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

基本信息

批准号：
10375376
负责人：
Cody Siciliano
金额：
$ 24.9万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375376
关键词：
Abstinence Animals Area Auditory Automobile Driving Aversive Stimulus Behavior Behavior Control Behavioral Brain Calcium Cells Chronic Clinical Clinical Research Cocaine Cocaine Abuse Cocaine Dependence Cocaine Users Cognitive Cognitive deficits Consumption Cues Data Drug Addiction Drug usage Food Future Human Image Intravenous Learning Light Medial Mediating Mentors Microscope Neurons Nucleus Accumbens Opsin Optics Organism Outcome Pathway interactions Patients Pharmaceutical Preparations Phase Population Positioning Attribute Prefrontal Cortex Process Quinine Rattus Regulation Relapse Reversal Learning Rewards Rodent Role Stimulus Sucrose Synapses Syndrome Techniques Technology Testing Therapeutic Time Training United States Food and Drug Administration Update Viral addiction approach avoidance behavior base calcium indicator classical conditioning cocaine exposure cocaine self-administration cocaine use design evidence base experience experimental study flexibility in vivo calcium imaging midbrain central gray substance neuromechanism neuropsychiatric disorder neurotransmission non-drug novel optogenetics pre-clinical preclinical study reinforcer relating to nervous system response

项目摘要

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. These deficits are similar to those seen in patients with damage to prefrontal cortical areas, and imagining studies in cocaine addicts also suggests that cocaine-induced plasticity in medial prefrontal cortex (mPFC) may be involved. 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 preliminary studies in rats 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. The cutting-edge technologies employed in this proposal will allow us to test the novel 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 my transition to an independent academic position, 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。这些缺陷类似于在前额皮质区域受损的患者中观察到，对可卡因成瘾者的想象研究也表明可能涉及可卡因诱导的内侧前额皮质（mPFC）的可塑性。虽然假设关于可卡因引起的认知缺陷的循环基础已经从临床研究中得出，在许多情况下我们缺乏直接的、机械的临床前数据来验证这些假设。在我们对老鼠的初步研究中，我们发现确定了 mPFC 中的两个投影定义的亚群，即投影到伏隔核或那些投射到导水管周围灰色区域的神经元，分别编码积极和消极的刺激。我们假设这些人群与认知灵活性以及可卡因的失调有关。这该提案中提出的实验将通过结合单细胞钙来系统地检验这一假设成像，记录内源性活动，光遗传学，操纵活动，静脉注射可卡因自我行政。该提案中采用的尖端技术将使我们能够检验新的假设 mPFC 中的特定亚群关键参与基本行为控制、认知这些过程中的灵活性和可卡因引起的缺陷。该提案的成功实施将促进我向独立学术职位的过渡，同时增进了我们对电路基础的理解可卡因成瘾。