Probing Neural Circuit Plasticity in Addiction Relapse

描述（由申请人提供）：成瘾是一种慢性复发性疾病。尽管长期禁欲，成瘾者可能会经历强烈的渴望，以回应药物重新暴露，线索或压力。强烈的渴望是如何重新出现的，神经生物学触发因素是什么？延髓核（NAc）是哺乳动物大脑中成瘾药物的关键靶点。动物模型暗示NAc在持久的脆弱性恢复药物寻求。虽然恢复涉及NAc AMPA型谷氨酸受体（AMPAR）的可塑性，但这种可塑性的身份尚不清楚。结合啮齿类动物复发模型与NAc全细胞记录在离体制剂，我们确定了一个假定的神经基板复发。期间 可卡因戒断（可卡因引发）在体内或体外诱导AMPAR长期抑制（“再暴露LTD”），表明戒断期间响应于环境刺激的NAc AMPAR可塑性是高度动态的。我们假设再暴露LTD为恢复提供了一个突触通道.为了测试这一点，我们将直接测量和操纵NAc AMPAR可塑性药物，线索和压力引发的恢复和孵化模型。此外，“引发在一个菜”给了我们一个易于处理的模型系统，研究分子机制的恢复连接的可塑性。我们推测，在禁欲期间“支撑”NAc AMPAR功能可能是对抗复发的有用工具。这个K02提案的目的是提供一个职业发展和最先进的研究方法培训的机会，以支持我们研究成瘾复发的神经生物学的计划。具体来说，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测神经奖励回路中的通路特异性可塑性，2）小鼠中的“金标准”临床前成瘾复发模型。这些专业知识将直接加强我目前的R01资助的上述研究。此外，这个机会，以跟上新的方法来模拟人类疾病的实验听话的物种和测量和操纵神经回路的可塑性是在我的研究领域的长期成功的关键。

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.