Defining the role of cortical circuit dynamics in learning and addiction

项目总结/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， 一个过程，允许最大限度地提高积极的，而最小化令人厌恶的结果。这一过程对于 存活率及其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的联系的能力很慢，而且尽管如此，也会做出危险的选择。 环境线索表明更有利的选择是可用的。这些赤字与那些 在前额叶皮质区受损的患者中可见，对可卡因成瘾者的想象研究也表明， 可卡因诱发的内侧前额叶皮层可塑性可能与此有关。虽然假设， 可卡因引起的认知缺陷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、机制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， 在mPFC中确定了两个投射定义的亚群，即投射到丘脑核的细胞， 那些投射到导水管周围灰质区域的神经元，它们分别编码正性和负性刺激。我们 假设这些人群参与了认知灵活性，以及可卡因对其的失调。的 本提案中提出的实验将系统地检验这一假设， 成像，以记录内源性活动，和光遗传学，以操纵活动，与静脉注射可卡因自我- 局这项提案中采用的尖端技术将使我们能够测试新的假设 mPFC中的特定亚群与基本的行为控制、认知控制、 灵活性和可卡因引起的这些过程中的缺陷。这一建议的成功结果将有助于 我过渡到一个独立的学术立场，同时推进我们的电路基础的理解， 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.