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

项目摘要 衰老的大脑经历神经递质和基因表达的波动，体积萎缩，细胞凋亡， 衰老、血管功能障碍、神经炎症和认知缺陷。年龄也是一个风险因素， 发展神经退行性疾病，如阿尔茨海默氏症（AD）和帕金森氏病（PD）。当前 AD和PD的主要治疗靶向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，是研究衰老的宝贵资源。像人类一样， 类人猿的记忆力、执行功能和认知灵活性会出现轻度下降，它们的大脑会承受 与老年人在基因表达、脑血管功能障碍和 神经炎症黑猩猩也表现出β淀粉样蛋白斑块和神经胶质瘤的AD特征。 在没有显著神经元损失或痴呆症状的情况下缠结。一种可能性是缺乏严重的 黑猩猩的认知能力下降，尽管存在AD病变，可能是物种特异性的改变， 神经传递素虽然先前的研究报告了老年人中与年龄相关的轻度胆碱能和多巴胺能减少， 尽管在猕猴脑中发现了这一点，但衰老和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 在人类中观察到的年龄、性别和AD病理学相关变化。利用免疫组织化学， 无偏见的体视学，以及来自成年和老年黑猩猩的死后大脑样本，这些黑猩猩先前被鉴定为 AD病理学，我们将测量神经递质神经元或轴突长度密度： 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;和去甲肾上腺素在蓝斑。我们还将研究参与细胞凋亡的基因的表达。 使用批量RNA测序和冷冻脑标本的神经递质的传输和代谢， 患有和不患有AD病理的年轻和老年黑猩猩。为了确定神经递质的变化 与行为变化相关，我们将使用存档的行为数据。此外，我们将评估纵向 使用自动触摸屏测试系统的认知功能变化，工具使用任务的运动技能， 行走速度，以及一群活着的黑猩猩中的竞争性和亲和性社会互动。区分 如果神经递质系统的物种差异与年龄相关的行为变化有关， 对于改善目前的神经退行性疾病和精神疾病模型至关重要，这项提案将填补 我们对衰老和AD神经病理学影响的进化知识中的一个关键空白， 黑猩猩的神经传递素，我们最近的祖先。

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.