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

衰老与运动和认知能力的下降有关， 这些行为缺陷的基础将是增加健康寿命的关键。黑质多巴胺神经元 黑质是自愿运动和奖励相关行为的关键中枢介质，这些功能 神经元会随着年龄的增长而衰退。不幸的是，目前对正常衰老如何影响 负责多巴胺神经元兴奋性的特定内在通道和突触输入， 功能我们的实验室已经开发出可靠的方法来进行多巴胺的电生理记录 神经元的大脑切片从先进的年龄，从而全面调查的影响，老龄化 对这些神经元中的离子通道生理学的研究是可能的。我们将联合收割机结合电生理学，行为学， 基因表达分析和光遗传学来阐明衰老对离子通道信号传导的影响， 多巴胺介导的行为此外，我们将使用饮食限制（一个既定的健康跨度- 增加干预），以确定抵消年龄相关的行为缺陷的离子机制。 我们的中心假设是，与年龄相关的运动和奖励相关行为的缺陷可能是 归因于黑质多巴胺神经元中特定的离子通道电导，并且这些缺陷 可以通过饮食限制来减弱。目的1是确定与年龄相关的缺陷， 特定的离子通道电流和细胞放电。我们还将（在单个小鼠中）将我们的电生理 在单个神经元中的发现与先前获得的运动行为数据相比较。目标2是确定 衰老对从下丘脑到多巴胺神经元的兴奋性输入以及奖励相关行为的影响。为 为此，我们将采用光遗传学以脑区域特异性方式研究所识别的谷氨酸输入。目的 3是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： 确定饮食限制对衰老小鼠的影响，作为一种干预措施，可以抵消年龄相关的 多巴胺神经元的离子电导下降和相关行为。这些研究将首次提供 详细了解衰老，多巴胺神经元活性和多巴胺介导的 行为，并确定对这些参数的饮食限制的保护作用。

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.