CA3
Carbonic anhydrase 3 (EC 4.2.1.1) (Carbonate dehydratase III) (Carbonic anhydrase III) (CA-III)
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Brain aging is a widely studied process, but due to its complexity, much of its progress is unknown. There are many studies linking memory loss and reduced interneuronal communication with brain aging. However, only a few studies compare young and old animals. In the present study, in male rats aged 3, 6, and 18 months, we analyzed the locomotor activity and also short and long-term memory using the novel object recognition test (NORT), in addition to evaluating the dendritic length and the number of dendritic spines in the prefrontal cortex (PFC) and in the CA1, CA3 and DG regions of the dorsal hippocampus using Golgi-Cox staining. We also analyzed the types of dendritic spines in the aforementioned regions. 6- and 18-month old animals showed a reduction in locomotor activity, while long-term memory deficit was observed in 18-month old rats. At 18 months old, the dendritic length was reduced in all the studied regions. The dendritic spine number was also reduced in layer 5 of the PFC, and the CA1 and CA3 of the hippocampus. The dynamics of dendritic spines changed with age, with a reduction of the mushroom spines in all the studied regions, with an increase of the stubby spines in all the studied regions except from the CA3 region, that showed a reduction. Our data suggest that age causes changes in behavior, which may be the result of morphological changes at the dendrite level, both in their length and in the dynamics of their spines.
Keywords
- Aging
- Hippocampus
- Locomotor activity
- Memory and learning
- Prefrontal cortex
- Pyramidal neurons
- dendritic spines
Fat-mass and obesity-associated protein (Fto) is highly expressed in the brain including, the hippocampus, and its expression is significantly decreased in the brain of Alzheimer's disease patients. In the present study, we measured Fto immunoreactivity and protein levels in the hippocampus of obese and aged mice, which were induced by high-fat diet for 12 weeks and D-galactose treatment for 10 weeks, respectively. The obesity and aging phenotypes were assessed by physiological parameters and Morris water maze test, respectively. High fat diet fed mice showed significant increases in body weight and blood glucose levels compared to that in the control or D-galactose-induced aged mice. In addition, treatment with D-galactose significantly decreased the spatial memory. Fto immunoreactivity in the control group was mainly detected in the pyramidal cells of the CA1 and CA3 regions and in the granule cells of the dentate gyrus. In the hippocampus of high-fat diet-fed mice, Fto immunoreactive structures were similarly found in the hippocampus compared to that in the control group, but Fto immunoreactivity in high-fat diet-fed mice was also found in the stratum oriens and radiatum of the CA1 and CA3 regions and the polymorphic layer of the dentate gyrus. In the hippocampus of D-galactose-induced aged mice, fewer Fto immunoreactive structures were detected in the granule cell layer of the dentate gyrus compared to the control group. Fto mRNA and protein levels based on quantitative real-time polymerase chain reaction and western blot assays were slightly increased in the hippocampus of high-fat diet-fed mice compared to that in control mice. In addition, Fto mRNA and protein levels were significantly decreased in the aged hippocampus compared to that in the control group. Fto protein levels are susceptible to the aging process, but not in the hippocampus of high-fat diet-induced obesity. The reduction of Fto in aged mice may be associated with reduced memory impairment in mice.
Keywords
- Aging
- Fto
- Hippocampus
- Mice
- Obesity
Aging is the major risk factor of the most common (∼95% of cases) sporadic Alzheimer's disease (AD). Accumulating data indicate middle age as a critical period for the relevant pathological processes, however, the question of when AD starts to develop remains open. It has been reported only recently that in the early postnatal period-when brain development is completing-preconditions for a decrease in cognitive abilities and for accelerated aging can form. Here, we hypothesized that specific features of early postnatal brain development may be considered some of the prerequisites of AD development at an advanced age. To test this hypothesis, we used OXYS rats, which are a suitable model of sporadic AD. The duration of gestation, litter size, and weight at birth were lower in OXYS rats compared to control Wistar rats. The shortened duration of gestation may result in developmental retardation. Indeed, we noted decreased locomotor activity and increased anxiety in OXYS rats already at a young age: possible signs of altered brain development. We demonstrated retardation of the peak of postnatal neurogenesis in the hippocampal dentate gyrus of OXYS rats. Delayed neuronal maturation led to alterations of mossy-fiber formation: a shortened suprapyramidal bundle and longer infrapyramidal bundle, less pronounced fasciculation of granule cells' axons, and smaller size and irregular shape of nuclei in the CA3 pyramidal layer. These changes were accompanied by altered astrocytic migration. The observed features of early development may be considered some of the risk factors of the AD-like pathology that manifests itself in OXYS rats late in life.
Keywords
- Alzheimer’s disease
- OXYS rats
- aging
- hippocampal mossy fibers
- hippocampus
- neurogenesis
- postnatal development
The present study was designed to follow neuroinflammation after ischemic brain injury in the long-term survival rat model. Immunohistochemistry was performed 2 years after 10 min global brain ischemia due to cardiac arrest. For the visualization of the cellular inflammatory reaction microglial marker Iba1 and astrocyte marker GFAP were used. In post-ischemic animals our study revealed significant activation of astrocytes in all tested brain regions (hippocampal CA1 and CA3 areas and dentate gyrus, motor and somatosensory cortex, striatum and thalamus), while microglial activation was only found in CA1 and CA3 areas, and the motor cortex. In the specifically sensitive brain areas microglia and astrocytes showed simultaneously significant activation, while in the resistant brain areas only astrocytes were activated. Thus, there was clear evidence of less intensive neuroinflammation in brain areas resistant to ischemia. Such neuroinflammatory processes are backed by microglia and astrocytes activity even up to 2 years after ischemia-reperfusion brain injury. Our study thus revealed a chronic effect of global cerebral ischemia on the neuroinflammatory reaction in the rat brain even 2 years after the insult.
Keywords
- Alzheimer’s disease
- aging
- brain ischemia
- glia
- neuroinflammation
The disabling effects of dementia, an incurable disease with little effect on mortality, affect society far more than many other conditions. The aim of this study was to stop or delay the onset of dementia using low-cost methods such as physical exercise. Senescence-accelerated model-prone (SAMP) 10 mice were made to perform a user-friendly shaking exercise for 25 weeks. The motor function and hippocampal functions (learning, spatial cognition) of the mice were evaluated using behavioral experiments. The degree of hippocampal aging was evaluated based on brain morphology. The association between behavioral performance of the mice and the degree of hippocampal aging was then evaluated. The behavioral test results showed that the shaking group had higher motor coordination (p < 0.01) and motor learning (p < 0.05). Significantly higher performances in the learning ability were observed in the shaking group at a middle-period experiment (p < 0.05); the spatial cognitive functions also improved (p < 0.05). The shaking group showed delayed ageing of cells in the dentate gyrus (DG; area: p < 0.01) and cornu Ammonis (CA; area: p < 0.01) regions of the hippocampus. The shaking exercise enhances the activity of mice and reduces age-associated decreases in learning and spatial cognitive functions. Regarding hippocampal morphology, shaking exercise can prevent non-functional protein accumulation, cell atrophy, and cell loss. Specifically, shaking exercise protects cell growth and regeneration in the DG area and enhances the learning function of the hippocampus. Furthermore, shaking exercise maintained the spatial cognitive function of cells in the CA3 and CA1 regions, and prevented the chronic loss of CA2 transmission that decreased the spatial memory decline in mice.
