TMS effects on circuit plasticity and drug seeking in mice.

项目总结/摘要 药物成瘾是美国发病率和死亡率的主要原因。阿片类药物成瘾尤其 成为前所未有的过量死亡的流行病，其中一半是由芬太尼引起的。我们 治疗阿片类药物成瘾的方法非常有限，在寻找有效治疗方法方面的进展 熄火了经颅磁刺激（TMS）正在成为一种潜在的治疗工具; FDA 一项初步研究表明TMS在治疗可卡因成瘾方面的作用。这 该提案将研究TMS在阿片类药物成瘾小鼠模型中使用的参数。通过 磁脉冲，TMS非侵入性激活目标区域的皮质神经元，导致大脑- 大的变化。然而，有几个问题仍然没有答案，包括TMS是否会引起长时间的 目标区域以外下游电路的持续变化，不同TMS参数如何影响 大脑回路，以及TMS是否可以逆转药物引起的变化和中断药物寻求。 这项建议将解决这些问题，使用TMS的嗅球在小鼠模型， 芬太尼自我给药与嗅觉提示配对。假设嗅球的TMS 诱导可塑性变化的下游回路参与学习和奖励，如梨状核 皮质和嗅结节（腹侧纹状体的一部分），因此可用于逆转药物- 诱导这些区域的可塑性，并抑制由嗅觉线索诱导的药物寻求复发。第一 aim将决定TMS对嗅球本身下游嗅球的激活程度 靶和邻近区域，使用c-fos免疫组织化学的共聚焦成像。第二个目的 将定义不同TMS参数对脑切片下游可塑性的影响 电生理学结合光遗传学。第三个目标是开发和验证一种新的小鼠 芬太尼蒸汽自我给药和嗅觉线索诱导的复发模型， TMS模型。第四个目的是研究嗅球经颅磁刺激对芬太尼诱导的大鼠脑皮层神经元损伤的影响。 嗅结节的可塑性和嗅觉线索诱导的对芬太尼寻求的复发。 这份建议书亦旨在协助首席研究员达致推行 一个独立的学术研究项目，专注于在药物治疗中使用神经调节 成瘾职业发展计划包括对必要技能的实践和教学式学习 实现K99目标（1和3）。它还包括广泛的专业发展培训 例如指导、撰写资助、建立网络、呈现科学数据、实验室管理，以及 准备工作面试。NIDA校内研究项目的制度环境， 该项目的主要位置，配备了所有必要的资源。

Project Summary/Abstract Drug addiction is a leading cause of morbidity and mortality in the US. Opioid addiction in particular has become an epidemic with unprecedented overdose fatalities, half of which are caused by fentanyl. Our repertoire to treat opioid addiction is very limited, and the progress in finding effective treatments has stalled. Transcranial Magnetic Stimulation (TMS) is emerging as a potential therapeutic tool; it is FDA approved for depression, and a pilot study suggested a role of TMS in treating cocaine addiction. This proposal will investigate the parameters of TMS use in a mouse model of opioid addiction. Through magnetic pulses, TMS non-invasively activates cortical neurons in the targeted area, resulting in brain- wide changes. However, several questions remain unanswered including whether TMS induces long- lasting changes in downstream circuits beyond the targeted area, how different TMS parameters affect brain circuits, and whether TMS can reverse drug-induced changes and interrupt drug seeking. This proposal will address these questions using TMS of the olfactory bulb in a mouse model of fentanyl self-administration paired with olfactory cues. The hypothesis is that TMS of the olfactory bulb induces plasticity changes in downstream circuits involved in learning and reward such as the piriform cortex and olfactory tubercle (part of the ventral striatum), and therefore can be used to reverse drug- induced plasticity in those areas and inhibit relapse to drug seeking induced by olfactory cues. The first aim will determine the extent of activation by TMS of the olfactory bulb on the bulb itself, downstream targets, and contiguous areas using confocal imaging of c-fos immunohistochemistry. The second aim will define the effects of different TMS parameters on downstream plasticity using brain slice electrophysiology combined with optogenetics. The third aim will develop and validate a novel mouse model of fentanyl vapor self-administration and olfactory-cue-induced relapse that is compatible with the TMS model. The last and fourth aim will study the effects of olfactory bulb TMS on fentanyl-induced plasticity in the olfactory tubercle and olfactory-cue-induced relapse to fentanyl seeking. This proposal is also crafted to help the Principal Investigator achieve his goal in launching an independent academic research program focused on using neuromodulation in the treatment of drug addiction. The career development plan includes hands-on and didactic learning of the skills necessary for accomplishing the K99 Aims (1 and 3). It also includes extensive professional development training such as mentorship, grant writing, networking, presenting scientific data, lab management, and preparing for job interviews. The institutional environment at the intramural research program at NIDA, the project primary location, furnishes all the necessary resources.