DRD3
D(3) dopamine receptor (Dopamine D3 receptor)
Publications[править]
A large proportion of the population suffers from endocrine disruption, e.g., menopausal women, which might result in accelerated aging and a higher risk for developing cognitive disorders. Therefore, it is crucial to fully understand the impact of such disruptions on the brain to identify potential therapeutic strategies. Here, we show using resting-state functional magnetic resonance imaging that ovariectomy and consequent hypothalamus-pituitary-gonadal disruption result in the selective dysconnectivity of 2 discrete brain regions in mice. This effect coincided with cognitive deficits and an underlying pathological molecular phenotype involving an imbalance of neurodevelopmental/neurodegenerative signaling. Furthermore, this quantitative mass spectrometry proteomics-based analysis of molecular signaling patterns further identified a strong involvement of altered dopaminergic functionality (e.g., DAT and predicted upstream regulators DRD3, NR4A2), reproductive signaling (e.g., Srd5a2), rotatin expression (rttn), cellular aging (e.g., Rxfp3, Git2), myelination, and axogenesis (e.g., Nefl, Mag). With this, we have provided an improved understanding of the impact of hypothalamus-pituitary-gonadal dysfunction and highlighted the potential of using a highly translational magnetic resonance imaging technique for monitoring these effects on the brain.
MeSH Terms
- Animals
- Brain
- Cell Cycle Proteins
- Cellular Senescence
- Cognitive Dysfunction
- Female
- Gene Expression
- Hypothalamo-Hypophyseal System
- Magnetic Resonance Imaging
- Membrane Proteins
- Mice, Inbred C57BL
- Nuclear Receptor Subfamily 4, Group A, Member 2
- Ovariectomy
- Pituitary-Adrenal System
- Receptors, Dopamine D3
- Receptors, G-Protein-Coupled
Keywords
- Aging
- Behavior
- Cognition
- Dopamine
- Functional connectivity
- Mass spectrometry
- Myelination
- Ovariectomy
- Quantitative proteomics
- Resting-state fMRI
To determine whether intervention-induced physical activity (PA) changes in sedentary older adults differed according to dopamine-related genotype. Randomized clinical trial (Lifestyle Interventions and Independence for Elders Trial (2010-13)). Multicenter study, 8 U.S. Volunteer sample of sedentary adults aged 70 to 89 at risk of disability (N=1635). Structured PA versus health education (HE) for an average of 2.6 years. Single-nucleotide polymorphisms of dopamine-related genes (dopamine receptor (DR) D1, DRD2, DRD3, and catechol-O-methyltransferase (COMT)) were assessed. Average moderate to vigorous PA (MVPA) was calculated using accelerometry (min/d) at baseline and 6, 12, and 24 months. Between-arm MVPA differences according to genotype and genotype with square root-transformed MVPA separately according to arm were tested, stratified according to race, and adjusted for multiple comparisons. White participants in the PA arm (n=513) had higher average square root transformed MVPA (4.91±1.91)than those in the HE arm (n=538) (4.51±1.82) (p=.001). Between-arm differences were greater for DRD2 Met/Met (high dopamine; HE: 4.76±1.80, PA: 5.53±1.60, p=.03) than Val/Val (low dopamine; HE: 4.58±1.92, PA: 4.81±1.83, p=.16); results were similar for COMT. In the PA arm, DRD2 Met/Met was associated with higher average MVPA (5.39±2.00) than Met/Val (4.46±2.51) (p=.01) and Val/Val (4.65±2.71) (p=.01). There were no associations for other genes. Associations were not significant in blacks but followed similar trends. Higher dopamine signaling may support changes in PA during an intervention. The role of dopamine-related pathways in promoting PA participation and enhancing response to interventions in sedentary older adults should be studied. clinicaltrials.gov Identifier: NCT01072500.
MeSH Terms
- Accelerometry
- Aged
- Catechol O-Methyltransferase
- Dopamine
- Exercise
- Exercise Therapy
- Female
- Humans
- Life Style
- Male
- Middle Aged
- Mobility Limitation
- Polymorphism, Single Nucleotide
- Receptors, Dopamine D2
- Risk Reduction Behavior
- Sedentary Behavior
- Signal Transduction
- Walking Speed
Keywords
- aging
- dopamine
- physical activity
- randomized controlled trial
Previous research shows that associative memory declines more than item memory in aging. Although the underlying mechanisms of this selective impairment remain poorly understood, animal and human data suggest that dopaminergic modulation may be particularly relevant for associative binding. We investigated the influence of dopamine (DA) receptor genes on item and associative memory in a population-based sample of older adults (n = 525, aged 60 years), assessed with a face-scene item associative memory task. The effects of single-nucleotide polymorphisms of DA D1 (DRD1; rs4532), D2 (DRD2/ANKK1/Taq1A; rs1800497), and D3 (DRD3/Ser9Gly; rs6280) receptor genes were examined and combined into a single genetic score. Individuals carrying more beneficial alleles, presumably associated with higher DA receptor efficacy (DRD1 C allele; DRD2 A2 allele; DRD3 T allele), performed better on associative memory than persons with less beneficial genotypes. There were no effects of these genes on item memory or other cognitive measures, such as working memory, executive functioning, fluency, and perceptual speed, indicating a selective association between DA genes and associative memory. By contrast, genetic risk for Alzheimer disease (AD) was associated with worse item and associative memory, indicating adverse effects of APOE ε4 and a genetic risk score for AD (PICALM, BIN1, CLU) on episodic memory in general. Taken together, our results suggest that DA may be particularly important for associative memory, whereas AD-related genetic variations may influence overall episodic memory in older adults without dementia.
MeSH Terms
- Aging
- Alzheimer Disease
- Apolipoproteins E
- Association
- Cohort Studies
- Female
- Genotyping Techniques
- Humans
- Male
- Memory
- Middle Aged
- Neuropsychological Tests
- Polymorphism, Single Nucleotide
- Receptors, Dopamine
Aging is a major co-risk factor in many neurodegenerative diseases. Cognitive enrichment positively affects the structural plasticity of the aging brain. In this study, we evaluated effects of a set of structured multimodal activities (Combination Training; CT) on cognitive performances, functional connectivity, and cortical thickness of a group of healthy elderly individuals. CT lasted six months. Neuropsychological and occupational performances were evaluated before and at the end of the training period. fMRI was used to assess effects of training on resting state network (RSN) functional connectivity using Independent Component Analysis (ICA). Effects on cortical thickness were also studied. Finally, we evaluated whether specific dopamine-related genes can affect the response to training. Results of the study indicate that CT improves cognitive/occupational performances and reorganizes functional connectivity. Intriguingly, individuals responding to CT showed specific dopamine-related genotypes. Indeed, analysis of dopamine-related genes revealed that carriers of DRD3 ser9gly and COMT Val158Met polymorphisms had the greatest benefits from exposure to CT. Overall, our findings support the idea that exposure to a set of structured multimodal activities can be an effective strategy to counteract aging-related cognitive decline and also indicate that significant capability of functional and structural changes are maintained in the elderly.
MeSH Terms
- Activities of Daily Living
- Aged
- Aging
- Brain Mapping
- Catechol O-Methyltransferase
- Cerebral Cortex
- Cognition
- Exercise
- Female
- Functional Neuroimaging
- Humans
- Magnetic Resonance Imaging
- Male
- Nerve Net
- Neuropsychological Tests
- Polymorphism, Single Nucleotide
- Receptors, Dopamine D3