Keywords
- Aging
- Behavior analysis
- Hippocampus
- Shaking exercise
- Spatial cognition
Pattern separation (PS) describes the process by which the brain discriminates similar stimuli from previously encoded stimuli. This fundamental process requires the intact processing by specific subfields in the hippocampus and can be examined using mnemonic discrimination tasks. Previous studies reported different patterns for younger and older individuals between mnemonic discrimination performance and hippocampal subfield activation. Here, we investigated the relationship between the lure discrimination index (LDI) and hippocampal subfield volume and activity across the adult lifespan (20-70 years old). Using ultra-high field functional and structural magnetic resonance imaging at 7 T, we found that lower DG volume and higher CA3 activation was associated with worse LDI performance in individuals (>60 years), suggesting that this higher activation may be an indication of aberrant neurodegenerative-related processes. In fact, higher activation in the CA1 and DG was associated with lower volumes in these subfields. For individuals around 40-50 years old, we observed that greater left and right DG volume, and greater activity in the CA3 was associated with lower LDI performance. Taken together, these results suggest that the relationship between memory and hippocampal subfield structure or function varies nonlinearly and possibly reciprocally with age, with midlife being a critically vulnerable period in life.
MeSH Terms
- Adult
- Age Factors
- Aged
- Brain Mapping
- Female
- Hippocampus
- Humans
- Longevity
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Young Adult
Mouse hippocampus retains the capacity for neurogenesis throughout lifetime, but such plasticity decreases with age. Adult hippocampal neurogenesis (AHN) involves the birth, maturation, and synaptic integration of newborn granule cells (GCs) into preexisting hippocampal circuitry. While functional integration onto adult-born GCs has been extensively studied, maturation of efferent projections onto CA3 pyramidal cells is less understood, particularly in aged brain. Here, using combined light and reconstructive electron microscopy (EM), we describe the maturation of mossy fiber bouton (MFB) connectivity with CA3 pyramidal cells in young adult and aged mouse brain. We found mature synaptic contacts of newborn GCs were formed in both young and aged brains. However, the dynamics of their spatiotemporal development and the cellular process by which these cells functionally integrated over time were different. In young brain newborn GCs either formed independent nascent MFB synaptic contacts or replaced preexisting MFBs, but these contacts were pruned over time to a mature state. In aged brain only replacement of preexisting MFBs was observed and new contacts were without evidence of pruning. These data illustrate that functional synaptic integration of AHN occurs in young adult and aged brain, but with distinct dynamics. They suggest elimination of preexisting connectivity is required for the integration of adult-born GCs in aged brain.
Keywords
- aging
- conditional transgenic
- giant synapse
- stratum lucidum
- synaptogenesis
The CA3 and CA1 principal cell fields of the hippocampus are vulnerable to aging, and age-related dysfunction in CA3 may be an early seed event closely linked to individual differences in memory decline. However, whether the differential vulnerability of CA3 and CA1 is associated with broader disruption in network-level functional interactions in relation to age-related memory impairment, and more specifically, whether CA3 dysconnectivity contributes to the effects of aging via CA1 network connectivity, has been difficult to test. Here, using resting-state fMRI in a group of aged rats uncontaminated by neurodegenerative disease, aged rats displayed widespread reductions in functional connectivity of CA3 and CA1 fields. Age-related memory deficits were predicted by connectivity between left CA3 and hippocampal circuitry along with connectivity between left CA1 and infralimbic prefrontal cortex. Notably, the effects of CA3 connectivity on memory performance were mediated by CA1 connectivity with prefrontal cortex. We additionally found that spatial learning and memory were associated with functional connectivity changes lateralized to the left CA3 and CA1 divisions. These results provide novel evidence that network-level dysfunction involving interactions of CA3 with CA1 is an early marker of poor cognitive outcome in aging.
Keywords
- aging
- functional connectivity
- hippocampus
- spatial memory
Metabotropic glutamate receptors (mGluRs) are a group of G-protein-coupled receptors that exert a broad array of modulatory actions at excitatory synapses of the central nervous system. In the hippocampus, the selective activation of the different mGluRs modulates the intrinsic excitability, the strength of synaptic transmission, and induces multiple forms of long-term plasticity. Despite the relevance of mGluRs in the normal function of the hippocampus, we know very little about the changes that mGluRs functionality undergoes during the non-pathological aging. Here, we review data concerning the physiological actions of mGluRs, with particular emphasis on hippocampal area CA3. Later, we examine changes in the expression and functionality of mGluRs during the aging process. We complement this review with original data showing an array of electrophysiological modifications observed in the synaptic transmission and intrinsic excitability of aged CA3 pyramidal cells in response to the pharmacological stimulation of the different mGluRs.
Keywords
- aging
- hippocampal area CA3
- mGluRs
- mossy fibers
- synaptic transmission
Aging is associated with functional alterations of synapses thought to contribute to age-dependent memory impairment (AMI). While therapeutic avenues to protect from AMI are largely elusive, supplementation of spermidine, a polyamine normally declining with age, has been shown to restore defective proteostasis and to protect from AMI in Drosophila. Here we demonstrate that dietary spermidine protects from age-related synaptic alterations at hippocampal mossy fiber (MF)-CA3 synapses and prevents the aging-induced loss of neuronal mitochondria. Dietary spermidine rescued age-dependent decreases in synaptic vesicle density and largely restored defective presynaptic MF-CA3 long-term potentiation (LTP) at MF-CA3 synapses (MF-CA3) in aged animals. In contrast, spermidine failed to protect CA3-CA1 hippocampal synapses characterized by postsynaptic LTP from age-related changes in function and morphology. Our data demonstrate that dietary spermidine attenuates age-associated deterioration of MF-CA3 synaptic transmission and plasticity. These findings provide a physiological and molecular basis for the future therapeutic usage of spermidine.
MeSH Terms
- Aging
- Animals
- CA3 Region, Hippocampal
- Long-Term Potentiation
- Mice
- Mossy Fibers, Hippocampal
- Spermidine
- Synaptic Transmission
- Synaptic Vesicles
Inflammation in the brain is mediated by the cyclooxygenase pathway, which leads to the production of prostaglandins. Prostaglandin (PG) D2, the most abundant PG in the brain, increases under pathological conditions and is spontaneously metabolized to PGJ2. PGJ2 is highly neurotoxic, with the potential to transition neuroinflammation into a chronic state and contribute to neurodegeneration as seen in many neurological diseases. Conversely, PACAP27 is a lipophilic peptide that raises intracellular cAMP and is an anti-inflammatory agent. The aim of our study was to investigate the therapeutic potential of PACAP27 to counter the behavioral and neurotoxic effects of PGJ2 observed in aged subjects. PGJ2 was injected bilaterally into the hippocampal CA1 region of 53-week-old and 12-week-old C57BL/6N male mice, once per week over 3 weeks (three total infusions) and included co-infusions of PACAP27 within respective treatment groups. Our behavioral assessments looked at spatial learning and memory performance on the 8-arm radial maze, followed by histological analyses of fixed hippocampal tissue using Fluoro-Jade C and fluorescent immunohistochemistry focused on IBA-1 microglia. Aged mice treated with PGJ2 exhibited spatial learning and long-term memory deficits, as well as neurodegeneration in CA3 pyramidal neurons. Aged mice that received co-infusions of PACAP27 exhibited remediated learning and memory performance and decreased neurodegeneration in CA3 pyramidal neurons. Moreover, microglial activation in the CA3 region was also reduced in aged mice cotreated with PACAP27. Our data show that PGJ2 can produce a retrograde spread of damage not observed in PGJ2-treated young mice, leading to age-dependent neurodegeneration of hippocampal neurons producing learning and memory deficits. PACAP27 can remediate the behavioral and neurodegenerative effects that PGJ2 produces in aged subjects. Targeting specific neurotoxic prostaglandins, such as PGJ2, offers great promise as a new therapeutic strategy downstream of cyclooxygenases, to combat the neuronal deficits induced by chronic inflammation.
