal and stress-induced corticosterone (CORT) secretion was increased in unisexually reared pups following maternal deprivation, an effect limited to PND 3. In general, neuroendocrine and behavioural responses to AMPH were found to be dissociated and were affected by sexual segregation only in conjunction with maternal deprivation. On PND 3, AMPH injection (1 or 3 mg/kg, i.p.) decreased CORT secretion in deprived unisexually reared subjects without affecting their behaviour. As a whole, behavioural changes due to unisexual rearing were limited to female subjects. On PND 8, unisexually reared females showed, upon maternal deprivation, a generalized shift to the left in the dose-response curve to AMPH for Crossing behaviour, while on PND 18 AMPH-induced stereotypies were considerably reduced in sexually segregated females, especially following maternal deprivation. Thus, maternal deprivation appeared to "sensitize" the monoaminergic system to an AMPH challenge. The individual behavioural and neuroendocrine profiles shown in response to a stressful challenge suggest that changes in social stimulation early during development might produce subtle shifts in the function of selected central monoaminergic systems.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- Body Weight
- Central Nervous System Stimulants
- Corticosterone
- Dextroamphetamine
- Dose-Response Relationship, Drug
- Female
- Individuality
- Male
- Maternal Behavior
- Mice
- Neurosecretory Systems
- Sex Characteristics
Mild hypercortisolemia is a frequent concomitant of Alzheimer's disease (AD). In an effort to ascertain the relationship between serum cortisol concentration (CORT) and disease progression, aging, and survival, we followed 9 persons with AD, ages from 56 to 84 years, from an original cohort of 19 enrollees with serial cognitive testing and CORT determinations. The cognitive instrument was a modification of the Alzheimer's Disease Assessment Scale-Cognitive (mADAS-COG). Serum cortisol determinations were performed at noon, and an Afternoon Cortisol Test (ACT) was used to obtain an estimate of average CORT. Baseline 12:00 hours CORT but not ACT correlated significantly with the change in mADAS-COG (r = .90, p < .01). ACT levels increased as the mADAS-COG increased over time (p = .037), by 0.156 /- 0.06 microgram/dL for each one-point increase (indicating greater impairment) in cognitive test score. ACT levels did not increase significantly simply with aging. For the entire cohort of 19 subjects, neither baseline ACT nor 12:00 hours CORT was significantly related to survival. Hypercortisolemia in AD appears related to the clinical progression of the disease, but not to aging or length of survival.
MeSH Terms
- Aged
- Aging
- Alzheimer Disease
- Disease Progression
- Female
- Humans
- Hydrocortisone
- Male
- Middle Aged
- Neurobehavioral Manifestations
- Psychiatric Status Rating Scales
- Survival
Sustained high levels of corticosterone (CORT), one of the major stress-induced hormones in the rat, were suggested as generating 'accelerated brain aging' and were shown to induce both specific brain changes in the hippocampus and learning impairments in young and middle-aged Fischer-344 rats. Evidence that altered calcium (Ca) homeostasis may play a major role in brain aging has accumulated over the last decade. Recently, new data established a connection between glucocorticoids and voltage-activated Ca influx in aged hippocampal neurons. In the present study, an attempt was made to block the CORT-induced 'accelerated aging' by the simultaneous administration of the L-type Ca channel blocker nimodipine. CORT or placebo sustained-release (SR) pellets were implanted subcutaneously in 3 months old Fischer male rats. Each group was further sub-divided between nimodipine and placebo SR treatments. Characteristic CORT-induced morphological changes were observed in pyramidal hippocampal cells, such as at the CA1 and CA4 sub-regions (22.2% /- 7.7 and 28.6% /- 8.4 of pyknotic cells without clear nuclei, respectively). Concomitant treatment with nimodipine conferred full protection against CORT-induced morphological changes (e.g. 3.2% /- 0.8 and 2.1% /- 1.9 of pyknotic cells in CA1 and CA4, n = 7 rats in each group; P < 0.04). The neuroprotective efficacy of nimodipine supports the theory of Ca involvement in CORT related 'accelerated brain aging'.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Body Weight
- Calcium Channel Blockers
- Corticosterone
- Hippocampus
- Male
- Neuroprotective Agents
- Nimodipine
- Rats
- Rats, Inbred F344
Corticotropin-releasing hormone (CRH), originally isolated from the hypothalamus, is widely distributed in many extrahypothalamic central nervous system sites, and in the periphery. Immunoreactive (ir)-CRH has been identified in rat and human inflammatory sites, in rat testicular Leydig cells, and in rat thecal and stromal ovarian cells. In the current study, we investigated whether aging and stress are associated with changes in ovarian ir-CRH in the rat. Healthy young (3-4 mo) and old (24 mo) female Fischer 344/N rats (6 per group) were studied in the morning, before and after being stressed by 120 min of immobilization, and were sacrificed by decapitation. Young females were all in proestrous, and old females were in constant anestrous. Pre-immobilization corticosterone (CORT) levels were similar in both age groups; immobilization produced a dramatic increase in CORT in both groups; however, the increase was smaller in the old rats, although this did not reach statistical significance (P < 0.06). Immunoreactive CRH was detected in the ovaries of all rats, and its distribution and intensity were quantified masked to the age and treatment group, in the theca, granulosa, stroma, and corpus luteum. At baseline, ir-CRH was 50% lower in old than in young rats in the theca and stroma by both distribution and intensity. Stress was associated with a decrease of ir-CRH levels in the theca in both age groups, albeit to a significantly lesser extent in old rats (old 35% versus young 70%). These data suggest a functional and, perhaps, developmental role for ovarian CRH.
