Defining the role of cortical circuit dynamics in learning and addiction

项目摘要/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 使积极的结果最大化，同时最大限度地减少不利的结果的过程。此过程对以下各项至关重要 生存及其调节失调是包括成瘾在内的许多神经精神障碍的标志。为 例如，可卡因成瘾者学习新联想的能力较慢，尽管如此，他们也会做出有风险的选择 环境线索表明有更有利的选择可用。这些赤字与那些 在前额叶皮质受损的患者中可见，对可卡因成瘾者的想象研究也表明 可卡因诱导的内侧前额叶皮质(MPFC)可塑性可能与此有关。而关于这个问题的假设 可卡因引起的认知障碍的电路基础已经从临床研究中产生，在许多情况下，我们 缺乏直接的、机械性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，我们有 确定了mPFC中两个投射定义的亚群，即投射到伏隔核或 投射到导水管周围灰质区域的神经元，不同地编码积极和消极的刺激。我们 假设这些人群参与了认知灵活性，并通过可卡因对其进行了失调。这个 这项提案中提出的实验将通过结合单细胞钙离子来系统地检验这一假说 成像，记录内源性活动，光遗传学，操纵活动，静脉注射可卡因自身 行政管理。这项提议中使用的尖端技术将使我们能够检验这一新的假设 MPFC中的特定亚群关键地参与了基本的行为控制、认知 灵活性，以及可卡因在这些过程中引起的缺陷。这项提议的成功结果将有助于 我过渡到一个独立的学术职位，同时促进了我们对电路基础的理解 可卡因成瘾。

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.