Keywords
- CA1
- CA3
- Fluoro-Jade C
- aging
- microglia
- radial arm maze
GABA is the primary inhibitory neurotransmitter in the nervous system. GABA receptors (GABA Rs) are pentameric ionotropic channels. Subunit composition of the receptors is associated with the affinity of GABA binding and its downstream inhibitory actions. Fluctuations in subunit expression levels with increasing age have been demonstrated in animal and human studies. However, our knowledge regarding the age-related hippocampal GABA R expression changes is limited and based on rat studies. This study is the first analysis of the aging-related changes of the GABA R subunit expression in the CA1, CA2/3, and dentate gyrus regions of the mouse hippocampus. Using Western blotting and immunohistochemistry we found that the GABAergic system is robust, with no significant age-related differences in GABA R α1, α2, α3, α5, β3, and γ2 subunit expression level differences found between the young (6 months) and old (21 months) age groups in any of the hippocampal regions examined. However, we detected a localized decrease of α2 subunit expression around the soma, proximal dendrites, and in the axon initial segment of pyramidal cells in the CA1 and CA3 regions that is accompanied by a pronounced upregulation of the α2 subunit immunoreactivity in the neuropil of aged mice. In summary, GABA Rs are well preserved in the mouse hippocampus during normal aging although GABA Rs in the hippocampus are severely affected in age-related neurological disorders, including Alzheimer's disease.
MeSH Terms
- Aging
- Animals
- Axon Initial Segment
- Hippocampus
- Male
- Mice, Inbred C57BL
- Protein Subunits
- Pyramidal Cells
- Receptors, GABA-A
Keywords
- GABAA receptor
- ageing
- hippocampus
- mouse
A distinct feature of the hippocampus of the brain is its unidirectional tri-synaptic pathway originating from the entorhinal cortex and projecting to the dentate gyrus (DG) then to area CA3 and subsequently, area CA1 of the Ammon's horn. Each of these areas of the hippocampus has its own cellular structure and distinctive function. The principal neurons in these areas are granule cells in the DG and pyramidal cells in the Ammon's horn's CA1 and CA3 areas with a vast network of interneurons. This review discusses the fundamental differences between the CA1 and DG areas regarding cell morphology, synaptic plasticity, signaling molecules, ability for neurogenesis, vulnerability to various insults and pathologies, and response to pharmacological agents.
MeSH Terms
- Aging
- Amyloid beta-Peptides
- Animals
- CA1 Region, Hippocampal
- Calcium
- Dentate Gyrus
- Humans
- Neuronal Plasticity
Keywords
- Alzheimer’ disease
- Calbindin
- Chronic stress
- Functional plasticity
- Granule cell
- Hypothyroidism
- Ischemia
- OZR
- Obesity
- Pyramidal cell
- Signaling molecules
- Structural plasticity
Inflammation is a critical feature of aging and its related diseases, including cardiovascular diseases. Recent epidemiological studies demonstrated that abdominal aortic aneurysm (AAA), an aging-related vascular pathological condition, is associated with cognitive decline. However, the underlying mechanism, especially the role of vascular inflammation, is largely unknown because of lack of an available animal model. In this study, we examined whether vascular inflammation affects synaptic and cognitive dysfunction, using an AAA mouse model. In young (3 months) and middle-aged (12 months) C57BL/6J mice, AAA was induced by angiotensin II infusion with calcium chloride application. After 4 weeks of induction, aortic diameter was significantly increased and excessive Mac3-positive inflammatory cells infiltrated the destroyed aorta in middle-aged mice. AAA-induced middle-aged mice further exhibited cognitive impairment. Neuronal loss was observed in the CA3 region of the hippocampus. IBA1/MHCII-double-positive microglia activation was also seen in the hippocampus, suggesting that vascular inflammation drives neuroinflammation and subsequent cognitive dysfunction. Furthermore, we found that senescence-accelerated mice prone 8 exhibited robust AAA formation and a marked decrease of cognitive and synaptic function in the hippocampus mediated by inflammation. In conclusion, this novel murine model convincingly suggested the occurrence of vascular inflammation-derived cognitive dysfunction.
MeSH Terms
- Aging
- Angiotensin II
- Animals
- Antigens, Differentiation
- Aorta, Abdominal
- Aortic Aneurysm, Abdominal
- Calcium Chloride
- Calcium-Binding Proteins
- Cognitive Dysfunction
- Disease Models, Animal
- Genes, MHC Class II
- Hippocampus
- Inflammation
- Macrophage Activation
- Male
- Mice
- Mice, Inbred C57BL
- Microfilament Proteins
- Microglia
Intervertebral disc degeneration is an important contributor to chronic low back and neck pain. Although many environmental and genetic factors are known to contribute to disc degeneration, age is still the most significant risk factor. Recent studies have shown that senescence may play a role in age-related disc degeneration and matrix catabolism in humans and mouse models. Clearance of p16 -positive senescent cells reduces the degenerative phenotype in many age-associated diseases. Whether p16 plays a functional role in intervertebral disc degeneration and senescence is unknown. We first characterized the senescence status of discs in young and old mice. Quantitative histology, gene expression and a novel p16 reporter mice showed an increase in p16 , p21 and IL-6, with a decrease in Ki67 with aging. Accordingly, we studied the spinal-phenotype of 18-month-old mice with conditional deletion of p16 in the disc driven by Acan-CreERT2 (cKO). The analyses of discs of cKO and age-matched control mice showed little change in cell morphology and tissue architecture. The cKO mice exhibited changes in functional attributes of aggrecan as well as in collagen composition of the intervertebral disc. While cKO discs exhibited a small decrease in TUNEL positive cells, lineage tracing experiments using ZsGreen reporter indicated that the overall changes in cell fate or numbers were minimal. The cKO mice maintained expression of NP-cell phenotypic markers CA3, Krt19 and GLUT-1. Moreover, in cKO discs, levels of p19 and RB were higher without alterations in Ki67, γH2AX, CDK4 and Lipofuscin deposition. Interestingly, the cKO discs showed lower levels of SASP markers, IL-1β, IL-6, MCP1 and TGF-β1. These results show that while, p16 is dispensable for induction and maintenance of senescence, conditional loss of p16 reduces apoptosis, limits the SASP phenotype and alters matrix homeostasis of disc cells.
MeSH Terms
- Aggrecans
- Aging
- Animals
- Cellular Senescence
- Collagen
- Cyclin-Dependent Kinase Inhibitor p16
- Disease Models, Animal
- Extracellular Matrix
- Gene Deletion
- Homeostasis
- Humans
- Intervertebral Disc Degeneration
- Mice
- Phenotype
Keywords
- Aggrecan
- Aging
- Extracellular matrix
- Ink4a
- Intervertebral disc degeneration
- Mouse models
- Nucleus pulposus
- SASP
- Senescence
- p16
- p19
Cyclohexane (CHX) is an organic solvent commonly used as a drug-of-abuse. This drug increases the oxidative stress and glial reactivity in the hippocampus, which suggests that this brain region is vulnerable to CHX effects. This study aimed to establish the behavioral changes and the pathological alterations that occur in the Cornu Ammonis 3 (CA3) and Dentate Gyrus (DG) after a long-lasting exposure to CHX. We exposed CD1 mice to a recreational-like dose of CHX (~ 30,000 ppm) for 30 days and explored its consequences in motor skills, reward-seeking behavior, and the CA3 and DG hippocampal subfields. Twenty-four hours after the last administration of CHX, we found a significant decrease in the number of c-Fos cells in the hippocampal CA3 and DG regions. This event coincided with an increased in NMDAR1 expression and apoptotic cells in the CA3 region. At day 13th without CHX, we found a persistent reduction in the number of c-Fos and TUNEL cells in DG. At both time points, the CHX-exposed mice showed a strong overexpression of neuropeptide Y (NPY) in the CA3 stratum lucidum and the hippocampal hilus. In parallel, we used an operant-based task to assess motor performance and operant conditioning learning. The behavioral analysis indicated that CHX did not modify the acquisition of operant conditioning tasks, but affected some motor skills and increased the reward-seeking behavior. Altogether, this evidence reveals that CHX exposure provokes long-lasting changes in the hippocampal subfields, induces motor impairments and increases the motivation-guided behavior. These findings can help understand the deleterious effect of CHX into the adult hippocampus and unveil its potential to trigger addiction-like behaviors.