MeSH Terms
- Acute Disease
- Aging
- Animals
- Corpus Luteum
- Corticosterone
- Corticotropin-Releasing Hormone
- Female
- Granulosa Cells
- Immobilization
- Immunohistochemistry
- Ovary
- Rats
- Rats, Inbred F344
- Stress, Physiological
- Stromal Cells
- Theca Cells
- Tissue Distribution
The purpose of the present study was to investigate the effects of elevated corticosterone (CORT) on circulating lipoprotein cholesterol during a 1-wk period. For this study, 15 commercial broilers were randomly assigned to one of three treatment groups. Group 1 served as the control (CON) and received no treatment, whereas Groups 2 and 3 received subcutaneous mini-osmotic pumps containing either physiological saline (PS) or adrenocorticotropin (ACTH), respectively. The ACTH was delivered at a rate of 8 IU/kg of BW/d. Blood samples were taken at Time 0 (before implants) and on Days 2, 4, and 7 postimplantation. Continuous infusion of ACTH increased plasma glucose, cholesterol, triglycerides, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and CORT during the postimplantation period. The group treated with ACTH also exhibited a decrease in BW during the last 2 sampling d. There were no differences in any of the serum constituents measured between CON and PS birds, which suggest that CON birds can serve as useful controls. These data suggest that birds given a continuous infusion of ACTH at 8 IU/kg of BW/d can experience changes in plasma lipoprotein cholesterol concentrations along with changes in other blood parameters and may serve as a useful model in accelerated lipoprotein production.
MeSH Terms
- Adrenocorticotropic Hormone
- Aging
- Animals
- Chickens
- Cholesterol
- Cholesterol, HDL
- Cholesterol, LDL
- Cholesterol, VLDL
- Corticosterone
- Infusion Pumps, Implantable
- Male
- Triglycerides
To elucidate some of the mechanisms underlying the neuroendocrine and neurochemical changes associated with age in female rats, we administered the serotonin (5-HT) releaser and reuptake inhibitor, d-fenfluramine (d-FEN; 0.0 or 0.6 mg/kg/day, PO) for 30-38 days to young (4 month) and old (21 month) F-344 female rats. Animals were placed into a novel open field (OF) for 20 min before sacrifice. Control animals were sacrificed immediately upon removal from their home cage (HC). Old rats exhibited significantly (p < 0.05) less exploratory behavior and a smaller CORT response to OF than young animals. d-FEN treatment had no effect on plasma ACTH and CORT levels or exploratory behavior. The old HC rats had significantly (p < 0.05) higher plasma levels of prolactin (PRL) than the young HC rats. A stress induced increase in PRL secretion was observed in the old rats only, which was attenuated by d-FEN treatment. In the OF groups, both the young and old rats showed elevated medial frontal cortex (MFC) dopamine turnover (DOPAC/DA ratio), but only the young rats exhibited an elevation in norepinephrine (NE) turnover (MHPG/NE ratio). d-FEN treatment blocked the stress-induced increase in NE turnover in the young rats and the increase in DA turnover in the old rats. These data suggest that 5-HT activity could be involved in the age-related changes in the MFC catecholamine and PRL responses to stress in female rats.
MeSH Terms
- Adrenocorticotropic Hormone
- Age Factors
- Aging
- Animals
- Behavior, Animal
- Corticosterone
- Female
- Fenfluramine
- Prolactin
- Rats
- Rats, Inbred F344
- Stress, Psychological
The present study investigates the protective effect of a chronic blockade of the glucocorticoid receptor (type II) by a single weekly SC injection (20 mg/kg) of RU486 (a potent antiglucocorticoid) from mid-age (12 months old) until senescence (20 to 22 months old) on perturbations of some electrophysiological parameters classically observed in CA1 hippocampal slices of aged BALB/c mice. In this CA1 hippocampal area, no electrophysiological difference was observed at a stimulation frequency of 0.3 Hz. However, an important age-related effect was observed in not-treated animals concerning the three phases of the synaptic response during and after 4 Hz repetitive stimulation ith impairment of the frequency potentiation (FP). Interestingly, this electrophysiological disturbance disappeared completely in aged animals treated previously with RU486. Furthermore, a 10 microM CORT bath application had no effect in CA1 of aged animals, while it produced the classical type II-mediated population spike (PS) decrease in adult animals. This PS amplitude decrease was maintained in aged animals previously treated with RU486. These electrophysiological findings suggest an important type II-mediated glucocorticoid action on age-related alterations of hippocampal function.
