Probing Neural Circuit Plasticity in Addiction Relapse

描述(申请人提供)：上瘾是一种慢性复吸障碍。尽管长期戒毒，吸毒者在再次接触毒品、线索或压力时可能会经历强烈的渴望。强烈的渴望是如何重新出现的？神经生物学的触发因素是什么？伏隔核(NAC)是哺乳动物大脑中成瘾药物的关键靶点。动物模型表明，NAC在恢复毒品寻求方面具有持久的脆弱性。虽然修复涉及NAc-AMPA型谷氨酸受体(AMPAs)的可塑性，但这种可塑性的身份尚不清楚。结合啮齿动物复原模型和体外制备的NAC全细胞记录，我们确定了复发的可能神经底物。在.期间 可卡因戒断，一种可卡因原料药，在体内或体外诱导AMPAR长期抑制(“再暴露有限公司”)，表明在戒断过程中NAC AMPAR对环境刺激的可塑性是高度动态的。我们假设，Re-Exposure Ltd为恢复提供了一个突触通道。为了测试这一点，我们将在药物、线索和压力启动的恢复和孵化模型中直接测量和操纵NAC AMPAR的可塑性。此外，“盘中启动”为我们提供了一个易于处理的模型系统来研究恢复连锁可塑性的分子机制。我们推测，在禁欲期间“支持”NAC AMPAR功能可能是对抗复发的有用工具。这项K02提案的目的是为职业发展和最先进的研究方法培训提供机会，以支持我们研究成瘾复发的神经生物学的计划。具体地说，我计划在两个领域发展专业知识：1)使用光遗传学作为一种手段来探索神经奖赏回路中特定路径的可塑性；2)“黄金标准”的小鼠临床前成瘾复发模型。这些专业知识将直接加强我目前上述由R01资助的研究。此外，在实验上容易驯服的物种中建立人类疾病模型的新方法，以及测量和操作神经回路可塑性的机会，对于我的研究领域的长期成功至关重要。

DESCRIPTION (provided by applicant): Addiction is a chronic relapsing disorder. Despite extended abstinence, addicts may experience intense craving in response to drug re-exposure, cues or stress. How do strong cravings re-emerge and what are the neurobiological triggers? Nucleus accumbens (NAc) is a key target of addictive drugs in the mammalian brain. Animal models implicate NAc in enduring vulnerability to reinstatement of drug seeking. Although reinstatement involves plasticity in NAc AMPA-type glutamate receptors (AMPARs), the identity of this plasticity is unclear. Combining rodent reinstatement models with NAc whole-cell recordings in an ex vivo preparation, we identified a putative neural substrate for relapse. During cocaine abstinence, a cocaine prime, in vivo or in vitro, induces AMPAR long-term depression ("re-exposure LTD"), indicating that NAc AMPAR plasticity in response to environmental stimuli during abstinence is highly dynamic. We hypothesize that re- exposure LTD provides a synaptic gateway for reinstatement. To test this, we will directly measure and manipulate NAc AMPAR plasticity in drug-, cue- and stress-primed reinstatement and incubation models. In addition, "priming in a dish" gives us a tractable model system to study molecular mechanisms of reinstatement-linked plasticity. We hypothesize that "propping up" NAc AMPAR function during abstinence may be a useful tool in combating relapse. The aim of this K02 proposal is to provide an opportunity for career development and training in state-of-the-art research methods to support our program studying the neurobiology of addiction relapse. Specifically, I plan to develop expertise in two areas: 1) the use of optogenetics as a means to probe pathway-specific plasticity in neural reward circuits and 2) "gold standard" preclinical addiction relapse models in mice. This expertise will directly enhance my current R01-funded research described above. Furthermore, this opportunity to stay abreast of new approaches for modeling human diseases in experimentally tractable species and for measuring and manipulating neural circuit plasticity is critical for long-term success in my research field.