MeSH Terms
- Administration, Inhalation
- Aging
- Animals
- Behavior, Animal
- CA3 Region, Hippocampal
- Cell Count
- Cyclohexanes
- Dentate Gyrus
- Hippocampus
- Male
- Mice
- Motivation
- Motor Activity
- Neuropeptide Y
- Posture
- Proto-Oncogene Proteins c-fos
- Receptors, N-Methyl-D-Aspartate
- Reinforcement, Psychology
- Reward
- Task Performance and Analysis
Keywords
- Apoptosis
- Excitotoxicity
- Hippocampus
- Inhalant abuse
- Motor skills
- NMDAR1
- Neuropeptide Y
- Reward motivation
- Solvent
Memory requires similar episodes with overlapping features to be represented distinctly, a process that is disrupted in many clinical conditions as well as normal aging. Data from humans have linked this ability to activity in hippocampal CA3 and dentate gyrus (DG). While animal models have shown the perirhinal cortex is critical for disambiguating similar stimuli, hippocampal activity has not been causally linked to discrimination abilities. The goal of the current study was to determine how disrupting CA3/DG activity would impact performance on a rodent mnemonic discrimination task. Rats were surgically implanted with bilateral guide cannulae targeting dorsal CA3/DG. In Experiment 1, the effect of intra-hippocampal muscimol on target-lure discrimination was assessed within subjects in randomized blocks. Muscimol initially impaired discrimination across all levels of target-lure similarity, but performance improved on subsequent test blocks irrespective of stimulus similarity and infusion condition. To clarify these results, Experiment 2 examined whether prior experience with objects influenced the effect of muscimol on target-lure discrimination. Rats that received vehicle infusions in a first test block, followed by muscimol in a second block, did not show discrimination impairments for target-lure pairs of any similarity. In contrast, rats that received muscimol infusions in the first test block were impaired across all levels of target-lure similarity. Following discrimination tests, rats from Experiment 2 were trained on a spatial alternation task. Muscimol infusions increased the number of spatial errors made, relative to vehicle infusions, confirming that muscimol remained effective in disrupting behavioral performance. At the conclusion of behavioral experiments, fluorescence [i]in situ[/i] hybridization for the immediate-early genes [i]Arc[/i] and [i]Homer1a[/i] was used to determine the proportion of neurons active following muscimol infusion. Contrary to expectations, muscimol increased neural activity in DG. An additional experiment was carried out to quantify neural activity in naïve rats that received an intra-hippocampal infusion of vehicle or muscimol. Results confirmed that muscimol led to DG excitation, likely through its actions on interneuron populations in hilar and molecular layers of DG and consequent disinhibition of principal cells. Taken together, our results suggest disruption of coordinated neural activity across the hippocampus impairs mnemonic discrimination when lure stimuli are novel.
Keywords
- CA3
- aging
- dentate gyrus
- epilepsy
- object recognition
- perirhinal cortex
Astrocytes are the main homeostatic cell of the central nervous system. In addition, astrocytes mediate an inflammatory response when reactive to injury or disease known as astrogliosis. Astrogliosis is marked by an increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Some degree of astrogliosis is associated with normal aging and degenerative conditions such as Alzheimer's disease (AD) and other dementing illnesses in humans. The recent observation of pathological markers of AD (amyloid plaques and neurofibrillary tangles) in aged chimpanzee brains provided an opportunity to examine the relationships among aging, AD-type pathology, and astrocyte activation in our closest living relatives. Stereologic methods were used to quantify GFAP-immunoreactive astrocyte density and soma volume in layers I, III, and V of the prefrontal and middle temporal cortex, as well as in hippocampal fields CA1 and CA3. We found that the patterns of astrocyte activation in the aged chimpanzee brain are distinct from humans. GFAP expression does not increase with age in chimpanzees, possibly indicative of lower oxidative stress loads. Similar to humans, chimpanzee layer I astrocytes in the prefrontal cortex are susceptible to AD-like changes. Both prefrontal cortex layer I and hippocampal astrocytes exhibit a high degree of astrogliosis that is positively correlated with accumulation of amyloid beta and tau proteins. However, unlike humans, chimpanzees do not display astrogliosis in other cortical layers. These results demonstrate a unique pattern of cortical aging in chimpanzees and suggest that inflammatory processes may differ between humans and chimpanzees in response to pathology.
MeSH Terms
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Animals
- Astrocytes
- Biomarkers
- Brain
- Brain Chemistry
- Female
- Glial Fibrillary Acidic Protein
- Gliosis
- Male
- Organ Specificity
- Pan troglodytes
- Plaque, Amyloid
- Primate Diseases
- tau Proteins
Keywords
- Alzheimer's disease
- RRID: AB_2109645
- RRID: AB_223647
- RRID: AB_2313952
- RRID: AB_2314223
- aging
- astrocytes
- cerebral cortex
- chimpanzees
- hippocampus
- prefrontal cortex
- stereology
Melatonin, the main product synthesized by the pineal gland, acts as a regulator of the generation of new neurons in the dentate gyrus (DG). Newborn neurons buffer the deleterious effects of stress and are involved in learning and memory processes. Furthermore, melatonin, through the regulation of the cytoskeleton, favors dendrite maturation of newborn neurons. Moreover, newborn neurons send their axons via the mossy fiber tract to Cornu Ammonis 3 (CA3) region to form synapses with pyramidal neurons. Thus, axons of newborn cells contribute to the mossy fiber projection and their plasticity correlates with better performance in several behavioral tasks. Thus, in this study, we analyzed the impact of exogenous melatonin (8 mg/kg) administered daily for one- or six-months on the structural plasticity of infrapyramidal- and suprapyramidal mossy fiber projection of granule cells in the DG in male Balb/C mice. We analyzed the mossy fiber projection through the staining of calbindin, that is a calcium-binding protein localized in dendrites and axons. We first found an increase in the number of calbindin-positive cells in the granular cell layer in the DG (11%, 33%) after treatment. Futhermore, we found an increase in the volume of suprapyramidal (>135%, 59%) and infrapyramidal (>128%, 36%) mossy fiber projection of granule neurons in the DG after treatment. We also found an increase in the volume of CA3 region (>146%, 33%) after treatment, suggesting that melatonin modulates the structural plasticity of the mossy fiber projection to establish functional synapses in the hippocampus. Together, the data suggest that, in addition to the previously reported effects of melatonin on the generation of new neurons and its antidepressant like effects, melatonin also modulates the structural plasticity of axons in granule cells in the DG.