MeSH Terms
- Age Factors
- Aging
- Animals
- Hippocampus
- Male
- Membrane Potentials
- Mice
- Mice, Inbred BALB C
- Mifepristone
- Time Factors
Glucocorticoid-induced cell loss in the dentate gyrus of rats of various ages was studied using the TUNEL procedure to detect apoptotic cells. A highly significant increase in the incidence of apoptosis was observed within the dentate hilus and granule cell layer within 24 h of a single injection of dexamethasone (DEX) in rats aged between 1 and 36 months; DEX-induced apoptosis was more pronounced with increasing age. Corticosterone (CORT) did not cause an increase in the rate of apoptosis above that found in age-matched controls. However, CORT pretreatment (3 h) resulted in a significantly attenuated DEX-induced apoptosis in both areas of the dentate gyrus. Serum CORT levels in saline-treated rats peaked at 6 months of age and reached a nadir at 36 months of age. The results indicate that (i) aged subjects are more susceptible to DEX in terms of dentate gyrus cell loss by apoptosis, (ii) CORT, which binds to Type I corticosteroid receptors with a high affinity, might serve to protect against the damaging effects of DEX which is a ligand of the Type II glucocorticoid receptor, and (iii) declining endogenous levels of CORT may increase the vulnerability of the dentate gyrus of aged rats to insult by DEX.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Corticosterone
- Dentate Gyrus
- Dexamethasone
- Male
- Rats
- Rats, Wistar
Cumulative exposure to corticosterone (CORT) during the lifespan plays an important role in the hippocampal aging process, and similar disturbances have been observed in chronic stress. However, there is little information on the electrophysiological changes observed in these two situations at the hippocampal level. The present study investigates the electrophysiological changes observed in control conditions and after a 10 microM CORT bath application on hippocampal slices taken from control adult BALB/c mice, from adult animals subjected to chronic overexposure to corticosterone (20 mg/kg/day during 3 months) and from aged animals. No electrophysiological difference was observed in the CA1 area of chronically CORT treated and aged groups compared to the control group. Conversely, the input/output curves from the dentate area showed a similar, statistically significant right shift in these two groups compared to the control group. Furthermore, in control subjects, a 10 microM CORT bath application produced the classical population spike amplitude decrease. However, in slices taken from chronically CORT-treated and aged mice, this effect did not occur in the CA1 while it was replaced by a population spike amplitude increase in the dentate. This increase was blocked by spironolactone. These electrophysiological alterations may indicate that a part of the aged-induced functional disturbances is mediated by glucocorticoids, and may progressively lead to impairment of neuroendocrine functions and behavioral adaptation.
MeSH Terms
- Aging
- Animals
- Corticosterone
- Electrophysiology
- Hippocampus
- In Vitro Techniques
- Male
- Mice
- Mice, Inbred BALB C
- Spironolactone
Twenty-four hours of maternal separation results in increased secretion of ACTH and corticosterone (CORT), suggesting the hypothalamic-pituitary-adrenal (HPA) axis is regulated by some aspect of maternal behavior. Previous results indicate that feeding plays a role in maintaining low levels of CORT in 12-day-old pups. In Experiment 1 basal and stress levels of CORT and ACTH were measured in maternally-deprived pups either provided or not with milk to determine whether: (1) feeding maintains ACTH secretion at low levels, and/or (2) feeding maintains the adrenal insensitive to ACTH. The results showed that, although ACTH levels were markedly low (compared to previous values reported by this laboratory) for both groups, only non-fed pups showed a robust increase in basal and stress CORT levels. During the deprivation period in Experiment 1, all pups were manually stroked to induce urination and defecation, suggesting an effect of stroking on ACTH secretion. Experiment 2 examined this hypothesis. Stroking suppressed stress-induced elevations of ACTH secretion due to maternal deprivation. CORT levels, however, were elevated in all deprived pups. The results indicate that maternal regulation of the infant's HPA axis occurs at multiple levels. Feeding appears to regulate adrenal sensitivity, whereas anogenital stroking inhibits the activation of centrally-controlled components of the axis.
MeSH Terms
- Adrenocorticotropic Hormone
- Aging
- Animals
- Corticosterone
- Feeding Behavior
- Female
- Hypothalamo-Hypophyseal System
- Male
- Maternal Behavior
- Maternal Deprivation
- Pituitary-Adrenal System
- Rats
- Rats, Sprague-Dawley
To understand some of the mechanisms underlying the neuroendocrine and neurochemical changes associated with aging, we administered the serotonin [5-hydroxytryptamine (5-HT)] releaser and reuptake inhibitor d-fenfluramine (d-FEN; 0.0, 0.2, or 0.6 mg/kg/day, p.o) for 30-38 days to young (4 months) and old (22 months) F344 male rats. Rats were stressed by placement into a novel open field (OF) for 20 min before sacrifice. Control animals were sacrificed immediately upon removal from their home cage (HC). Old rats exhibited less (p < 0.05) exploratory behavior than young rats, which was not altered by treatment with d-FEN. Old HC rats also had higher (p < 0.05) basal plasma levels of adrenocorticotropic hormone (ACTH) and prolactin (PRL) than young HC rats. Old OF rats showed higher (p < 0.05) levels of ACTH and corticosterone (CORT) than young OF animals. A stress-induced increase in PRL secretion was not observed in old rats. Subchronic low-dose d-FEN normalized the enhanced ACTH and CORT responses of old animals to novelty. In addition to these endocrine changes, stress-induced increases in medial frontal cortex (MFC) dopamine (DA) and norepinephrine (NE) turnover also were observed. The increase in NE turnover was greater (p < 0.01) in old than in young rats. d-FEN treatment blocked the stress-induced increase in MFC NE but not MFC DA turnover in both young and old rats. These data support a role for 5-HT and/or NE in some age-related neuroendocrine perturbations and suggest that increased 5-HT neurotransmission can normalize the hyperactivation of the hypothalamo-pituitary-adrenal axis of old male rats.
