项目来源
美国卫生和人类服务部基金(HHS)
项目主持人
ST HILLAIRE-CLARKE, CORYSE
项目受资助机构
CALIFORNIA INSTITUTE OF TECHNOLOGY
立项年度
2018
立项时间
未公开
项目编号
5R01AG047664-05
研究期限
未知 / 未知
项目级别
国家级
受资助金额
374625.00美元
学科
Aging; Basic Behavioral and Social Science; Behavioral and Social Science; Genetics; Neurodegenerative; Neurosciences;
学科代码
未公开
基金类别
Non-SBIR/STTR RPGs
关键词
未公开
参与者
GRADINARU, VIVIANA
参与机构
NATIONAL INSTITUTE ON AGING
项目标书摘要：DESCRIPTION (provided by applicant): During aging, motor function declines, with deficits in fine and fast movement and coordination. Experimental studies associate age-dependent motor deficits with the malfunction of dopaminergic (DA) pathway, which originates in the substantia nigra pars compacta (SNc). However we do not understand how the activity of DA neurons varies throughout aging in the different tiers of nigral neurons in vivo, what type of activity changes precede neurodegeneration, how these activity changes affect behavior, and whether restoring perturbed activity can delay neurodegeneration and/or behavioral deficits. To characterize, for the first time in the intact circuit, the function and anatomy of aging nigral dopaminergic circuits, we propose to use two powerful technological advances in neuroscience: one for cell-type specific bidirectional control of neuronal activity in vivo with high temporal precision (optogenetics); and one for intact brain circuit mapping and phenotyping, slicing-free (CLARITY). Optogenetics uses microbial opsins, light-sensitive proteins that can be expressed in specified cells via targeting promoters and turned on/off with millisecond speed, thus providing control of cell function with high spatial, temporal, and genetic specificity. Their abilty to control the electrical activity of neural circuits and confer reversible gain and loss of functin of specific neuronal phenotypes allows us to study neural systems and diseases in unprecedented manner. To target subsets of SNc DA neurons we will take advantage of the TH- Cre transgenic lines as well as localized stereotaxic opsin delivery and targeted light application We hypothesize that throughout aging, DA neurons in different SNc tiers have distinct behavioral contributions (Aim 1), which is due to differences in their intrinsic excitability (Aim 2) and changes in synaptic inputs (Aim 3). This proposal combines powerful complementary techniques (optogenetics, electrophysiology, and neuroanatomy by CLARITY) to advance our understanding of dopaminergic function and contribution to behavior throughout aging by performing studies in the intact circuit. The PI has been involved in the development of both techniques and our laboratory is ideally positioned to apply these techniques to the aging brain with a focus on the DA system. A better understanding of the properties of DA neurons in the aging SNc can aid in identifying circuit targets and/or behavioral/nutritional methods to delay/reverse age-related alterations in these neurons and in motor functions.