MeSH Terms
- Animals
- Axons
- CA3 Region, Hippocampal
- Calbindins
- Dentate Gyrus
- Male
- Melatonin
- Mice
- Mice, Inbred BALB C
- Nerve Fibers
- Neuronal Plasticity
Keywords
- adult hippocampal neurogenesis
- aging
- calbindin
- hippocampus
- melatonin
- mossy fibers
Measures of amyloid-β (Aβ) and phosphorylated tau (p-tau) concentrations in cerebrospinal fluid are extensively used for diagnostic and research purposes in Alzheimer's disease (AD) as correlates of cortical thinning and cognitive outcomes. The present study investigated the relationship of Aβ and p-tau with hippocampal subfield volumes Cornu Ammonis (CA) 1-4, dentate gyrus (DG), and subiculum. Subfields were segmented from T1-weighted images from the ADNI-population using FreeSurfer v6. Linear and polynomial regression models revealed distinct associations of Aβ and p-tau with subfield volumes. Aβ had a quadratic relationship with all hippocampal subfield volumes and the inflection point was higher than the validated cut-off for Aβ. For p-tau the relationships were linear, except for CA3, in which it was quadratic. For the CA1 and CA3, these quadratic relationships with Aβ were only observed when p-tau was low. Amyloid and p-tau contributed equally to the explained variance in CA4 and DG volume. Subicular volume was best explained by Aβ alone. These biomarker relationships with hippocampal subfield volumes seem to mirror the hippocampal-specific topography of Aβ and tau reported in neuropathological staging models. In addition, using continuous values of Aβ reveals positive patterns with imaging markers for individuals around the positivity threshold that would be masked when using dichotomized biomarker groups, which can be important for early detection and accurate inclusion of potential participants at risk for AD in clinical trials.
MeSH Terms
- Aged
- Aged, 80 and over
- Alzheimer Disease
- Amyloid beta-Peptides
- Biomarkers
- Cognitive Dysfunction
- Female
- Hippocampus
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Peptide Fragments
- tau Proteins
Keywords
- Aging
- Alzheimer’s disease
- amyloid
- hippocampus
- polynomial
- subfields
- tau
Recent findings show that parvalbumin (PV) interneuron function is impaired in Alzheimer's disease (AD), and that this impairment in PV function can be linked to network dysfunction and memory deficits. PV cells are often associated with a specific extracellular matrix, the perineuronal net (PNN). PNNs are believed to protect PV cell integrity, and whether the amyloidopathy affects PNNs remains unclear. Here, we evaluated the number of PV cells with and without PNNs in the hippocampus of the Tg2576 mouse model of AD at different stages of the disease. We show a deficit of PV and/or PV /PNN cells in the areas CA1, CA2, and CA3 in Tg2576 as young as 3 months of age. Importantly, transient exposure to an enriched environment, which has proven long-lasting beneficial effects on memory in AD subjects, rescues the PV/PNN cell number deficits. We conclude that cognitive improvements induced by enriched environment in AD mouse models could be supported by a remodeling of hippocampal PV cell network and their PNNs.
MeSH Terms
- Age Factors
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Animals
- Disease Models, Animal
- Environment
- Extracellular Matrix
- Female
- Hippocampus
- Interneurons
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Parvalbumins
Keywords
- Alzheimer's disease
- Enriched housing
- Hippocampus
- Parvalbumin-expressing interneuron
- Perineuronal net
The incidence of seizures increases with old age. Stroke, dementia and brain tumors are recognized risk factors for new-onset seizures in the aging populations and the incidence of these conditions also increased with age. Whether aging is associated with higher seizure susceptibility in the absence of the above pathologies remains unclear. We used classic kindling to explore this issue as the kindling model is highly reproducible and allows close monitoring of electrographic and motor seizure activities in individual animals. We kindled male young and aging mice (C57BL/6 strain, 2-3 and 18-22 months of age) via daily hippocampal CA3 stimulation and monitored seizure activity via video and electroencephalographic recordings. The aging mice needed fewer stimuli to evoke stage-5 motor seizures and exhibited longer hippocampal afterdischarges and more frequent hippocampal spikes relative to the young mice, but afterdischarge thresholds and cumulative afterdischarge durations to stage 5 motor seizures were not different between the two age groups. While hippocampal injury and structural alterations at cellular and micro-circuitry levels remain to be examined in the kindled mice, our present observations suggest that susceptibility to hippocampal CA3 kindling seizures is increased with aging in male C57 black mice.
Keywords
- Aging
- EEG
- Epilepsy
- Hippocampus
- Kindling
- Mice
Age-related changes in the hippocampus (HC) result in the disturbances of all types of memory and the shifts of emotional reactions. The aim of the present study was to examine the morphometric parameters of neurons of human HC during the aging process. The material was obtained at autopsy of the bodies of 43 individuals of both sexes aged 21–92 years that were divided into 4 age groups. The sections were stained with Nissl’s cresyl violet for identification of neurons. The neurons were counted within the standard area and their profile field area was measured in HC proper, in the area of fields CA1 and CA3, and in dentate gyrus in the hippocampal pes. It was found that with aging human HC underwent a heterochronic loss of nerve cells, the intensity of which differed at the level of the middle part and the hippocampal pes. The degree of age-related loss of nerve cells in human HC increased in the direction: dentate gyrus → CA3 → CA1. In most compartments of HC, a compensatory increase of the neuron profile field area was observed in the period from 36 to 74 years, giving place to its reduction in individuals older than 75 years.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Female
- Hippocampus
- Humans
- Male
- Middle Aged
- Neurons
In Alzheimer's disease (AD), the brain's primary immune cells, microglia, become activated and are found in close apposition to amyloid beta (Aβ) protein plaques and neurofibrillary tangles (NFT). The present study evaluated microglia density and morphology in a large group of aged chimpanzees (n = 20, ages 37-62 years) with varying degrees of AD-like pathology. Using immunohistochemical and stereological techniques, we quantified the density of activated microglia and morphological variants (ramified, intermediate, and amoeboid) in postmortem chimpanzee brain samples from prefrontal cortex, middle temporal gyrus, and hippocampus, areas that show a high degree of AD pathology in humans. Microglia measurements were compared to pathological markers of AD in these cases. Activated microglia were consistently present across brain areas. In the hippocampus, CA3 displayed a higher density than CA1. Aβ42 plaque volume was positively correlated with higher microglial activation and with an intermediate morphology in the hippocampus. Aβ42-positive vessel volume was associated with increased hippocampal microglial activation. Activated microglia density and morphology were not associated with age, sex, pretangle density, NFT density, or tau neuritic cluster density. Aged chimpanzees displayed comparable patterns of activated microglia phenotypes as well as an association of increased microglial activation and morphological changes with Aβ deposition similar to AD patients. In contrast to human AD brains, activated microglia density was not significantly correlated with tau lesions. This evidence suggests that the chimpanzee brain may be relatively preserved during normal aging processes but not entirely protected from neurodegeneration as previously assumed.
MeSH Terms
- Aging
- Alzheimer Disease
- Animals
- Brain
- Female
- Male
- Microglia
- Neurofibrillary Tangles
- Pan troglodytes
- Plaque, Amyloid
Keywords
- Alzheimer's disease
- RRID: AB_223647
- RRID: AB_2313890
- RRID: AB_2313952
- RRID: AB_2315150
- RRID: AB_839504
- amyloid beta protein
- chimpanzee
- microglia
- neurofibrillary tangle
- neuroinflammation
Menopause is associated with cognitive decline, and hormone therapies (HTs) may improve cognition depending on type and timing of HTs. Previous parity may influence cognition in later life. We investigated how primiparity and long-term ovariectomy influence cognition, neurogenesis, hormones, cytokines, and neuronal activation in middle-aged rats in response to Premarin, an HT. Nulliparous and primiparous rats were sham-ovariectomized or ovariectomized, administered vehicle or Premarin 6 months later, and all rats were trained in the Morris water maze. Premarin improved early spatial learning and memory in nulliparous rats but impaired early learning in primiparous rats. With training, primiparity increased hippocampal neurogenesis, and Premarin decreased immature neurons, regardless of parity. Moreover, Premarin increased serum tumor necrosis factor α and the CXC chemokine ligand 1 (CXCL1) in trained nulliparous, but not primiparous, rats. However, Premarin decreased the expression of the immediate early gene zif268 in the dorsal CA3 region in primiparous rats after training. Thus, primiparity alters how Premarin affects spatial learning, neuronal activation, and serum cytokines. These findings have implications for the treatment of age-associated cognitive decline in women.
MeSH Terms
- Animals
- Cell Proliferation
- Cytokines
- Estrogens
- Estrogens, Conjugated (USP)
- Female
- Hippocampus
- Hormone Replacement Therapy
- Maternal Behavior
- Microtubule-Associated Proteins
- Neurogenesis
- Neurons
- Neuropeptides
- Ovariectomy
- Parity
- Rats, Sprague-Dawley
- Spatial Learning
- Spatial Memory
Keywords
- Aging
- Cytokines
- Estrone
- Hippocampus
- Memory
- Neurogenesis
- Parity
- Premarin
A redox-mediated decrease in N-methyl-D-aspartate (NMDA) receptor function contributes to psychiatric diseases and impaired cognition during aging. Inflammation provides a potential source of reactive oxygen species for inducing NMDA receptor hypofunction. The present study tested the hypothesis that the nonsteroidal anti-inflammatory drug indomethacin, which improves spatial episodic memory in aging rats, would enhance NMDA receptor function through a shift in the redox state. Male F344 young and aged rats were prescreened using a 1-day version of the water maze task. Animals were then treated with the indomethacin or vehicle, delivered in a frozen milk treat (orally, twice per day, 18 days), and retested on the water maze. Indomethacin treatment enhanced water maze performance. Hippocampal slices were prepared for examination of CA3-CA1 synaptic responses, long-term potentiation, and NMDA receptor-mediated synaptic responses. No effect of treatment was observed for the total synaptic response. Long-term potentiation magnitude and NMDA receptor input-output curves were enhanced for aged indomethacin-treated animals. To examine redox regulation of NMDA receptors, a second group of aged animals was treated with indomethacin or vehicle, and the effect of the reducing agent, dithiothreitol ([DTT], 0.5 mM) on NMDA receptor-mediated synaptic responses was evaluated. As expected, DTT increased the NMDA receptor response and the effect of DTT was reduced by indomethacin treatment. The results indicate that indomethacin acted to diminish the age-related and redox-mediated NMDA receptor hypofunction and suggest that inflammation contributes to cognitive impairment through an increase in redox stress.
MeSH Terms
- Aging
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
- Dithiothreitol
- Excitatory Postsynaptic Potentials
- Hippocampus
- Indomethacin
- Long-Term Potentiation
- Male
- Rats, Inbred F344
- Receptors, N-Methyl-D-Aspartate
- Reducing Agents
- Spatial Memory
Keywords
- Aging
- Indomethacin
- LTP
- NMDA receptor
- Redox
- Spatial memory
Western society is facing a health epidemic due to the increasing incidence of dementia in aging populations, and there are still few effective diagnostic methods, minimal treatment options, and no cure. Aging is the greatest risk factor for memory loss that occurs during the natural aging process, as well as being the greatest risk factor for neurodegenerative disease such as Alzheimer's disease. Greater understanding of the biochemical pathways that drive a healthy aging brain toward dementia (pathological aging or Alzheimer's disease), is required to accelerate the development of improved diagnostics and therapies. Unfortunately, many animal models of dementia model chronic amyloid precursor protein overexpression, which although highly relevant to mechanisms of amyloidosis and familial Alzheimer's disease, does not model well dementia during the natural aging process. A promising animal model reported to model mechanisms of accelerated natural aging and memory impairments, is the senescence accelerated murine prone strain 8 (SAMP8), which has been adopted by many research group to study the biochemical transitions that occur during brain aging. A limitation to traditional methods of biochemical characterization is that many important biochemical and elemental markers (lipid saturation, lactate, transition metals) cannot be imaged at meso- or microspatial resolution. Therefore, in this investigation, we report the first multimodal biospectroscopic characterization of the SAMP8 model, and have identified important biochemical and elemental alterations, and colocalizations, between 4 month old SAMP8 mice and the relevant control (SAMR1) mice. Specifically, we demonstrate direct evidence of Zn deficiency within specific subregions of the hippocampal CA3 sector, which colocalize with decreased lipid unsaturation. Our findings also revealed colocalization of decreased lipid unsaturation and increased lactate in the corpus callosum white matter, adjacent to the hippocampus. Such findings may have important implication for future research aimed at elucidating specific biochemical pathways for therapeutic intervention.
MeSH Terms
- Aging
- Animals
- CA3 Region, Hippocampal
- Corpus Callosum
- Dementia
- Disease Models, Animal
- Fatty Acids, Unsaturated
- Hippocampus
- Lactic Acid
- Lipid Metabolism
- Mice
- Spectrum Analysis
- White Matter
- Zinc
Keywords
- FTIR
- XFM
- aging
- dementia
- metabolism
- metals
Gut microbiota can influence the aging process and may modulate aging-related changes in cognitive function. Trimethylamine-N-oxide (TMAO), a metabolite of intestinal flora, has been shown to be closely associated with cardiovascular disease and other diseases. However, the relationship between TMAO and aging, especially brain aging, has not been fully elucidated. To explore the relationship between TMAO and brain aging, we analysed the plasma levels of TMAO in both humans and mice and administered exogenous TMAO to 24-week-old senescence-accelerated prone mouse strain 8 (SAMP8) and age-matched senescence-accelerated mouse resistant 1 (SAMR1) mice for 16 weeks. We found that the plasma levels of TMAO increased in both the elderly and the aged mice. Compared with SAMR1-control mice, SAMP8-control mice exhibited a brain aging phenotype characterized by more senescent cells in the hippocampal CA3 region and cognitive dysfunction. Surprisingly, TMAO treatment increased the number of senescent cells, which were primarily neurons, and enhanced the mitochondrial impairments and superoxide production. Moreover, we observed that TMAO treatment increased synaptic damage and reduced the expression levels of synaptic plasticity-related proteins by inhibiting the mTOR signalling pathway, which induces and aggravates aging-related cognitive dysfunction in SAMR1 and SAMP8 mice, respectively. Our findings suggested that TMAO could induce brain aging and age-related cognitive dysfunction in SAMR1 mice and aggravate the cerebral aging process of SAMP8 mice, which might provide new insight into the effects of intestinal microbiota on the brain aging process and help to delay senescence by regulating intestinal flora metabolites.