MeSH Terms
- Adrenocorticotropic Hormone
- Aging
- Animals
- Body Weight
- Brain Chemistry
- Catecholamines
- Corticosterone
- Exploratory Behavior
- Fenfluramine
- Male
- Neurosecretory Systems
- Prolactin
- Rats
- Rats, Inbred F344
- Serotonin
- Stress, Psychological
A variety of stressors activate the hypothalamic-pituitary-adrenal axis, with secretion and compensatory enhanced synthesis of hypothalamic corticotropin-releasing hormone (CRH). Whether CRH is a major effector in the stress response of the neonatal rat and whether the peptide's gene expression is subsequently up-regulated are not fully understood. We studied the effect of cold-separation stress on plasma corticosterone (CORT) levels and CRH messenger RNA (CRH-mRNA) abundance in the paraventricular nucleus. Rats (4-16 days old) were subjected to maximal tolerated cold-separation. CORT and CRH-mRNA abundance were measured before and at several time points after stress. Cold-separation stress resulted in a significant plasma CORT increase in all age groups studied. This was abolished by the administration of an antiserum to CRH on both postnatal days 6 and 9. CRH-mRNA increased in rats aged 9 days or older, but not in 6-day-old rats, by 4 h after stress. These results suggest the presence of robust CRH-mediated adrenal responses to cold-separation stress in neonatal rats. Before postnatal day 9, however, the compensatory increase in CRH-mRNA abundance is minimal.
MeSH Terms
- Adaptation, Physiological
- Aging
- Animals
- Animals, Newborn
- Cold Temperature
- Corticosterone
- Corticotropin-Releasing Hormone
- Gene Expression Regulation
- Paraventricular Hypothalamic Nucleus
- RNA, Messenger
- Rats
- Rats, Sprague-Dawley
- Stress, Physiological
- Time Factors
This study was designed to examine adrenocortical function in old (30 months) and young (6 months) male Brown Norway rats. The following observations were made. First, stress induced a higher pituitary adrenocorticotropic hormone (ACTH) response in the aged male Brown Norway rats than in young rats, while peak circulating corticosterone (CORT) levels were not different. Moreover, this type of "repeated" stress involving subcutaneous injection and blood sampling at various time points by pinching the tail vein, evoked a prolonged ACTH and CORT response in the aged animal. Second, exogenous ACTH1-24 administered to dexamethasone-pretreated Brown Norway rats, used as an in vivo challenge test for adrenocortical function, resulted in a delayed CORT response in the aged rats. The termination of the CORT response to ACTH, however, was not different between young and old rats. Third, ACTH1-24 stimulation of adrenocortical cells in vitro showed a tendency to a reduced CORT output, when these cells were obtained from old animals. Fourth, adrenalectomy (ADX) differentially affected pituitary ACTH release at both ages. The initial post-ADX ACTH surge was more pronounced in the aged animals. Beyond 4 days post-ADX the old Brown Norway rats did not show the pronounced afternoon peak in circulating ACTH as was observed in the young animals. This study demonstrates that during the aging process a deficiency in adrenocortical function develops in the male Brown Norway rat. This deficiency involves a less efficient stress-induced activation of adrenocortical output of CORT having enhanced pituitary ACTH release as one of the consequences.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH Terms
- Adrenal Cortex
- Adrenalectomy
- Adrenocorticotropic Hormone
- Aging
- Animals
- Body Weight
- Circadian Rhythm
- Corticosterone
- Cosyntropin
- Culture Techniques
- Dexamethasone
- Feedback
- Male
- Organ Size
- Peptide Fragments
- Pilot Projects
- Pituitary Gland
- Rats
- Sensitivity and Specificity
- Stress, Physiological
We tested the hypothesis that in preweanling rats central administration of exogenous corticosterone (CORT) is sufficient to facilitate the development of behavioral inhibition. 28-gauge cannulae containing varying concentrations of CORT (0, 25, 50 and 100%) were implanted unilaterally into the lateral ventricles of 9-day-old rat pups. After a 24-h postoperative recovery period, pups were adrenalectomized. At 14 days of age, pups were tested for behavioral inhibition which consisted of removing the pup from the nest and exposing it to an unfamiliar adult male rat. Pups implanted with cannulae containing 0, 25 and 50% concentrations of CORT spent significantly less time in freezing postures than pups implanted with cannulae containing 100% CORT. These freezing pups also tended to emit fewer ultrasonic vocalizations than pups in the other three implant conditions, albeit the level obtained was not statistically significant. RIAs indicated that, in general, hormone-filled cannulae produced no detectable concentrations of plasma CORT on the day of the test or on days preceding testing. Results suggest that in the early postnatal period endogenous CORT acts centrally to facilitate the development of neural pathways involved in the ontogenetic expression of behavioral inhibition.
