Targeted chemogenetic stimulation of rat VTA GABA neurons in cocaine extinction and reinstatement

大鼠 VTA GABA 神经元的靶向化学遗传学刺激可卡因消除和恢复

基本信息

批准号：
9386981
负责人：
Caroline Evelyn Bass
金额：
$ 23.93万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9386981
关键词：
Affect Alcohols Behavior Brain Brain region Cells Cocaine Cocaine Dependence Consumption Cues Data Discrimination Extinction (Psychology)Female Future GAD67 enzyme Gene Expression Gene Targeting Genetic Glutamate Decarboxylase Heroin Incentives Infusion procedures Interneurons Laboratories Mediating Modeling Mus Neurons Nucleus Accumbens Optics Outcome Pharmaceutical Preparations Pilot Projects Process Psychological reinforcement Rattus Relapse Rewards Role Self Administration Self-Administered Sex Characteristics Site Stimulus Sucrose Synapses System Therapeutic Intervention Training Transgenic Mice Ventral Tegmental Area Viral Viral Vector Virus adeno-associated viral vector alcohol seeking behavior behavioral response cholinergic classical conditioning combinatorial craving designer receptors exclusively activated by designer drugs dopaminergic neuron drug reward drug seeking behavior experimental study gamma-Aminobutyric Acid innovation learning extinction male motivated behavior novel novel therapeutic intervention optogenetics preference relating to nervous system reward processing targeted treatment transmission process vector

项目摘要

Dopaminergic neurons originating from the ventral tegmental area (VTA) regulate a variety of reward and drug- related behaviors. However, up to 20% of VTA neurons are GABAergic interneurons, and ~5% are GABA projection neurons (GPNs) that send projections to several brain regions involved in drug reward, including the nucleus accumbens (NAc). Recently the role of VTA GABA neurons and GPNs in reinforcement has been explored using transgenic mice that allow for selective manipulation of VTA GABA neurons. However, the role of these GABAergic neurons in drug-related behaviors is much less understood. We propose to use a novel combinatorial adeno-associated viral (AAV) vector system to target gene expression to either VTA GABA neurons or VTAàNAc core GPNs in wildtype rats that have been trained to self-administer cocaine. The targeted GABA neurons will express DREADDs (designer receptors exclusively activated by designer drugs) which will allow us to selectively stimulate these neuronal subtypes during extinction of cocaine self- administration, and reinstatement of cocaine-seeking behavior, a rat model of relapse. We hypothesize that VTA GABA neurons will enhance responding during extinction learning and cocaine- and cue-induced reinstatement by disrupting learned cue-reward associations. Furthermore, we believe that VTAàNAc core GPN activation will selectively enhance cue-induced reinstatement, but have little influence on cocaine-induced reinstatement or extinction. In aim 1 of this proposal, we will determine the role of VTA GABA neurons in extinction learning and reinstatement of cocaine-seeking. We will also undertake a pilot study in female rats to determine if sex differences exist. In aim 2 we will selectively target the VTA GPNs projecting to the NAc core. By contrasting these results of aim 1 and 2, we will determine if the VTAàNAc core GPN effects differ substantially from stimulating all VTA GABA neurons, and whether these specific projections alone may serve as a potential target for therapeutic intervention. These experiments will establish the role of VTA GABA neurons in drug-seeking behaviors, and will provide the necessary groundwork for future exploration into the mechanisms underlying VTA GABA neuron effects on responding to drug cues and the processes underlying relapse.

源自腹侧被盖区（VTA）的多巴胺能神经元调节多种奖赏和药物- 然而，高达 20% 的 VTA 神经元是 GABA 能中间神经元，约 5% 是 GABA 神经元。投射神经元（GPN）将投射发送到涉及药物奖励的几个大脑区域，包括伏核 (NAc)。最近，VTA GABA 神经元和 GPN 的强化作用是。然而，使用转基因小鼠探索了选择性操纵 VTA GABA 神经元的作用。我们建议使用一种新颖的方法来了解这些 GABA 能神经元在药物相关行为中的作用。组合腺相关病毒 (AAV) 载体系统将基因表达靶向 VTA GABA 野生型大鼠中的神经元或 VTAàNAc 核心 GPN，经过训练可以自行服用可可。目标 GABA 神经元将表达 DREADD（仅由设计药物激活的设计受体）这将使我们能够在可卡因自我灭绝期间选择性地刺激这些神经元亚型管理，并恢复可卡因寻求行为，这是一个复发的老鼠模型。 VTA GABA 神经元将增强消退学习以及可卡因和提示诱导期间的反应。此外，我们认为 VTAàNAc 是通过破坏习得的提示-奖励关联来恢复的。 GPN 激活将选择性地增强提示诱导的恢复，但对可可诱导的恢复影响不大恢复或灭绝。本提案的目标 1，我们将确定 VTA GABA 神经元在灭绝学习和恢复可卡因寻求。我们还将在雌性大鼠中进行一项试点研究确定是否存在性别差异在目标 2 中，我们将选择性地针对投射到 NAc 核心的 VTA GPN。通过对比目标 1 和 2 的结果，我们将确定 VTAàNAc 核心 GPN 效果是否不同基本上来自刺激所有 VTA GABA 神经元，以及这些特定的投射是否可以单独发挥作用作为治疗干预的潜在目标。这些实验将确立 VTA GABA 的作用。神经元在药物寻求行为中的作用，并将为未来的探索提供必要的基础 VTA GABA 神经元对药物信号反应的机制及其背后的过程复发。