Role of Novel VTA Neurons in Addiction

新型 VTA 神经元在成瘾中的作用

基本信息

批准号：
8720419
负责人：
Thomas Hnasko
金额：
$ 33.96万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720419
关键词：
Adaptive Behaviors Addictive Behavior Amino Acid Neurotransmitters Behavior Behavior Control Behavior Disorders Behavioral Biological Assay Brain Cell Nucleus Cocaine Corpus striatum structure Data Development Discipline Disease Dopamine Drug Addiction Electrophysiology (science)Genetic Globus Pallidus Glutamates Goals Habenula Health Heterogeneity Intervention Knowledge Lateral Learning Mediating Mental disorders Methods Molecular Motivation Mus Neurobiology Neuronal Plasticity Neurons Neurosciences Nucleus Accumbens Physiological Population Process Property Psychological reinforcement Rewards Ribosomal Proteins Role Signal Transduction Slice Specific qualifier value Synapses System Testing Ventral Tegmental Area Viral Viral Vector addiction avoidance behavior classical conditioning defined contribution dopaminergic neuron drug abuse prevention drug of abuse excitatory neuron gamma-Aminobutyric Acid in vivo motivated behavior mouse model neural circuit neuroadaptation neurotransmission novel optogenetics postsynaptic prevent receptor research study response tool

项目摘要

DESCRIPTION (provided by applicant): The ventral tegmental area (VTA) is a core component of the neural circuitry that drives goal-directed behavior and a primary target upon which drugs of abuse manipulate behavior. Although generally regarded as a dopaminergic nucleus, about half of VTA neurons signal through release of the amino acid neurotransmitters GABA or glutamate. Unlike dopamine, these transmitters activate fast ionotropic postsynaptic receptors indicating VTA neurons signal across multiple modes and timescales. Recent evidence suggests important roles for VTA GABA neurons in encoding negative reward value, but little is known regarding the behavioral relevance of the recently identified glutamate neurons in the VTA. However, developmental, anatomical, and electrophysiological evidence suggests overlapping but distinct roles for VTA glutamate and dopamine signaling in the neural circuit processes underlying behavioral reinforcement. The goal of this proposal is to identify how excitatory VTA signaling contributes to the processes underlying behavioral reinforcement and how VTA glutamate neurons functionally integrate into the mesolimbic neural circuits that regulate motivated behavior. We will use mouse genetics, optogenetics, and viral vectors to selectively manipulate discrete excitatory VTA circuits. Behavioral, anatomical, electrophysiological, and molecular assays will then be used to assess VTA glutamate neurons, determine their physiological and behavioral functions, and define the anatomical and molecular factors distinguishing them from neighboring dopamine and GABA-releasing neurons. Together these studies comprise a comprehensive plan to define the form and function of a novel class of VTA neurons while enhancing our understanding of intrinsic VTA heterogeneity. These studies will identify new opportunities and specify new targets for the treatment and prevention of drug addiction and other compulsive behavioral disorders.

描述（由申请人提供）：腹侧对接区域（VTA）是神经电路的核心组成部分，它驱动了目标指导行为，也是滥用滥用行为的主要目标。尽管通常被视为多巴胺能核，但通过释放氨基酸神经递质GABA或谷氨酸的VTA神经元的一半信号。与多巴胺不同，这些发射机激活快速离子智后受体，表明跨多种模式和时间尺度上的VTA神经元信号。最近的证据表明，VTA GABA神经元在编码负奖励价值中的重要作用，但对于VTA中最近确定的谷氨酸神经元的行为相关性知之甚少。然而，发育，解剖学和电生理学证据表明，在行为加强的神经回路过程中，VTA谷氨酸和多巴胺信号传导重叠但不同的作用。该提案的目的是确定兴奋性VTA信号如何有助于行为强化的过程以及VTA谷氨酸神经元如何在功能上将其整合到调节动机行为的中溶胶神经回路中。我们将使用小鼠遗传学，光遗传学和病毒载体来选择性操纵离散的兴奋性VTA电路。然后，将使用行为，解剖学，电生理和分子测定法来评估VTA谷氨酸神经元，确定其生理和行为功能，并定义解剖学和分子因素，以区分它们与邻近的多巴胺和GABA蛋白元的神经元。这些研究共同制定了一个综合计划，以定义新型VTA神经元的形式和功能，同时增强我们对内在VTA异质性的理解。这些研究将确定新的机会，并指定用于治疗和预防药物成瘾和其他强迫行为障碍的新目标。