The effect of aging on neurotransmitters and motor performance in a primate model

衰老对灵长类动物模型中神经递质和运动表现的影响

• 批准号: 10573386
• 负责人: Melissa K. Edler
• 金额: $ 31.54万
• 依托单位: KENT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10573386
• 关键词: Acetylcholine; Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Atrophic; Autopsy; Axon; Behavior; Behavioral; Biological; Brain; Brain region; Cell Aging; Cerebrovascular Disorders; Cognition; Cognitive; Cognitive deficits; Corpus striatum structure; Cross-Sectional Studies; Data; Data Correlations; Dementia; Dopamine; Dorsal; Elderly; Exhibits; Freezing; Gene Expression; Gene Proteins; Homologous Gene; Human; Immunohistochemistry; Impaired cognition; Individual; Knowledge; Length; Lesion; Macaca; Measures; Memory; Mental disorders; Midbrain structure; Modeling; Modification; Motor; Motor Skills; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurotransmitters; Norepinephrine; Pan Genus; Parkinson Disease; Pathologic; Pathology; Performance; Pharmaceutical Preparations; Physiological; Pongidae; Pontine structure; Primates; Reporting; Resources; Risk Factors; Rodent; Rodent Model; Sampling; Senile Plaques; Serotonin; Social Behavior; Social Interaction; Specimen; Symptoms; System; Testing; Therapeutic Effect; Treatment Efficacy; Variant; Vascular Diseases; age effect; age related; age related neurodegeneration; aged; aging brain; basal forebrain; behavior test; cholinergic; cholinergic neuron; cognitive function; cognitive performance; cohort; executive function; experience; flexibility; improved; locus ceruleus structure; motor behavior; motor impairment; nervous system disorder; neuroinflammation; neuron loss; neuropathology; neurotransmitter metabolism; nonhuman primate; preclinical development; preservation; prospective; raphe nuclei; sex; social; species difference; tool; touchscreen; transcriptome sequencing; transmission process; walking speed

Project Summary The aging brain undergoes fluctuations in neurotransmitters and gene expression, volumetric atrophy, cellular senescence, vascular dysfunction, neuroinflammation, and cognitive deficits. Age also is a risk factor for developing neurodegenerative disorders like Alzheimer's (AD) and Parkinson's diseases (PD). The current primary therapies for AD and PD target transmission of neurotransmitters acetylcholine and dopamine, and neurotransmitter deficiencies are associated with cognitive and motor impairments. Thus, investigating species differences in neurotransmitters is vital to developing effective models of age-related neurological disorders. Nonhuman primates, particularly chimpanzees, are an invaluable resource for aging studies. Like humans, older apes experience mild decline in memory, executive function, and cognitive flexibility, and their brains bear remarkable similarities to elderly humans in gene expression, cerebrovascular dysfunction, and neuroinflammation. Chimpanzees also exhibit the AD hallmarks of amyloid-beta plaques and neurofibrillary tangles in the absence of significant neuronal loss or dementia symptoms. One possibility for the lack of severe cognitive decline in chimpanzees, despite the presence of AD lesions, may be species-specific alterations in neurotransmitters. While prior studies report mild age-related cholinergic and dopaminergic reductions in aged macaque brains, the effect of aging and AD pathology on neurotransmitters in chimpanzees remains unknown. To address this issue, we will investigate neurotransmitter gene expression and protein levels in the chimpanzee brain for age-, sex- and AD pathology-related changes as observed in humans. Utilizing immunohistochemistry, unbiased stereology, and postmortem brain samples from adult and aged chimpanzees previously identified with AD pathology, we will measure neurotransmitter neuron or axon length densities for: dopamine in the dorsal striatum and midbrain; acetylcholine in the dorsal striatum, basal forebrain, and pons; serotonin in the raphe nucleus; and norepinephrine in the locus coeruleus. We also will examine expression of genes involved in the transmission and metabolism of neurotransmitters using bulk RNA sequencing and frozen brain specimens from young and aged chimpanzees with and without AD pathology. To determine if modifications in neurotransmitters correlate with behavioral changes, we will use archival behavioral data. In addition, we will assess longitudinal changes in cognitive functions using an automated touchscreen testing system, motor skill on a tool use task, walking speed, and agonistic and affiliative social interactions in a cohort of living chimpanzees. Distinguishing if species differences in neurotransmitter systems are associated with age-related behavioral changes is essential for improving current models of neurodegenerative and psychiatric disorders, and this proposal will fill a critical gap in our evolutionary knowledge of the influence of aging and AD neuropathology on neurotransmitters in chimpanzees, our closest living ancestor.

项目概要 衰老的大脑会经历神经递质和基因表达的波动、体积萎缩、细胞萎缩等。 衰老、血管功能障碍、神经炎症和认知缺陷。年龄也是一个危险因素 发展成神经退行性疾病，如阿尔茨海默病 (AD) 和帕金森病 (PD)。目前的 AD 和 PD 的主要治疗目标是神经递质乙酰胆碱和多巴胺的传递，以及 神经递质缺乏与认知和运动障碍有关。因此，调查物种 神经递质的差异对于开发与年龄相关的神经系统疾病的有效模型至关重要。 非人类灵长类动物，特别是黑猩猩，是衰老研究的宝贵资源。和人类一样，年纪大了 猿类的记忆力、执行功能和认知灵活性会出现轻微下降，并且它们的大脑承受着 在基因表达、脑血管功能障碍和 神经炎症。黑猩猩还表现出淀粉样蛋白斑块和神经原纤维的 AD 特征 在没有明显神经元损失或痴呆症状的情况下出现缠结。一种可能性是缺乏严重的 尽管存在 AD 病变，黑猩猩的认知能力下降可能是物种特异性的改变 神经递质。虽然之前的研究报告称，老年人的胆碱能和多巴胺能有轻微的与年龄相关的减少。 在猕猴大脑中，衰老和 AD 病理学对黑猩猩神经递质的影响仍然未知。 为了解决这个问题，我们将研究黑猩猩的神经递质基因表达和蛋白质水平 大脑中观察到的与年龄、性别和 AD 病理相关的变化。利用免疫组织化学， 无偏见的体视学，以及先前鉴定出的成年和老年黑猩猩的死后大脑样本 AD 病理学，我们将测量神经递质神经元或轴突长度密度： 背侧多巴胺 纹状体和中脑；背侧纹状体、基底前脑和脑桥中的乙酰胆碱；中缝中的血清素 核;和蓝斑中的去甲肾上腺素。我们还将检查参与的基因的表达 使用批量 RNA 测序和来自冷冻脑样本的神经递质的传输和代谢 患有或不患有 AD 病理的年轻和老年黑猩猩。确定神经递质是否发生改变 与行为变化相关联，我们将使用档案行为数据。此外，我们还将纵向评估 使用自动触摸屏测试系统改变认知功能、工具使用任务的运动技能、 一群现存黑猩猩的行走速度、竞争性和亲和性社交互动。区分 神经递质系统的物种差异是否与年龄相关的行为变化有关 对于改善当前的神经退行性和精神疾病模型至关重要，该提案将填补 我们对衰老和 AD 神经病理学影响的进化知识存在重大差距 黑猩猩（我们现存的最近祖先）的神经递质。