TMS effects on circuit plasticity and drug seeking in mice.

TMS 对小鼠回路可塑性和药物寻找的影响。

• 批准号: 10754693
• 负责人: KHALED MOUSSAWI
• 金额: $ 8.32万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10754693
• 关键词: Address; Affect; Animal Model; Anterior; Area; Behavior; Brain; Cells; Clinical; Cocaine Dependence; Collaborations; Cue-induced relapse; Cues; Data; Development; Development Plans; Disease; Distant; Drug Addiction; Drug Delivery Systems; Electrophysiology (science); Environment; Epidemic; FDA approved; FOS gene; Fentanyl; Foundations; Frequencies; Genetic Complementation Test; Goals; Grant; Head; Human; Immunohistochemistry; Institution; Interruption; Interview; Intramural Research Program; Knowledge; Learning; Learning Skill; Location; Magnetism; Measures; Mental Depression; Mentorship; Modeling; Modification; Morbidity - disease rate; Motivation; Mus; National Institute of Drug Abuse; Nature; Neurobiology; Neurons; Occupations; Olfactory Pathways; Olfactory tubercle; Opiate Addiction; Opioid; Pathology; Pharmaceutical Preparations; Phase; Physiologic pulse; Physiology; Pilot Projects; Prefrontal Cortex; Principal Investigator; Property; Protocols documentation; Relapse; Research; Resources; Rest; Rewards; Role; Self Administration; Site; Slice; Surface; Synapses; Synaptic plasticity; Techniques; Therapeutic; Training; Transcranial magnetic stimulation; Transgenic Mice; Treatment Protocols; Ventral Striatum; Writing; addiction; association cortex; awake; career development; confocal imaging; drug of abuse; drug seeking behavior; effective therapy; fentanyl seeking; fentanyl self-administration; mortality; mouse model; neuroadaptation; neuronal circuitry; neuropsychiatric disorder; neuroregulation; novel; novel strategies; olfactory bulb; optogenetics; overdose death; piriform cortex; programs; reward processing; tool; vapor

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.

项目摘要/摘要 吸毒成瘾是美国发病率和死亡率的主要原因。阿片类药物成瘾特别是 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。我们的 治疗阿片类药物成瘾的曲目非常有限，寻找有效治疗的进展 停滞不前。经颅磁刺激（TMS）作为潜在的治疗工具出现。是FDA 批准抑郁症，一项试点研究表明，TMS在治疗可卡因成瘾中的作用。这 提案将研究阿片类成瘾的鼠标模型中TMS使用的参数。通过 磁性脉冲，TMS非侵入性激活靶向区域的皮质神经元，导致脑 广泛的变化。但是，几个问题仍未得到答案，包括TMS是否引起了长期 超出目标区域以外的下游电路的持久变化，不同的TMS参数如何影响 脑电路，以及TMS是否可以逆转药物引起的变化和寻求药物的中断。 该建议将使用鼠标模型中的嗅球的TMS来解决这些问题 芬太尼自我管理与嗅觉提示配对。假设是嗅球的TMS 引起学习和奖励涉及的下游电路的可塑性变化，例如梨形 皮质和嗅觉结节（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，并抑制嗅觉提示引起的寻求药物的复发。第一个 AIM将确定TMS在灯泡本身上的TMS的激活程度，下游 使用C-FOS免疫组织化学的共聚焦成像的靶标和连续区域。第二个目标 将使用大脑切片来定义不同TMS参数对下游可塑性的影响 电生理结合光遗传学。第三个目标将发展并验证新型鼠标 芬太尼蒸气自动给药和嗅觉诱导的复发的模型，与与之兼容的复发模型 TMS模型。最后和第四个目标将研究嗅球TMS对芬太尼诱导的影响 嗅觉结节的可塑性和嗅觉 - 诱导的芬太尼寻求的复发。 该建议还旨在帮助首席调查员实现他的目标 独立的学术研究计划的重点是使用神经调节治疗药物 瘾。职业发展计划包括对必要技能的实践和教学学习 用于完成K99目标（1和3）。它还包括广泛的专业发展培训 例如指导，赠款写作，网络，介绍科学数据，实验室管理和 准备工作面试。 NIDA壁内研究计划的机构环境， 项目主要位置提供了所有必要的资源。

项目成果

Excitation of medium spiny neurons by 'inhibitory' ultrapotent chemogenetics via shifts in chloride reversal potential.

• DOI: 10.7554/elife.64241
• 发表时间: 2021-04-06
• 期刊: eLife
• 影响因子: 7.7
• 作者: Gantz SC;Ortiz MM;Belilos AJ;Moussawi K
• 通讯作者: Moussawi K

A 33-Year-Old Man with Progressive Diffuse and Focal Neuropsychiatric Signs without Localizing Correlates on Brain Imaging: A Systematic Approach to Diagnosis.

• DOI: 10.26502/jppd.2572-519x0113
• 发表时间: 2020
• 期刊: Journal of psychiatry and psychiatric disorders
• 作者: Moussawi K;Gholipour T;Rao V
• 通讯作者: Rao V

Cell type and sex specific insights into ventral striatum deep brain stimulation for cocaine relapse.

细胞类型和性别对腹侧纹状体深部脑刺激可卡因复发的具体见解。

• DOI: 10.1038/s41386-022-01513-z
• 发表时间: 2023
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Lehmann,CollinM;Moussawi,Khaled
• 通讯作者: Moussawi,Khaled