The Role of Transient Corticostriatal Synaptic Plasticity in Extinction from Cocaine

描述(申请人提供)：吸毒成瘾仍然是一个主要的公共卫生问题。上瘾的特点是缺乏对寻求毒品的抑制控制。缓解期，即抑制性控制回归的时期，不时会被活跃成瘾的复发所打断。然而，在行为疗法中学到的技能可以防止复发。研究抑制学习背后的突触可塑性机制可以通过新的治疗方法来增强抑制控制。然而，对药物寻找灭绝背后的突触可塑性的相对有限的理解阻碍了成功的治疗以增强灭绝学习。因此，这项建议概述了一系列实验，以确定瞬时突触增强(t-LTP)在下缘(IL)到伏隔壳(NAShell)环路中的作用，在可卡因的消退中。我们的初步数据显示，在消亡过程中，NAShell中的树突状脊柱头部直径中存在t-LTP，这意味着脊柱头部直径迅速增加(15分钟)，然后在45分钟后正常化。我们假设，电生理学t-LTP在灭绝期间将局限于NAShell，在恢复期间将局限于NAcore。我们进一步假设，IL到NAShell的回路对于消光和相关的t-LTP是必要和充分的。这些假设基于初步数据，将通过两个具体目标进行检验。目的1将利用膜片钳电生理学来确定NAShell和NAcore在消退和恢复过程中AMPA/NMDA比值变化的时间进程。AIM 2将采用DREADD(由设计者药物独占激活的设计者受体)策略来确定IL到NAShell回路在灭绝相关中的作用 T-LTP。除了阐明短暂的皮质纹状体突触可塑性在可卡因戒断中的作用外，该奖学金还将培训申请者操纵神经回路和评估突触增强的现代技术。

DESCRIPTION (provided by applicant): Drug addiction remains a major public health issue. Addiction is characterized by lack of inhibitory control over drug seeking. Periods of remission, in which inhibitory control returns, are punctuated by relapses to active addiction. However, skills learned during behavioral therapies can protect against relapses. Investigation of the synaptic plasticity mechanisms underlying inhibitory learning may enable enhancement of inhibitory control by novel therapies. However, the relatively limited understanding of synaptic plasticity underlying extinction in drug seeking has precluded successful therapies to augment extinction learning. Hence, this proposal outlines a series of experiments that will determine the role of transient synaptic potentiation (t-LTP) in the infralimbic (IL) to accumbens shell (NAshell circuit in extinction from cocaine. Our preliminary data demonstrates t-LTP in dendritic spine head diameter in NAshell during an extinction session, meaning that spine head diameter rapidly (15 min) increases and then normalizes by 45 min. We hypothesize that electrophysiological t-LTP will be confined to NAshell during extinction and to NAcore during reinstatement. We further hypothesize that the IL to NAshell circuit is necessary and sufficient for extinction and associated t-LTP. These hypotheses, based upon preliminary data, will be tested through two specific aims. Aim 1 will employ patch clamp electrophysiology to determine the time course of changes in AMPA:NMDA ratio during extinction and reinstatement in NAshell and NAcore. Aim 2 will employ a DREADD (Designer Receptor Exclusively Activated by Designer Drug) strategy to determine the role of the IL to NAshell circuit in extinction-associated t-LTP. In addition to clarifying the role of transient corticostriatal synaptic plasticity in extintion from cocaine, this fellowship will train the applicant in modern techniques for manipulating neural circuits and assessing synaptic potentiation.