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。

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要吸毒成瘾是美国发病和死亡的主要原因。阿片类药物成瘾尤其严重成为一种流行病，造成前所未有的服药过量死亡，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药物非常有限，并且在寻找有效治疗方法方面取得了进展停滞了。经颅磁刺激 (TMS) 正在成为一种潜在的治疗工具；这是FDA 批准用于治疗抑郁症，一项初步研究表明 TMS 在治疗可卡因成瘾方面发挥着作用。这该提案将研究 TMS 在阿片类药物成瘾小鼠模型中的使用参数。通过磁脉冲，TMS 非侵入性地激活目标区域的皮质神经元，从而导致大脑广泛的变化。然而，仍有几个问题尚未得到解答，包括 TMS 是否会导致长期目标区域之外下游电路的持续变化，不同 TMS 参数的影响脑回路，以及 TMS 是否可以逆转药物引起的变化并中断药物寻求。该提案将使用小鼠模型中嗅球的 TMS 来解决这些问题芬太尼自我给药与嗅觉提示相结合。假设嗅球的 TMS 引起涉及学习和奖励的下游回路（例如梨状体）的可塑性变化皮层和嗅结节（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，并抑制嗅觉线索引起的药物寻找复发。第一个目的将确定嗅球下游 TMS 的激活程度使用 c-fos 免疫组织化学共聚焦成像来确定目标和连续区域。第二个目标将使用脑切片定义不同 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新型鼠标芬太尼蒸气自我给药和嗅觉提示诱导的复发模型与 TMS 模型。最后一个和第四个目标将研究嗅球TMS对芬太尼诱导的影响嗅结节的可塑性和嗅觉提示诱导的芬太尼寻求复发。该提案也是为了帮助首席研究员实现他的目标而制定的专注于使用神经调节治疗药物的独立学术研究项目瘾。职业发展计划包括必要技能的实践和教学学习实现 K99 目标（1 和 3）。它还包括广泛的专业发展培训例如指导、资助写作、网络、展示科学数据、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，该项目的主要地点，提供所有必要的资源。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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
影响因子：
0
作者：
Lehmann,CollinM;Moussawi,Khaled
通讯作者：
Moussawi,Khaled