TMS effects on circuit plasticity and drug seeking in mice.

项目摘要/摘要 在美国，吸毒成瘾是导致发病率和死亡率的主要原因。尤其是阿片成瘾 成为一种史无前例的过量死亡的流行病，其中一半是由芬太尼引起的。我们的 治疗阿片成瘾的曲目非常有限，在寻找有效治疗方法方面取得了进展 停滞不前。经颅磁刺激(TMS)正在成为一种潜在的治疗工具；它是FDA 被批准用于抑郁症，一项初步研究表明，TMS在治疗可卡因成瘾方面发挥了作用。这 该提案将在阿片成瘾小鼠模型中调查TMS的使用参数。穿过 磁脉冲，TMS非侵入性地激活目标区域的皮质神经元，导致大脑- 变化很大。然而，有几个问题仍然没有得到回答，包括TMS是否会导致长时间的 目标区域以外的下游电路的持续变化，不同的TMS参数如何影响 大脑回路，以及TMS是否可以逆转药物诱导的变化和中断药物寻找。 这项建议将使用小鼠模型中的嗅球TMS来解决这些问题 芬太尼自主给药配合嗅觉提示。假设是嗅球的TMS 在参与学习和奖励的下游回路(如梨状核)中诱导可塑性变化 皮质和嗅结节(腹侧纹状体的一部分)，因此可以用来逆转药物- 诱导这些区域的可塑性，并抑制对嗅觉线索诱导的药物寻找的复发。第一 AIM将确定TMS对下游嗅球本身的激活程度 靶区及邻近区域采用共聚焦成像的c-fos免疫组织化学方法。第二个目标 将使用脑切片来确定不同TMS参数对下游可塑性的影响 电生理学与光遗传学相结合。第三个目标是开发和验证一种新型鼠标 芬太尼蒸气自身给药与嗅觉线索诱导复吸模型的兼容 TMS型号。第四个目标是研究嗅球TMS对芬太尼诱导的影响。 嗅结节的可塑性和嗅觉线索诱导的芬太尼寻求复发。 这项建议也是为了帮助首席调查员实现他的目标，推出一个 专注于在药物治疗中使用神经调节的独立学术研究计划 上瘾。职业发展计划包括亲身实践和讲授必要的技能 实现K99目标(1和3)。它还包括广泛的职业发展培训。 例如指导、拨款撰写、联网、展示科学数据、实验室管理以及 为求职面试做准备。NIDA内部研究项目的机构环境， 项目的主要位置，提供了所有必要的资源。

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.