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Intact Circuit Assessment of Aging Dopamine Neurons vis Optogenetics and CLARITY

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

项目级别

国家级

研究期限

未知 / 未知

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.

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  • 1.Viral Strategies for Targeting the Central and Peripheral Nervous Systems

    • 关键词：
    • RECOMBINANT-ADENOASSOCIATED-VIRUS; DRIVE SELECTIVE EXPRESSION; BLOOD-BRAIN-BARRIER; GENE-THERAPY; NONHUMAN-PRIMATES; TRANSGENE EXPRESSION; RABIES VIRUS; MOUSE-BRAIN; SPINAL-CORD; IN-VIVO
    • Bedbrook, Claire N.;Deverman, Benjamin E.;Gradinaru, Viviana
    • 《ANNUAL REVIEW OF NEUROSCIENCE, VOL 41》
    • 2018年
    • 会议

    Recombinant viruses allow for targeted transgene expression in specific cell populations throughout the nervous system. The adeno-associated virus (AAV) is among the most commonly used viruses for neuroscience research. Recombinant AAVs (rAAVs) are highly versatile and can package most cargo composed of desired genes within the capsid's similar to 5-kb carrying capacity. Numerous regulatory elements and intersectional strategies have been validated in rAAVs to enable cell type-specific expression. rAAVs can be delivered to specific neuronal populations or globally throughout the animal. The AAV capsids have natural cell type or tissue tropism and trafficking that can be modified for increased specificity. Here, we describe recently engineered AAV capsids and associated cargo that have extended the utility of AAVs in targeting molecularly defined neurons throughout the nervous system, which will further facilitate neuronal circuit interrogation and discovery.

    ...

  • 2.Hydrogel-Tissue Chemistry:Principles and Applications

    • 关键词：
    • SINGLE-CELL RESOLUTION; INTACT-TISSUE; 3-DIMENSIONAL VISUALIZATION; MOLECULAR INTERROGATION; LIGHT-MICROSCOPY; BRINGING CLARITY; CLEARING AGENT; WHOLE-BRAIN; MOUSE; PROTEINS
    • Gradinaru, Viviana;Treweek, Jennifer;Overton, Kristin;Deisseroth, Karl
    • 《ANNUAL REVIEW OF BIOPHYSICS, VOL 47》
    • 2018年
    • 会议

    Over the past five years, a rapidly developing experimental approach has enabled high-resolution and high-content information retrieval from intact multicellular animal (metazoan) systems. New chemical and physical forms are created in the hydrogel-tissue chemistry process, and the retention and retrieval of crucial phenotypic information regarding constituent cells and molecules (and their joint interrelationships) are thereby enabled. For example, rich data sets defining both single-cell-resolution gene expression and single-cell-resolution activity during behavior can now be collected while still preserving information on three-dimensional positioning and/or brain-wide wiring of those very same neurons-even within vertebrate brains. This new approach and its variants, as applied to neuroscience, are beginning to illuminate the fundamental cellular and chemical representations of sensation, cognition, and action. More generally, reimagining metazoans as metareactants-or positionally defined three-dimensional graphs of constituent chemicals made available for ongoing functionalization, transformation, and readout-is stimulating innovation across biology and medicine.

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