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.

项目摘要 老化的大脑经历神经递质和基因表达的波动，体积萎缩，细胞 衰老、血管功能障碍、神经炎症和认知障碍。年龄也是一个危险因素 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)。海流 AD和PD的主要治疗方法是针对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疾病的有效模型至关重要。 非人灵长类动物，特别是黑猩猩，是衰老研究的宝贵资源。像人类一样，年纪更大 类人猿的记忆力、执行功能和认知灵活性都有轻微的下降，他们的大脑 在基因表达、脑血管功能障碍和 神经炎。黑猩猩也表现出淀粉样β蛋白斑块和神经原纤维的AD特征 在没有明显神经元丢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 尽管存在阿尔茨海默病的损害，但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。虽然先前的研究报告了与年龄相关的轻度胆碱能和多巴胺能在老年人中的下降 在猕猴脑中，衰老和AD病理对黑猩猩神经递质的影响尚不清楚。 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水平。 在人类中观察到的与年龄、性别和AD病理相关的大脑变化。利用免疫组织化学， 无偏见的体视学和来自成年和老年黑猩猩的死后大脑样本 在病理学方面，我们将测量神经递质神经元或轴突的长度密度：背部的多巴胺 纹状体和中脑；背侧纹状体、基底前脑和脑桥的乙酰胆碱；中缝的5-羟色胺 蓝斑内有去甲肾上腺素。我们还将检查参与基因表达的 用批量RNA测序和冰冻脑组织标本研究神经递质的传递和代谢 患有和不患有阿尔茨海默病的幼年和老年黑猩猩。以确定神经递质的修饰是否 与行为变化相关，我们将使用档案行为数据。此外，我们还将评估纵向 使用自动触摸屏测试系统的认知功能的变化，工具使用任务中的运动技能， 在一群活着的黑猩猩中，行走速度、竞技性和关联性社会互动。与众不同 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障碍模型是必不可少的，这项提议将填补 我们关于衰老和AD神经病理影响的进化知识中的一个关键差距 黑猩猩的神经递质，这是我们最接近的现存祖先。