Defining the role of cortical circuit dynamics in learning and addiction

定义皮质回路动力学在学习和成瘾中的作用

• 批准号: 10403730
• 负责人: Cody Siciliano
• 金额: $ 1.66万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403730
• 关键词: Abstinence; Area; Automobile Driving; Award; Behavior; Behavior Control; Behavioral; Brain; Calcium; Cells; Chronic; Clinical Research; Cocaine; Cocaine Abuse; Cocaine Dependence; Cognitive; Cognitive deficits; Cues; Data; Development; Image; Intravenous; Learning; Medial; Mediating; Neurons; Nucleus Accumbens; Outcome; Phase; Population; Prefrontal Cortex; Process; Rattus; Relapse; Research; Role; Stimulus; Syndrome; Testing; Therapeutic; United States Food and Drug Administration; Update; addiction; behavioral response; cocaine self-administration; cocaine use; design; evidence base; experimental study; flexibility; midbrain central gray substance; neuromechanism; neuropsychiatric disorder; optogenetics; pre-clinical; programs; relating to nervous system; response

Project Summary/Abstract The ability to update strategies as contingencies change, or cognitive flexibility, is a fundamental behavioral process that allows for maximizing positive, while minimizing aversive, outcomes. This process is critical for survival, and its dysregulation is a hallmark of a number neuropsychiatric disorders including addiction. For example, cocaine addicts have a slowed ability to learn new associations, and also make risky choices despite environmental cues indicating that more advantageous choices are available. In the K99 phase of this award, we defined the role of multiple projection-defined populations in the medial prefrontal cortex (mPFC) in mediating responses to natural stimuli with positive and negative value. By both observing and manipulating the activity of these neuronal populations we showed that these populations are integrally involved in producing adaptive behavioral responses. In the current R00 phase of this proposal, we aim to combine cutting-edge approaches to observing and manipulating neural activity with intravenous cocaine self-administration in rats to determine how fundamental behavioral processes are altered by excessive cocaine use. While hypotheses as to the circuit basis of cocaine-induced cognitive deficits have been generated from clinical studies, in many cases we lack direct, mechanistic preclinical data verifying these hypotheses. In our previous studies we have identified two projection- defined subpopulations in the mPFC, cells that project to the nucleus accumbens or those that project to the periaqueductal gray area, which divergently encode positive and negative stimuli. We hypothesize that these populations are involved in cognitive flexibility, and its dysregulation by cocaine. The experiments put forth in this proposal will systematically test this hypothesis by combining single-cell calcium imaging, to record endogenous activity, and optogenetics, to manipulate activity, with intravenous cocaine self-administration. We test the hypothesis that specific subpopulations in the mPFC are critically involved in fundamental behavioral control, cognitive flexibility, and cocaine-induced deficits in these processes. A successful outcome of this proposal will facilitate the development of my new independent research program, while advancing our understanding of the circuit basis of cocaine addiction.

项目概要/摘要 随着突发事件的变化而更新策略的能力或认知灵活性是一种基本的行为能力 允许最大化积极结果，同时最小化厌恶结果的过程。这个过程对于 生存及其失调是包括成瘾在内的许多神经精神疾病的标志。为了 例如，可卡因成瘾者学习新联想的能力较慢，尽管如此，他们也会做出危险的选择 环境线索表明存在更有利的选择。在本次颁奖的K99阶段， 我们定义了内侧前额叶皮层（mPFC）中多个投影定义的群体在调解中的作用 对自然刺激的反应具有积极和消极的价值。通过观察和操纵 我们证明这些神经元群体整体参与产生适应性 行为反应。在该提案当前的 R00 阶段，我们的目标是将尖端方法结合起来 观察和操纵大鼠静脉注射可卡因自我给药的神经活动，以确定如何 过度使用可卡因会改变基本行为过程。虽然关于电路基础的假设 可卡因引起的认知缺陷是从临床研究中产生的，在许多情况下我们缺乏直接的、 机械临床前数据验证了这些假设。在我们之前的研究中，我们已经确定了两种预测 - mPFC 中定义的亚群、投射到伏隔核的细胞或投射到伏隔核的细胞 导水管周围灰色区域，分别编码正面和负面刺激。我们假设这些 人群的认知灵活性及其因可卡因而失调。中提出的实验 该提案将通过结合单细胞钙成像来系统地检验这一假设，以记录 内源性活性和光遗传学，通过静脉注射可卡因自我给药来操纵活性。我们 检验 mPFC 中特定亚群与基本行为密切相关的假设 这些过程中的控制、认知灵活性和可卡因引起的缺陷。此次活动取得圆满成功 该提案将促进我新的独立研究计划的发展，同时推进我们的 了解可卡因成瘾的回路基础。