MeSH Terms
- Adrenalectomy
- Aging
- Animals
- Behavior, Animal
- Body Temperature
- Corticosterone
- Female
- Injections, Intraventricular
- Male
- Rats
- Rats, Sprague-Dawley
- Ultrasonics
- Vocalization, Animal
We used two methods to examine altered patterns of gene expression in rat hippocampus in response to administered glucocorticoids: analysis of RNA in vitro translation products on 2-d gels and cloning of cDNAs from a rat hippocampal library by differential hybridization ( /- CORT). We determined that two of the CORT-responsive cDNA clones encoded the 35- and 50-kd RNA translation products and identified them as GPDH and GFAP, respectively, by sequence analysis. Cloned mRNAs that increased and decreased in response to CORT were determined to be under positive and negative regulation by glucocorticoids in intact rats. Despite their similarities in glucocorticoid response characteristics, we found three subsets of hippocampal mRNA responses to CORT and shaking stress which differ in temporal and level-dependent aspects of CORT regulation. In addition, GPDH gene expression represents a glucocorticoid-dependent stress response which is rapidly increased in a dose- and stressor-dependent manner. It is a candidate for a sensitive indicator of stress responsiveness in the brain as a function of neuroendocrine activity. Mechanisms of adaptation to stress in the brain are likely to involve responses that are both mediated by glucocorticoids and opposed by them. GFAP and TGF-beta 1 mRNA responses may be examples of the latter, since they are decreased in response to glucocorticoids, are under negative regulation by glucocorticoids in intact rats, and are increased in response to brain injury and disease and during aging. If these astrocytic and microglial responses are involved in cellular defense mechanisms in the brain, then their regulation by glucocorticoids would be important in maintaining and restoring cellular homeostasis in physiological and pathophysiological states. Future studies using these sensitive probes for glucocorticoid-regulated gene expression may identify new mechanisms by which the brain coordinates acute and chronic responses to stress and disease.
MeSH Terms
- Adrenal Cortex Hormones
- Adrenalectomy
- Aging
- Animals
- Cloning, Molecular
- Corticosterone
- Gene Expression
- Glial Fibrillary Acidic Protein
- Hippocampus
- Humans
- In Situ Hybridization
- Nerve Degeneration
- Protein Biosynthesis
- RNA, Messenger
- Rats
- Stress, Physiological
- Transforming Growth Factor beta
Recent investigations revealed that adrenalectomized (ADX) rat pups exhibit deficits in behavioral inhibition. Furthermore, administration of exogenous corticosterone (CORT) restores behavioral inhibition in ADX pups. Although these studies suggest that CORT has an important role in the development of behavioral inhibition, the relative behavioral effects of elevated pituitary hormone secretion induced by ADX are not known. Therefore, experiments were conducted to assess the potential behavioral effects of elevated adrenocorticotropin (ACTH) secretion induced by ADX and to further evaluate the contribution of endogenous CORT to the development of behavioral inhibition. In Experiment 1., we verified that 10-day-old ADX rats exhibit high levels of plasma ACTH throughout the preweaning period associated with the development of behavioral inhibition. In Experiment 2, 10-day-old pups were hypophysectomized (HYPOX) and ADX and were compared behaviorally to sham-operated controls on day 14. When tested in the presence of an anesthetized unfamiliar adult male rat, HYPOX ADX pups exhibited low levels of freezing accompanied by ultrasonic vocalizations. These pups also had reduced concentrations of plasma ACTH and CORT. In Experiment 3, 10-day-old pups were HYPOX and tested for behavioral inhibition on day 14. In comparison to sham-operated controls, HYPOX rats exhibited significantly lower levels of freezing and had reduced plasma concentrations of ACTH and CORT. Results demonstrate clearly that deficits in freezing occur even in the presence of low plasma ACTH concentrations. Therefore, elevated secretion of pituitary hormones is not a major factor that contributes to the ADX-induced deficits in behavioral inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH Terms
- Adrenal Cortex Hormones
- Adrenalectomy
- Adrenocorticotropic Hormone
- Aging
- Animals
- Behavior, Animal
- Female
- Hypophysectomy
- Pituitary Hormones
- Pituitary-Adrenal System
- Rats
- Rats, Sprague-Dawley
- Vocalization, Animal
Broiler chicks were given a standard commercial starter diet from day 0 (day of hatch) to 9 days of age. Body weight and concentrations of the following serum constituents were measured daily: glucose (GLU), triglycerides (TRI), corticosterone (CORT), cholesterol (CHOL), and high (HDL) and low (LDL) density lipoproteins. Serum GLU and TRI increased at each sampling day to reach a peak on days 3 and 4, respectively, and then decreased thereafter. However, CHOL, HDL, and LDL decreased sharply by day 1 and then gradually decreased to day 5. Conversely, CORT peaked on day 1 and then decreased to day 4. It peaked again on day 5 and remained at that level throughout the remainder of the experiment. In summary, serum concentrations of all constituents measured fluctuated drastically between 1 and 5 days of age, with few changes occurring between days 6 and 9.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Blood Glucose
- Chickens
- Cholesterol
- Corticosterone
- Lipids
- Lipoproteins
- Lipoproteins, HDL
- Lipoproteins, LDL
- Triglycerides
Chronic exposure to glucocorticoids affects both the structure and function of vertebrate skeletal muscles. As little is known about the effects of such steroids on the neuromuscular junctions (NMJs) of different muscle fiber types, the influence of chronic corticosterone (CORT) administration on the ultrastructure of NMJs of soleus (SOL) and extensor digitorum longus (EDL) was studied. Ten Fischer 344 male rats, the same animals used previously, were either injected daily with 5-10 mg CORT or received vehicle as control animals for 3 months and were sacrificed at 5 months of age. Muscles were bathed in situ in 4% phosphate buffered glutaraldehyde for ten minutes, then removed and conventional electron microscopic procedures were followed. Qualitative and quantitative observations of nerve terminal ultrastructures were statistically treated with multivariate analysis of variance to determine differences between control and CORT-treated animals. Fast-twitch EDL muscles were more affected by CORT-treatment than slow-twitch SOL muscles. Morphometric analysis of NMJ's in CORT-treated rats revealed significant decrease in fiber diameter, nerve terminal area and synaptic vesicle density, but a significant increase in synaptic cleft (P < 0.05). The NMJ's underwent partial denervation and reinnervation processes as demonstrated by large areas of presynaptic nerve terminal occupied by microtubules and electron dense granular material. Chronic CORT-treatments induced degenerative changes which were more pronounced in fast-twitch EDL muscles than slow-twitch SOL muscles, suggesting that pattern or amount of activity affect the CORT-treatment outcome. These steroid-induced stress changes are similar to those observed in aging and disuse studies of NMJ. Thus, glucocorticoid hormones may play an etiological role in the homeostasis of the NMJ in response to various stimuli.
