Midbrain cellular and circuit dynamics of cocaine seeking

可卡因寻找的中脑细胞和电路动力学

• 批准号: 9757732
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757732
• 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

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.

项目摘要 成瘾是一种主要的公共卫生问题的疾病，其特征是强迫性渴望，寻求毒品， 以及相关线索的存在通常刺激的复发可能性很高。药物引起的 认为中脑电路的变化，包括腹侧对接区域（VTA）和黑质Nigra（SN） 为了这些行为，但神经元亚型和投影的异质混合物 中脑阻止了​​对特定神经元和电路在行为中的作用的清晰了解。在 先前利用光遗传学方法专门操纵中脑多巴胺神经元的研究，I 发现在向伏隔核投射的神经元的贡献中有功能解离 在条件线索的动机作用中，背纹状体表明奖励过程是 在中脑的解剖学划分之间进行了分析。在这里，我扩展了这些发现以识别和 比较多巴胺和GABA神经元在VTA和SN中的作用在可卡因诱发的行为中 可卡因寻求可卡因相关提示引起的可卡因复发。我会使用最先进的基于病毒的 可视化和操纵神经元活性的方法。 在K99的目的中，我首先建议使用体内深脑成像来可视化钙动力学 可卡因暴露期间，中脑中大量的多巴胺和GABA神经元。接下来，我建议 使用化学发生方法，这些方法依靠设计器受体插入靶神经元中，以进行音调 沉默多巴胺和GABA神经元的活性，以评估其在行为敏化中的功能作用 可卡因。这些研究将定义可卡因诱导的基因定义VTA和 SN神经元及其在可卡因诱发的行为中的作用。 基于新的培训和对可卡因的神经生理影响的见解 K99时期，我将利用体内钙成像和光遗传学来确定活动模式和 精选中脑预测在可卡因寻求和提示触发的复发中的时间作用 R00期。首先，我将图像投射到纹状体或丘脑的多巴胺和GABA神经元的活动为 动物寻求可卡因并对可卡因相关的提示做出反应。接下来，我将利用时间精度 光遗传学在离散时间点上对这些预测进行定位操纵以确定其必要性 和/或可卡因自我管理和提示触发复发测试的充分性。拟议的研究将 提供中脑神经元的电路机制的新颖而全面的表征 编排可卡因和可卡因与库克相关的行为。