MeSH Terms
- Adolescent
- Adult
- Aged
- Animals
- Brain
- Cellular Senescence
- Cognitive Dysfunction
- Humans
- Male
- Methylamines
- Mice
- Middle Aged
- Young Adult
Keywords
- brain aging
- cognitive function
- mammalian target of rapamycin
- neuron senescence
- oxidative stress
- trimethylamine-N-oxide
The hippocampus is a structurally and functionally complex brain area that plays important and diverse roles in higher brain functions, such as learning and memory, and mounting evidence indicates that different hippocampal subregions play distinctive roles. The hippocampus is also one of the first regions in the brain to suffer damage in Alzheimer's disease (AD). Synaptic dysfunction in the hippocampus, rather than neuronal loss per se, is paralleled by behavioural and functional deficits in AD. The membrane-associated guanylate kinase (MAGUK) family of proteins, including SAP102, PSD-95, PSD-93 and SAP97, have long been recognized as essential components of the postsynaptic density (PSD) at excitatory synapses. Hippocampal spines are the predominant synaptic transmission sites of excitatory glutamatergic synapses. During postnatal brain development, individual MAGUK members show distinct expression patterns. Although SAP102 has been confirmed as the dominant scaffold protein in neonatal synapses, its expression profiles in adult and ageing rodent hippocampi are discrepant. Furthermore, in AD brains, significantly reduced SAP102 protein levels have been found, suggesting that SAP102 may be related to AD progression; however, the precise mechanism underlying this result remains unclear. Herein, we observed distinct SAP102 expression profiles in the hippocampal CA1, CA3 and DG subregions of rats and APPswe/PS1dE9 (APP/PS1) mice at various ages using immunofluorescence. In Wistar rats, SAP102 was not only highly expressed in the hippocampal subregions of neonatal rats but also maintained relatively high expression levels in adult hippocampi and displayed no obvious decreases in the CA1 and DG subregions of aged rats. Surprisingly, we observed abnormally high SAP102 expression levels in the CA1 stratum moleculare and CA3 stratum polymorphum subregions of 2-month-old APP/PS1 mice, but low SAP102 levels in the DG and CA3 subregions of 7-month-old APP/PS1 mice, reflecting the subregion-specific reactivity and vulnerability of AD mouse models in different disease stages. Our findings provide fundamental data to support the functional differences of SAP102 in different hippocampal subregions during postnatal periods and may serve as the basis for additional functional studies on SAP102 in normal physiological conditions and different stages of AD.
MeSH Terms
- Aging
- Alzheimer Disease
- Animals
- Guanylate Kinases
- Hippocampus
- Membrane Proteins
- Mice
- Mice, Transgenic
- Neuropeptides
- Rats
- Rats, Wistar
Keywords
- APP/PS1
- Alzheimer's disease
- SAP102
- hippocampus
Memories become less precise and generalized over time as memory traces reorganize in hippocampal-cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal-cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC-SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC-SLIN connectivity, increase PV SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG-CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.
MeSH Terms
- Aging
- Amygdala
- Animals
- CA3 Region, Hippocampal
- Dentate Gyrus
- Down-Regulation
- Excitatory Postsynaptic Potentials
- Fear
- Female
- Generalization, Response
- HEK293 Cells
- Humans
- Interneurons
- LIM Domain Proteins
- Memory, Long-Term
- Mice, Inbred C57BL
- Microfilament Proteins
- Neural Inhibition
Aging is associated with a substantial decline in the expression of social behavior as well as increased neuroinflammation. Since immune activation and subsequent increased expression of cytokines can suppress social behavior in young rodents, we examined age and sex differences in microglia within brain regions critical to social behavior regulation (PVN, BNST, and MEA) as well as in the hippocampus. Adult (3-month) and aged (18-month) male and female F344 (N = 26, n = 5-8/group) rats were perfused and Iba-1 immunopositive microglia were assessed using unbiased stereology and optical density. For stereology, microglia were classified based on the following criteria: (1) thin ramified processes, (2) thick long processes, (3) stout processes, or (4) round/ameboid shape. Among the structures examined, the highest density of microglia was evident in the BNST and MEA. Aged rats of both sexes displayed increased total number of microglia number exclusively in the MEA. Sex differences also emerged, whereby aged females (but not males) displayed greater total number of microglia in the BNST relative to their young adult counterparts. When morphological features of microglia were assessed, aged rats exhibited increased soma size in the BNST, MEA, and CA3. Together, these findings provide a comprehensive characterization of microglia number and morphology under ambient conditions in CNS sites critical for the normal expression of social processes. To the extent that microglia morphology is predictive of reactivity and subsequent cytokine release, these data suggest that the expression of social behavior in late aging may be adversely influenced by heightened inflammation.
MeSH Terms
- Aging
- Animals
- Brain
- Female
- Male
- Microglia
- Rats, Inbred F344
- Sex Characteristics
- Social Behavior
Keywords
- Fischer 344
- aging
- limbic system
- microglia
- rat
- social behavior
Reduced estrogen levels and decreased expression of related receptors are typical cerebral features of aging. The G protein-coupled estrogen receptor 1 (GPER1, also known as GPR30) is considered a novel therapeutic target for neurodegenerative diseases. In this study, we demonstrated that hippocampal GPR30 expression was reduced in middle-aged mice compared with young adult mice. GPR30 agonist G1 improved both fear and spatial memory in both male and female middle-aged mice, but not in young adult mice, which were blocked by the GPR30 antagonist G15. Interestingly, a group I metabotropic glutamate receptor (mGluR) agonist, 3,5-dihydroxyphenylglycine (DHPG)-induced long-term depression (LTD) in mossy fiber-cornu ammonis 3 (MF-CA3) synapses but not Schaffer collateral-CA1 (SC-CA1) synapses was facilitated in brain slices from G1-treated middle-aged mice. Long-term potentiation (LTP) in SC-CA1 synapses was not affected in slices from G1-treated mice. The effects of GPR30 activation on memory and DHPG-LTD in MF-CA3 synapses were further confirmed by viral expression of GPR30 in the CA3. The regulation of hippocampal synaptic plasticity by G1 treatment might be related to brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling, as G15 also blocked G1-induced activation of the BDNF-TrkB pathway. Moreover, we found that DHPG triggered GluA internalization in slices from G1-treated mice but not control mice. Pharmacological experiments showed that G1-mediated facilitation of DHPG-induced LTD in MF-CA3 synapses was dependent on protein kinase B (Akt), mammalian target of rapamycin (mTor), and TrkB signaling. In conclusion, our results indicate that GPR30 activation improves memory in middle-aged mice, likely through facilitating synaptic plasticity in the CA3. This study provides novel evidence that GPR30 activation can improve memory in middle-aged animals.
MeSH Terms
- Age Factors
- Animals
- Benzodioxoles
- Brain-Derived Neurotrophic Factor
- CA3 Region, Hippocampal
- Excitatory Amino Acid Agonists
- Fear
- Female
- Long-Term Synaptic Depression
- Male
- Membrane Glycoproteins
- Methoxyhydroxyphenylglycol
- Mice
- Neuronal Plasticity
- Protein-Tyrosine Kinases
- Quinolines
- Receptors, Estrogen
- Receptors, G-Protein-Coupled
- Receptors, Metabotropic Glutamate
- Signal Transduction
- Spatial Memory
- Synapses
Keywords
- Aging
- BDNF
- GPR30
- Long-term depression
- Memory deficit
Study of the developmental characteristics and mechanisms of senescence is an important field in brain aging research. The OXYS strain was selected from Wistar rats in Novosibirsk, and it serves as a rat model of accelerated aging. Previously, neurodegenerative processes and aberrant behavior were reported in experiments with adult OXYS rats. In our study, neurodevelopmental reflexes, neuronal density in the prefrontal cortex and hippocampus, and global DNA methylation in the hippocampus are compared between OXYS and WAG (Wistar Albino Glaxo) neonatal pups. The development of the righting, forelimb grasp, and cliff avoidance reflexes is delayed, and body weight gain was deferred in neonatal OXYS pups. Neuronal density in the hippocampus does not differ between one-day-old OXYS and WAG pups. On the sixth day, the neuronal density in OXYS pups is reduced in the CA2 hippocampal zone, augmented in CA3 and DG, and unchanged in CA1. Six-day-old OXYS pups have fewer and smaller pyramidal neurons in the prefrontal cortex as compared to WAG controls. Global DNA methylation levels in the hippocampus of OXYS newborns are significantly lower than in the WAG newborn pups. At the age of six days, the global DNA methylation level decreases in WAG pups, but does not change in OXYS pups. Thus, neonatal OXYS rats show delayed neurodevelopment accompanied by changes in the global DNA methylation pattern in the hippocampus and in neuronal density in the hippocampus and the prefrontal cortex. These changes may be related to accelerated senescence in adult OXYS rats.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Behavior, Animal
- Cell Count
- DNA Methylation
- Female
- Hippocampus
- Male
- Neurons
- Prefrontal Cortex
- Rats, Transgenic
- Rats, Wistar
- Reflex
Keywords
- Global DNA methylation
- Hippocampus
- Neurodevelopmental reflexes
- Neuronal density
- OXYS rats
- Prefrontal cortex
The current study employed next-generation RNA sequencing to examine gene expression differences related to brain aging, cognitive decline, and hippocampal subfields. Young and aged rats were trained on a spatial episodic memory task. Hippocampal regions CA1, CA3, and the dentate gyrus were isolated. Poly-A mRNA was examined using two different sequencing platforms, Illumina, and Ion Proton. The Illumina platform was used to generate seed lists of genes that were statistically differentially expressed across regions, ages, or in association with cognitive function. The gene lists were then retested using the data from the Ion Proton platform. The results indicate hippocampal subfield differences in gene expression and point to regional differences in vulnerability to aging. Aging was associated with increased expression of immune response-related genes, particularly in the dentate gyrus. For the memory task, impaired performance of aged animals was linked to the regulation of Ca and synaptic function in region CA1. Finally, we provide a transcriptomic characterization of the three subfields regardless of age or cognitive status, highlighting and confirming a correspondence between cytoarchitectural boundaries and molecular profiling.