MeSH Terms
- Aging
- Animals
- Corticosterone
- Injections, Subcutaneous
- Male
- Microscopy, Electron
- Muscle Fibers, Fast-Twitch
- Muscle Fibers, Slow-Twitch
- Neuromuscular Junction
- Rats
- Rats, Inbred F344
1. The effects of corticosterone (CORT) on diet selection of broiler chickens offered a choice of a high protein concentrate (381 g CP/kg, 17.5 MJ/kg ME) and whole wheat (113 g CP/kg, 15.9 MJ/kg ME) in relation to age were examined in two experiments. 2. Daily intramuscular injections of 2 and 4 mg/kg of CORT for a 5-d period in both 2- and 5-week-old chickens resulted in increases in total food, protein and energy intakes. This led to a decrease in protein accretion in older but not younger chicks, an increase in total lipid contents of the carcase at both ages, and produced changes in internal organs. 3. CORT significantly reduced body weight gain of young but not old chickens, suggesting that mature birds respond better than young ones to the physiological changes caused by treatment, by making subsequent appropriate food choices. 4. Administration of CORT in young chicks increased wheat intake at 2 and 4 h after injection, while in older birds a similar increase was maintained up to 24 h after injection. Intake of HP food was decreased by both doses of CORT in young chicks but there was no significant effect in older chickens. 5. Changes in energy: protein ratio in the chosen diet appeared at 4 h after treatment in old chickens and at 24 h in younger chicks. 6. The results suggest that birds are able to detect metabolic changes caused by CORT administration and attempt to redress them by modifying their food pattern. The time course of the response of birds to these changes is age related. However, the food selection pattern did not completely compensate for the physiological defects.
MeSH Terms
- Aging
- Analysis of Variance
- Animals
- Chickens
- Corticosterone
- Dietary Proteins
- Eating
- Energy Metabolism
- Female
- Food Preferences
- Triticum
- Weight Gain
The development of the cytoplasmic progestin receptor (CPR) system in male and female guinea pigs was examined to determine if insensitivity to the lordosis promoting activity of estrogen-progestin treatment in adult males and neonatal guinea pigs is correlated with alterations in this receptor system. Gonadectomized neonatal (4-6 days old) and adult (50-65 days old) guinea pigs of both sexes were injected with estradiol benzoate (EB) and killed 40 h later. CPRs were measured in the hypothalamus (HYPO), preoptic area (POA) and cortex ( CORT ). Neonatal brain contained both high (Kd congruent to 0.1 nM) and low (Kd greater than 10 nM) affinity binders for [3H]R5020 similar to those found in adult brain. In the absence of EB-priming the concentration of CPR in HYPO, POA and CORT was lower in neonatal animals than adults. In both males and females, neither a low (1.6 micrograms) nor a high (10 micrograms) dose of EB resulted in a concentration of estrogen inducible CPR in neonatal HYPO greater than that found in adult HYPO after 1.6 micrograms EB. Even after treatment with 50 micrograms EB the concentration of CPR in neonatal female HYPO was not different from adult female HYPO after 1.6 micrograms EB. In neonatal POA, 10 micrograms EB resulted in a concentration of CPR greater than that found in adult POA after 1.6 micrograms EB. Finally, there was a sex difference in the concentration of estrogen inducible CPR in HYPO (female greater than male) but not POA of adult guinea pigs. No sex difference in CPR concentration was found in any neonatal brain area.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Brain
- Castration
- Cytoplasm
- Estradiol
- Female
- Guinea Pigs
- Male
- Receptors, Progesterone
- Receptors, Steroid
- Sex Characteristics
Glucocorticoids, the adrenocortical hormones secreted during stress, can be cumulatively toxic to hippocampal neurons, and this steroid-induced neuron loss has a role in functional impairments of the senescent hippocampus. The glucocorticoids, through their varied catabolic actions, appear to non-specifically induce metabolic vulnerability in the hippocampal neurons. As such, a wide variety of unrelated toxic insults which damage the hippocampus have their toxicity exacerbated by glucocorticoid treatment and attenuated by adrenalectomy. The present report demonstrates such a synergy between corticosterone (CORT), the species-specific glucocorticoid of rats, and 3-acetylpyridine (3-AP), a neurotoxic antimetabolite which inhibits ATP synthesis. When microinfused into Ammon's horn, 3-AP destroys dentate gyrus neurons preferentially. Administration of CORT at a concentration producing titers equivalent to those seen after prolonged stress, prior to and following 3-AP infusion, caused a 5-fold increase in the volume of hippocampal damage induced by the toxin. Conversely, adrenalectomy prior to microinfusion reduced the toxin's potency by more than 60%. Both the history of elevated CORT (i.e. prior to the 3-AP infusion) and the elevated CORT titers in the aftermath of the infusion contributed to the exaggerated damage. Finally, as little as 24 h of elevated CORT prior to and following the microinfusion could significantly potentiate toxin-induced damage. These studies present further evidence for CORT compromising the capacity of hippocampal neurons to survive a variety of toxic insults. Furthermore, the time-course of this effect suggests the relatively rapid metabolic actions of CORT as critical to this endangerment.
