Role of Novel VTA Neurons in Addiction

描述(申请人提供)：腹侧被盖区(VTA)是驱动目标导向行为的神经回路的核心组成部分，也是滥用药物操纵行为的主要目标。虽然通常被认为是多巴胺能核，但大约一半的VTA神经元通过释放氨基酸神经递质GABA或谷氨酸来传递信号。与多巴胺不同，这些递质激活快速电离子突触后受体，表明VTA神经元在多种模式和时间尺度上发出信号。最近的证据表明，VTA GABA神经元在编码负奖赏价值方面发挥了重要作用，但关于VTA中最近发现的谷氨酸神经元的行为相关性知之甚少。然而，发育、解剖和电生理证据表明，VTA谷氨酸和多巴胺信号在潜在的行为强化的神经回路过程中扮演着重叠但不同的角色。这项提议的目的是确定兴奋性VTA信号如何参与行为强化的潜在过程，以及VTA谷氨酸神经元如何在功能上整合到调节动机行为的中脑边缘神经回路。我们将使用小鼠遗传学、光遗传学和病毒载体来选择性地操纵离散的兴奋性VTA电路。然后，将使用行为、解剖、电生理和分子分析来评估VTA谷氨酸神经元，确定它们的生理和行为功能，并确定它们区别于邻近的多巴胺和GABA释放神经元的解剖学和分子因素。总之，这些研究构成了一个全面的计划，以确定一类新的VTA神经元的形态和功能，同时加强我们对VTA内在异质性的理解。这些研究将为治疗和预防药物成瘾和其他强迫性行为障碍确定新的机会和明确新的目标。

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.