Keywords
- Illumina HiSeq
- Ion proton
- aging
- cognitive function
- gene expression
- hippocampus
- transcription
Hilar mossy cells (HMCs) in the hippocampus receive glutamatergic input from dentate granule cells (DGCs) via mossy fibers (MFs) and back-projections from CA3 pyramidal neuron collateral axons. Many fundamental features of these excitatory synapses have not been characterized in detail despite their potential relevance to hippocampal cognitive processing and epilepsy-induced adaptations in circuit excitability. In this study, we compared pre- and postsynaptic parameters between MF and CA3 inputs to HMCs in young and adult mice of either sex and determined the relative contributions of the respective excitatory inputs during [i]in vitro[/i] and [i]in vivo[/i] models of hippocampal hyperexcitability. The two types of excitatory synapses both exhibited a modest degree of short-term plasticity, with MF inputs to HMCs exhibiting lower paired-pulse (PP) and frequency facilitation than was described previously for MF-CA3 pyramidal cell synapses. MF-HMC synapses exhibited unitary excitatory synaptic currents (EPSCs) of larger amplitude, contained postsynaptic kainate receptors, and had a lower NMDA/AMPA receptor ratio compared to CA3-HMC synapses. Pharmacological induction of hippocampal hyperexcitability [i]in vitro[/i] transformed the abundant but relatively weak CA3-HMC connections to very large amplitude spontaneous bursts of compound EPSCs (cEPSCs) in young mice (∼P20) and, to a lesser degree, in adult mice (∼P70). CA3-HMC cEPSCs were also observed in slices prepared from mice with spontaneous seizures several weeks after intrahippocampal kainate injection. Strong excitation of HMCs during synchronous CA3 activity represents an avenue of significant excitatory network generation back to DGCs and might be important in generating epileptic networks.
MeSH Terms
- Animals
- CA3 Region, Hippocampal
- Excitatory Postsynaptic Potentials
- Female
- Male
- Mice
- Mice, Inbred C57BL
- Mossy Fibers, Hippocampal
- Neural Pathways
- Neuronal Plasticity
- Organ Culture Techniques
- Pyramidal Cells
- Synapses
- Synaptic Transmission
Keywords
- CA3
- aging
- hilus
- mossy cell
- seizure
Aging is associated with impaired performance in behavioral pattern separation (PS) tasks based on similarities in object features and in object location. These deficits have been attributed to functional alterations in the dentate gyrus (DG)-CA3 region. Animal studies suggested a role of adult-born DG neurons in PS performance. The present study investigated the effect of aging in C57BL/6J mice performing PS tasks based on either object features or object location. At the age of 18 months or more, performance was severely impaired in both tasks. Spatial PS performance declined gradually over adult lifespan from 3 to 21 months. Subchronic treatment with the cognitive enhancer D-serine fully rescued spatial PS performance in 18-month-old mice and induced a modest increase in the number of 4-week-old adult-born cells in the DG. Performance of mice in these PS tasks shows an age dependence, which appears to translate well to that found in humans. This model should help in deciphering physiological changes underlying PS deficits and in identifying future therapeutic targets.
MeSH Terms
- Animals
- CA3 Region, Hippocampal
- Cognitive Aging
- Dentate Gyrus
- Male
- Mice, Inbred C57BL
- Pattern Recognition, Physiological
- Serine
Keywords
- Cognitive aging
- D-serine
- Object feature
- Object location
- Pattern separation
Both aging and Alzheimer's disease (AD) are associated with widespread epigenetic changes, with most evidence suggesting global hypomethylation in AD. It is, however, unclear how these age-related epigenetic changes are linked to molecular aberrations as expressed in animal models of AD. Here, we investigated age-related changes of epigenetic markers of DNA methylation and hydroxymethylation in a range of animal models of AD, and their correlations with amyloid plaque load. Three transgenic mouse models, including the J20, APP/PS1dE9 and 3xTg-AD models, as well as Caribbean vervets (a non-transgenic non-human primate model of AD) were investigated. In the J20 mouse model, an age-related decrease in DNA methylation was found in the dentate gyrus (DG) and a decrease in the ratio between DNA methylation and hydroxymethylation was found in the DG and cornu ammonis (CA) 3. In the 3xTg-AD mice, an age-related increase in DNA methylation was found in the DG and CA1-2. No significant age-related alterations were found in the APP/PS1dE9 mice and non-human primate model. In the J20 model, hippocampal plaque load showed a significant negative correlation with DNA methylation in the DG, and with the ratio a negative correlation in the DG and CA3. For the APP/PS1dE9 model a negative correlation between the ratio and plaque load was observed in the CA3, as well as a negative correlation between DNA methyltransferase 3A (DNMT3A) levels and plaque load in the DG and CA3. Thus, only the J20 model showed an age-related reduction in global DNA methylation, while DNA hypermethylation was observed in the 3xTg-AD model. Given these differences between animal models, future studies are needed to further elucidate the contribution of different AD-related genetic variation to age-related epigenetic changes.
MeSH Terms
- Aging
- Alzheimer Disease
- Amyloid beta-Protein Precursor
- Animals
- Chlorocebus aethiops
- DNA Methylation
- Disease Models, Animal
- Epigenesis, Genetic
- Hippocampus
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Species Specificity
Keywords
- Aging
- Alzheimer's disease
- Animal models
- DNA hydroxymethylation
- DNA methylation
- DNA methyltransferase
- Hippocampus
{{medline-entry |title=Time of day but not aging regulates 5-HT receptor binding sites in the hamster hippocampus. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29107707 |abstract=Activation of 5-HT receptors influences memory as well as circadian rhythms and other processes. This study investigated the regulation of the 5-HT receptors in the hippocampus, a likely substrate for the effects of 5-HT receptor compounds on memory. Because endogenous serotonin release is higher during the active phase, and chronic treatment with a serotonin-selective reuptake inhibitor down-regulates 5-HT receptors, we hypothesized that 5-HT receptors exhibit 24-h variations. We also hypothesized that aging decreases 5-HT receptors in the hippocampus, as it does in the dorsal raphe nucleus, a brain site for serotonergic resetting of circadian rhythms. Male hamsters (young, 3-5 mos; old, 17-21 mos) exposed to a light:dark cycle were euthanized at 4 times of day (zeitgeber times [ZT]1, 6, 13,