MeSH Terms
- Adrenalectomy
- Aging
- Animals
- Corticosterone
- Drug Synergism
- Hippocampus
- Pyridines
- Rats
- Rats, Inbred Strains
The hippocampus of the rat loses neurons with age, a loss which may eventuate in some of the functional impairments typical of senescence. Cumulative exposure to corticosterone (CORT) over the lifespan may be a cause of this neuronal loss, as it is prevented by adrenalectomy at mid-age. In this study, we demonstrate that prolonged exposure to CORT accelerates the process of cell loss. Rats were injected daily with sufficient CORT to produce prolonged elevations of circulating titers within the high physiological range. Animals treated for 3 months (chronic subjects) resembled aged rats in a number of ways. First, both groups had extensive and persistent depletions of CORT receptors in the hippocampus; in the case of chronic rats, no recovery of receptor concentrations occurred 4 months after the end of steroid treatment. Second, autoradiographic analysis revealed that the receptor depletion was due, in part, to a loss of CORT-concentrating cells, especially in the CA3 cell field. Remaining cells bound significantly less [3H]corticosterone than did those of control rats. Finally, analysis of size distributions of hippocampal cell bodies indicated that chronic subjects lost neurons of the same size as those lost in the aged hippocampus. Furthermore, chronic subjects also had increased numbers of small, darkly staining cells of CA3; these corresponded in size to the dark glia whose numbers increase in the aged hippocampus, and which are thought to infiltrate in response to neuronal damage or destruction. Thus, this study supports the hypothesis that cumulative exposure to CORT over the lifespan may contribute to age-related loss of neurons in the hippocampus, and that prolonged stress or exposure to CORT accelerates this process.
MeSH Terms
- Aging
- Animals
- Glucocorticoids
- Hippocampus
- Male
- Neurons
- Rats
- Rats, Inbred Strains
Old (28 months) male Wistar rats were treated chronically for two weeks with ginsenoside Rg1 or with vehicle delivered via sc implanted Alzet mini-pumps (rate of ginsenoside release 2.4 micrograms/0.5 microliter/h). The number of Type 1 corticosterone-preferring receptor sites (CR) and Type 2 glucocorticoid receptors (GR) was measured in the cytosol of hippocampus tissue of rat brain with an in vitro binding assay. In old rats the Bmax of Type 1 CR and Type 2 GR was reduced by 51.5% and 28.3% respectively. Following the two week treatment with Rg1 the Bmax of Type 1 CR increased by 60% and a receptor concentration was reached which was 21% lower than that observed in the young control animals. Minor differences in affinity of steroid binding to both receptor systems were observed in the groups of rats. The possible binding of ginsenosides to brain corticosteroid receptors in vitro was investigated as well. The inclusion of a 500 fold molar excess of Rg1 in hippocampus cytosol did not displace 3H-corticosterone from its soluble receptor sites. The affinity of Rg1 with these sites in vitro is therefore negligible. In conclusion, the binding capacity of Type 1 CR and Type 2 GR is reduced in the hippocampal brain region of aged rats. Upon chronic infusion of ginsenoside Rg1, only Type 1 CR capacity is restored towards the level observed in young control animals. This finding suggests that in old rats the ginsenoside enhances the CORT signal via Type 1 CR on the function of the hippocampus, which is a limbic brain structure involved in cognition, mood and affect.
MeSH Terms
- Aging
- Animals
- Binding, Competitive
- Brain
- Corticosterone
- Ginsenosides
- Hippocampus
- Kinetics
- Male
- Rats
- Rats, Inbred Strains
- Receptors, Glucocorticoid
- Saponins
The ontogeny of the corticoid receptors in the rat hippocampus was examined by in vitro [3H]corticosterone (CORT) binding to soluble molecules in the cytosol, using the selective Type II glucocorticoid agonist, RU 28362, to discriminate between Type I and Type II receptor sites. Type I receptors were undetectable until 8 days after birth. From this age on, the receptor showed adult characteristics for both the binding capacity (Bmax) and affinity (Kd). The Type II receptor concentration increased gradually over the observed period; however, at 3 weeks of age concentrations were still only about 65% those found in adults. The binding affinity of Type II to CORT was high during the first week of life but decreased thereafter towards adult value. These data thus suggest clear distinctions in the developmental patterns of Type I and Type II receptors for corticosteroids in the rat.
MeSH Terms
- Aging
- Aldosterone
- Androstanols
- Animals
- Binding, Competitive
- Cytosol
- Dexamethasone
- Hippocampus
- Male
- Rats
- Rats, Inbred Strains
- Receptors, Glucocorticoid
Compared to younger rats, old rats exhibit prolonged elevations of plasma ACTH and corticosterone (CORT) in response to stress. In addition, CORT crosses the placenta. To investigate whether fetuses of older rats may be exposed to higher concentrations of CORT during development than fetuses of young rats, we compared the effects of stress on hypothalamic-pituitary-adrenal (HPA) axis function in young and aging pregnant rats and their 19-day-old fetuses. The plasma of the mothers and fetuses was assayed for ACTH and CORT by radioimmunoassay. Both young and aging pregnant rats showed a significant increase in plasma ACTH and CORT immediately after exposure to stress. However, aging rats had more prolonged elevations of ACTH and CORT than young rats. This suggests that, like old male rats, aging pregnant rats have an alteration in feedback inhibition of the HPA axis. Prolonged elevation of CORT was also seen in fetuses of aging mothers. These results have important implications concerning the effects of stress during pregnancy at different maternal ages, and for the potential deleterious consequences of prolonged prenatal elevation in stress hormones on the offspring of aging females.
MeSH Terms
- Adrenocorticotropic Hormone
- Aging
- Animals
- Corticosterone
- Electroshock
- Female
- Fetal Blood
- Kinetics
- Pregnancy
- Pregnancy, Animal
- Rats
- Rats, Inbred Strains
- Stress, Physiological
To explore the effects of repeated episodes of hypercortisolemia on hypothalamic-pituitary-adrenal axis regulation, we studied plasma ACTH and cortisol (CORT) responses to 100 micrograms human CRH (hCRH) in 10 dexamethasone (1.5 mg)-pretreated elderly endurance athletes who had abstained from physical activity for at least 48 h before testing and 13 sedentary age-matched controls. Basal CORT and ACTH levels were indistinguishable between runners and sedentary controls, whereas CORT responses to hCRH were significantly increased in endurance athletes, and ACTH responses tended to be higher in this group. Comparing the dexamethasone/hCRH test results of the runners with those of an age-matched sample of previously studied depressed patients (n = 9), similar hormone responses to CRH challenge were noted. The mechanisms underlying these alterations may either be a stepwise decrease in corticotropic sensitivity to the negative feedback signal leading to a switch to positive glucocorticoid feedback, an enhanced cosecretion of ACTH secretagogues such as vasopressin, or a combination of both. In conclusion, hypothalamic-pituitary-adrenal axis physiology seems to be determined by previous stressful events associated with hypercortisolemia, regardless of its etiology.
MeSH Terms
- Adrenocorticotropic Hormone
- Aged
- Aging
- Corticotropin-Releasing Hormone
- Dexamethasone
- Humans
- Hydrocortisone
- Hypothalamo-Hypophyseal System
- Male
- Middle Aged
- Physical Endurance
- Pituitary-Adrenal System
Mean arterial pressure (MAP), heart rate (HR), plasma epinephrine (E), plasma norepinephrine (NE), and plasma corticosterone (CORT) were measured in 3-month- and 24-month-old male Wistar rats exposed to a conditioned emotional stress response (CER) paradigm and a conditioned defensive burying (CDB) paradigm. In the CER situation blood samples were taken during reexposure to the training environment one day after a single inescapable footshock (0.6 mA, AC for 3 s) had been administered. In the CER paradigm the young rats displayed passive behavior (immobility) accompanied by an increase in plasma levels of CORT and E, whereas both the control and conditioned animals showed increased NE responses. Previously shocked aged rats exhibited an attenuated plasma NE response, whereas levels of E remained elevated to a greater extent. Aged animals showed elevated basal levels of CORT one day after footshock administration. Stress-induced immobility was preserved in the aged rats. These animals had an increase in basal MAP values and a decrease in basal HR values compared to young ones. In the CDB paradigm, rats were exposed to a nonelectrified probe 1 day after the repeated shock (2 mA/contact) procedure. Young rats displayed defensive burying accompanied by increments in MAP, HR, CORT, and NE. The aged animals showed similar hormonal, autonomic, and behavioral stress responses. Thus, the age-related alterations in neuroendocrine and autonomic response patterns are apparent in stressed animals during behavioral passivity in absence of control (CER) rather than during active control (defensive burying).
MeSH Terms
- Adaptation, Psychological
- Aging
- Animals
- Arousal
- Blood Pressure
- Conditioning, Classical
- Corticosterone
- Epinephrine
- Heart Rate
- Male
- Motor Activity
- Norepinephrine
- Rats
- Rats, Inbred Strains
- Stereotyped Behavior