Effects of dietary restriction on age-related neurophysiological adaptations: from behavior to single dopaminergic neurons

饮食限制对年龄相关神经生理适应的影响：从行为到单个多巴胺能神经元

• 批准号: 9240155
• 负责人: Michael J Beckstead
• 金额: $ 30.87万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240155
• 关键词: Adaptive Behaviors; Affect; Age; Age-associated memory impairment; Aging; Attenuated; Autoreceptors; Back; Behavior; Behavioral; Biological Assay; Brain; Brain region; Calcium; Cells; Chronic; Cognition; Data; Dopamine; Elderly; Electrophysiology (science); Etiology; Exhibits; Future; Gene Expression; Gene Expression Profiling; Glutamate Receptor; Glutamates; Goals; Hypothalamic structure; Individual; Intervention; Investigation; Ion Channel; Ions; Knowledge; L-Type Calcium Channels; Maintenance; Measurement; Mediating; Mediator of activation protein; Methodology; Motor; Movement; Mus; Neurodegenerative Disorders; Neurons; Pacemakers; Parkinson Disease; Pharmacology; Physiological Adaptation; Physiology; Potassium Channel; Probability; Rewards; Signal Transduction; Slice; Substantia nigra structure; Synapses; Synaptic Potentials; Testing; Time; age effect; age related; base; dietary restriction; dopaminergic neuron; improved; innovation; neurophysiology; neurotransmission; normal aging; optogenetics; paraventricular nucleus; patch clamp; prevent; protective effect; uptake; young adult

Aging is associated with a decrease in movement and cognition, and understanding the neurophysiological bases of these behavioral deficits will be key to increasing healthspan. Dopamine neurons in the substantia nigra are key central mediators of voluntary movement and reward-related behavior, and the function of these neurons is known to decline with age. Unfortunately, little is currently known about how normal aging affects the specific intrinsic channels and synaptic inputs that are responsible for dopamine neuron excitability and function. Our lab has developed reliable methodology for making electrophysiological recordings of dopamine neurons in brain slices from mice of advanced age, thus a comprehensive investigation into the effects of aging on ion channel physiology in these neurons is now possible. We will combine electrophysiology, behavior, gene expression analysis, and optogenetics to elucidate the effects of aging on ion channel signaling and dopamine-mediated behaviors. Furthermore, we will use dietary restriction (an established healthspan- increasing intervention) to identify the ionic mechanisms that counteract age-related deficits in behavior. Our central hypothesis is that age-related deficits in movement and reward-related behaviors can be attributed to specific ion channel conductances in substantia nigra dopamine neurons, and that these deficits can be attenuated by dietary restriction. Aim 1 is to determine the relationship between age-related deficits in specific ion channel currents and cell firing. We will also relate (in individual mice) our electrophysiological findings in single neurons to previously obtained locomotor behavioral data. Aim 2 is to determine the effects of aging on excitatory inputs from the hypothalamus to dopamine neurons as well as reward-related behavior. For this aim we will employ optogenetics to study identified glutamate inputs in a brain region-specific manner. Aim 3 is to determine the effects of aging on dopamine autoreceptor-mediated neurotransmission. Aim 4 is to determine the effects of dietary restriction in aging mice as an intervention that can counteract age-related decline of ion conductances in dopamine neurons and related behaviors. These studies will provide the first detailed understanding of the relationship between aging, dopamine neuron activity, and dopamine-mediated behaviors, and determine the protective effects of dietary restriction on these parameters.

衰老与运动和认知的减少有关，并了解神经生理学 这些行为缺陷的基础将是增加健康状况的关键。黑质中的多巴胺神经元 Nigra是自愿运动和与奖励相关行为的关键中心调解人，这些行为的功能 众所周知，神经元会随着年龄的增长而下降。不幸的是，目前对正常衰老的影响知之甚少 负责多巴胺神经元兴奋性和 功能。我们的实验室开发了可靠的方法来制作多巴胺的电生理记录 高龄小鼠的脑切片中的神经元，因此对衰老的影响进行了全面研究 现在可以在这些神经元中的离子通道生理上进行生理。我们将结合电生理学，行为， 基因表达分析和光遗传学，以阐明衰老对离子通道信号传导和 多巴胺介导的行为。此外，我们将使用饮食限制（已建立的HealthSpan- 增加干预措施）以确定抵消与年龄相关的行为缺陷的离子机制。 我们的核心假设是，运动和奖励相关行为的年龄相关的赤字可能是 归因于黑质多巴胺神经元中特定的离子通道电导，这些缺陷 可以通过饮食限制减轻。目标1是确定与年龄相关的赤字之间的关系 特定的离子通道电流和电池射击。我们还将（在单个小鼠中）我们的电生理学 单个神经元中的发现先前获得了运动行为数据。目标2是确定的影响 从下丘脑到多巴胺神经元以及与奖励相关的行为的兴奋投入衰老。为了 我们将采用光遗传学以大脑区域特异性方式研究鉴定出的谷氨酸输入。目的 3是为了确定衰老对多巴胺自身受体介导的神经传递的影响。目标4是 确定饮食限制在衰老小鼠中的影响，作为一种可以抵消与年龄有关的干预措施 多巴胺神经元和相关行为中离子电导的下降。这些研究将提供第一个 详细了解衰老，多巴胺神经元活性和多巴胺介导的关系之间的关系 行为，并确定饮食限制对这些参数的保护作用。