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Determining the function of TRPC6 channels in a subpopulation of VTA dopamine neurons

确定 VTA 多巴胺神经元亚群中 TRPC6 通道的功能

基本信息

批准号：
10676673
负责人：
Mollie Xiaoqi Bernstein
金额：
$ 4.41万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-16 至 2025-08-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676673
关键词：
Action Potentials Adult Agonist Antidepressive Agents Bathing Behavior Borates CRISPR/Cas technology Calcium Calcium Signaling Calcium ion Cells Central Nervous System Control Groups Coupled Decision Making Depressive disorder Dopamine Electrophysiology (science)Exhibits Fluorescence G alpha q Protein Genes Genetic Markers Goals Hypericum perforatum Hypothalamic structure Image Ion Channel KISS1 gene Learning Link Mental Depression Mental disorders Midbrain structure Motivation Mus Mutate Neurons Neuropeptide Receptor Neuropeptides Pathway interactions Physiology Play Population Probability Psychological reinforcement Receptor Signaling Rewards Role Schizophrenia Serotonin Signal Pathway Signal Transduction Slice Stimulus Substance Use Disorder TACR3 gene Testing Therapeutic Transgenic Mice Ventral Tegmental Area cell type channel blockers comparison control discounting dopaminergic neuron experimental group experimental study genetic technology hyperforin in vivo insight loss of function motivated behavior nervous system disorder patch clamp receptor reuptake

项目摘要

Project Summary/Abstract: Midbrain dopamine (DA)-producing neurons of the ventral tegmental area (VTA) play a critical role in modulating reward-seeking behavior. VTA-DA neurons are functionally and genetically heterogeneous, and genetic markers for neuropeptides and neuropeptide receptors can be used to isolate VTA subpopulations. Though distinct neuropeptidergic pathways have been shown to potently modulate DA neurons, the intracellular signaling pathways that act downstream of neuropeptide receptors are unknown. VTA-DA neurons that express the Gq-protein coupled receptor, tachykinin receptor 3 (Tacr3), are a minimally sufficient subpopulation of DA neurons that promote reward reinforcement behavior. Tacr3 activation has recently been shown to be dependent on transient receptor potential canonical (TRPC) channel signaling in the hypothalamus. TRPC type 6 (TRPC6) channels are enriched in DA neurons and are activated by stimulation of Gq-coupled receptor signaling. Therefore, I hypothesize that TRPC6 is likely the main type of TRPC channel in VTA-DA neurons that acts downstream of Tacr3 activation. To establish the role of TRPC6 in regulating the physiology and function of VTA-Tacr3 neurons, I propose to selectively mutate the Trpc6 gene to generate a loss of function in a cell-type specific manner within the VTA of adult mice using an advanced CRISPR/Cas9 genetic technology. I will perform ex vivo slice electrophysiology and slice calcium imaging (Aim 1), as well as in vivo recordings of calcium dynamics during a probabilistic discounting paradigm and progressive ratio motivational task (Aim 2). Determining the function of TRPC6 in VTA-Tacr3 neurons will provide important insights into the therapeutic potential of this understudied ion channel in the central nervous system.

项目总结/文摘: