Neural systems mediating the extinction and inhibition of cocaine seeking

再次使用可卡因仍然是治疗可卡因成瘾的一个重大挑战，但我们的 对那些使个人能够抑制寻求可卡因和复发的神经系统的理解 可怜。我们实验室的长期目标是识别神经回路和这些回路中的变化 使用可卡因寻找的大鼠模型，抑制可卡因寻找行为的基础。目前的提案 建立在我们最近几年获得的发现以及我们在 我们的实验室。在我们的研究中，大鼠经历了可卡因自我管理、灭绝训练和恢复 测试他们寻找可卡因的情况。我们发现，下缘皮质是大脑皮质的中枢组成部分。 涉及消灭和抑制可卡因寻觅行为的系统。下缘皮质的活动是 对于消光学习和消光表达的正常编码是必要的。例如, 边缘下层激活抑制消退训练后的可卡因寻找。然而，其中更大的电路 下缘皮质执行这些功能尚不清楚。特别是，正如证据表明的那样， 就其在寻找可卡因方面的作用而言，下缘皮质内的异质性，理解更大 电路可以提供对这些问题的洞察。拟议的工作将集中在具体的路径上 伸入和伸出下缘，这说明了它在消灭和抑制寻找可卡因方面的作用。 据我们所知，这项工作将包括在寻找可卡因的研究中从未使用过的方法 因此，这将使我们对这些系统的了解取得显著进展。特别是，我们的研究将 使用多点记录可卡因期间的神经活动，试图了解大脑网络是如何 区域协调行为。此外，拟议的研究将使用光遗传学方法来检查 不同的途径如何调节可卡因寻找的消亡和抑制的不同方面。这个 这项工作的发现将揭示与IL相关的特定通路和网络活动 寻求可卡因的灭绝/抑制。此外，拟议的工作将1)审查以下方面的变化 作为可卡因自我管理和灭绝的结果的基于IL的回路，以及2)操纵这些 以确定它们如何在功能上控制对可卡因寻找的抑制。调查结果来自于 研究将为抑制可卡因的神经系统提供关键的新的基础知识 寻求这一点可能会导致更有效的治疗方法的开发，以加强这种系统 在吸食可卡因上瘾的人身上。

Relapse to cocaine use remains a significant challenge in the treatment of cocaine addiction, yet our understanding of those neural systems that enable individuals to inhibit cocaine seeking and relapse remains poor. The long-term goal of our laboratory is to identify the neural circuits and the changes in those circuits that underlie the inhibition of cocaine-seeking behavior, using rat models of cocaine seeking. The current proposal builds upon the findings we have obtained in recent years as well as new approaches we have developed in our laboratory. In our studies, rats undergo cocaine self-administration, extinction training and reinstatement testing of their cocaine seeking. We have found that the infralimbic cortex is a central component of the systems involved in the extinction and inhibition of cocaine-seeking behavior. Activity in the infralimbic cortex is necessary for the normal encoding of the extinction learning as well as extinction expression. For example, infralimbic activation inhibits cocaine seeking following extinction training. However, the larger circuit in which the infralimbic cortex performs these functions remains unclear. In particular, as evidence suggests functional heterogeneity within the infralimbic cortex in terms of its role in cocaine seeking, understanding the larger circuitry may provide insight into these issues. The proposed work will focus on the specific pathways projecting into and out of the infralimbic that account for its role in extinction and inhibition of cocaine seeking. The work will include approaches that have not, to our knowledge, been used in studies of cocaine seeking and, therefore, will enable notable progress in our knowledge of these systems. In particular, our studies will use multi-site recordings of neural activity during cocaine seeking to understand how a network of brain regions coordinates behavior. Moreover, the proposed studies will use optogenetic approaches to examine how different pathways mediate different aspects of the extinction and inhibition of cocaine seeking. The findings from this work will reveal those specific pathways and network activity related to the IL with regard to the extinction/inhibition of cocaine seeking. Furthermore, the proposed work will both 1) examine changes in IL-based circuits as a consequence of cocaine self-administration and extinction and 2) manipulate these circuits to determine how they functionally control the inhibition of cocaine seeking. The findings from the studies will furnish critical new basic knowledge of the neural systems underlying the suppression of cocaine seeking that will potentially lead to the development of more effective treatments that strengthen such systems in cocaine-addicted individuals.