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Midbrain cellular and circuit dynamics of cocaine seeking

可卡因寻找的中脑细胞和电路动力学

基本信息

批准号：
9978022
负责人：
Benjamin Thomas Saunders
金额：
$ 24.9万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978022
关键词：
Acute Affect Anatomy Animals Area Award Behavior Behavioral Brain Brain imaging Calcium Cocaine Corpus striatum structure Coupled Cues Disease Dissociation Dopamine Dorsal Drug Controls Drug Exposure Exhibits Fluorescence Goals Heterogeneity Human Image Implant Locomotion Measures Methods Midbrain structure Modeling Monitor Motivation Mus Neurons Nucleus Accumbens Pattern Pharmaceutical Preparations Phase Photons Physiological Population Probability Process Public Health Rattus Relapse Research Rewards Role Self Administration Substantia nigra structure System Testing Thalamic structure Training Ventral Tegmental Area Viral addiction adverse outcome base behavioral sensitization calcium indicator cell type cocaine exposure cocaine relapse craving designer receptors exclusively activated by designer drugs discrete time dopaminergic neuron experience gamma-Aminobutyric Acid imaging genetics in vivo in vivo calcium imaging in vivo imaging inducible gene expression insight microendoscope neurophysiology novel optogenetics prevent programs receptor response skills stem

项目摘要

Project Summary Addiction is a disorder of major public health concern, characterized by compulsive craving, drug seeking, and a high probability of relapse that is often spurred by the presence of drug-associated cues. Drug-induced changes in midbrain circuits, including the ventral tegmental area (VTA) and substantia nigra (SN), are thought to underlie these behaviors, but the heterogeneous mixture of neuronal subtypes and projections of the midbrain has prevented a clear understanding of the role of specific neurons and circuits in behavior. In previous studies, which utilized optogenetics methods to specifically manipulate midbrain dopamine neurons, I found a functional dissociation in the contribution of neurons projecting to the nucleus accumbens versus dorsal striatum in the motivational effects of conditioned cues, suggesting that reward processes are parcellated across anatomical divisions in the midbrain. Here, I expand on these findings to identify and compare the role of dopamine and GABA neurons in the VTA and SN in cocaine-evoked behaviors and relapse of cocaine seeking evoked by cocaine-associated cues. I will do so using state-of-the-art viral-based methods to visualize and manipulate neuronal activity. In the K99 Aims, I first propose to employ in vivo deep brain imaging to visualize the calcium dynamics of large numbers of dopamine and GABA neurons in the midbrain during cocaine exposure. Next, I propose to use chemogenetic methods, which rely on the insertion of designer receptors into target neurons, to tonically silence the activity of dopamine and GABA neurons to assess their functional role in behavioral sensitization to cocaine. These studies will define the cocaine-induced physiological responses of genetically defined VTA and SN neurons, and their role in cocaine-evoked behavior. Building on the new training and insights into the neurophysiological effects of cocaine I gain during the K99 period, I will utilize in vivo calcium imaging and optogenetics to determine to the activity patterns and temporal role of select midbrain projections in operant cocaine seeking and cue-triggered relapse during the R00 period. First, I will image activity of dopamine and GABA neurons projecting to the striatum or thalamus as animals seek cocaine and respond to cocaine-associated cues. Next, I will harness the temporal precision optogenetics to phasically manipulate these projections at discrete time points to determine their necessity and/or sufficiency for cocaine self-administration and cue-triggered relapse test. The proposed studies will provide a novel and comprehensive characterization of the circuit mechanisms by which midbrain neurons orchestrate cocaine and cocaine-cue related behaviors.

项目概要成瘾是一种引起重大公共卫生问题的疾病，其特征是强迫性渴望、寻求药物、并且复发的可能性很高，这通常是由药物相关线索的存在引起的。药物引起的人们认为中脑回路的变化，包括腹侧被盖区（VTA）和黑质（SN）是这些行为的基础，但神经元亚型和预测的异质混合中脑阻碍了我们对特定神经元和回路在行为中的作用的清晰理解。在之前的研究利用光遗传学方法专门操纵中脑多巴胺神经元，我发现投射到伏隔核的神经元的贡献与背侧纹状体在条件线索的动机效应中的作用，表明奖励过程是分布在中脑的解剖分区中。在这里，我扩展了这些发现，以确定并比较 VTA 和 SN 中多巴胺和 GABA 神经元在可卡因诱发行为中的作用，由可卡因相关线索引起的可卡因寻求复发。我将使用最先进的基于病毒的技术来做到这一点可视化和操纵神经元活动的方法。在 K99 Aims 中，我首先提出采用体内深部脑成像来可视化钙动态接触可卡因期间，中脑中出现大量多巴胺和 GABA 神经元。接下来我建议使用化学遗传学方法，依赖于将设计受体插入目标神经元，以强效沉默多巴胺和 GABA 神经元的活性，以评估它们在行为敏感中的功能作用可卡因。这些研究将定义可卡因诱导的基因定义的 VTA 和 SN 神经元及其在可卡因诱发行为中的作用。基于我在可卡因的神经生理学影响方面获得的新培训和见解 K99期间，我将利用体内钙成像和光遗传学来确定活性模式和选择中脑投射在操作性可卡因寻求和提示触发的复发中的时间作用 R00时期。首先，我将投射到纹状体或丘脑的多巴胺和 GABA 神经元的活动成像为动物寻找可卡因并对可卡因相关的暗示做出反应。接下来，我将利用时间精度光遗传学在离散时间点分阶段操纵这些预测以确定其必要性和/或足以进行可卡因自我给药和提示触发的复发测试。拟议的研究将提供中脑神经元的电路机制的新颖且全面的表征协调可卡因和可卡因提示相关的行为。