Investigating circuit-specific effects of high-frequency repetitive transcranial magnetic stimulation

研究高频重复经颅磁刺激的电路特异性效应

• 批准号: 10827239
• 负责人: Michael W. Gongwer
• 金额: $ 3.98万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-16 至 2025-09-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10827239
• 关键词: Address; Affect; Anhedonia; Animal Model; Attenuated; Behavior; Behavioral; Behavioral Assay; Brain; Brain region; Chronic; Chronic stress; Clinical; Clinical Treatment; Collaborations; Coping Behavior; Coping Skills; Corpus striatum structure; Dendritic Spines; Disease; Excitatory Synapse; FDA approved; Face; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Hippocampus; Human; Individual; Label; Left; Long-Term Potentiation; Major Depressive Disorder; Measurement; Mediating; Mental Depression; Mental disorders; Methods; Midbrain structure; Miniaturization; Motor; Mus; Neocortex; Neurons; Neurosciences; Obsessive-Compulsive Disorder; Outcome; Patients; Pilot Projects; Play; Prefrontal Cortex; Protocols documentation; Pyramidal Tracts; Research; Rewards; Risk Factors; Rodent; Rodent Model; Role; Site; Stress; Synapses; Synaptic plasticity; System; Testing; Thalamic structure; Therapeutic Effect; Treatment Protocols; United States National Institutes of Health; Vertebral column; Work; behavioral outcome; clinical effect; coping; density; design; effective intervention; excitatory neuron; experience; forced swim test; genetic approach; genetic manipulation; improved; improved outcome; in vivo; insight; maladaptive behavior; neocortical; nervous system disorder; neuropsychiatric disorder; novel; rational design; repetitive transcranial magnetic stimulation; stress reduction; tool; virus genetics

PROJECT SUMMARY Repetitive transcranial magnetic stimulation (rTMS) is noninvasive method for brain stimulation and is an FDA- approved treatment for major depression and obsessive compulsive disorder. It also shows promise in treating numerous other neurological and psychiatric disorders. High frequency (HF) rTMS targeting prefrontal cortex (PFC), the original and most widely used paradigm, is thought to exert its therapeutic effects by enhancing cortical excitability. However, clinical outcomes following HF-rTMS treatment are variable, and the detailed mechanisms of action are not known. Previous mechanistic studies have been limited by a lack of established animal models of rTMS with strong face validity. Our lab has acquired the first rodent TMS coil capable of generating focal, suprathreshold stimulation of individual cortical regions in the rodent brain. I will use this coil to determine how in vivo chronic HF-rTMS modifies prefrontal excitatory neurons and which projection classes underlie improved behavioral outcomes. By combining rTMS with cutting edge neuroscience tools, I will test the hypothesis that HF-rTMS specifically induces structural plasticity in intratelencephalic (IT) circuits and that activation of these circuits underlies HF-rTMS-induced changes in behavior. In Aim 1, I will determine how and where chronic HF-rTMS induces synaptic changes by using sparse fluorescent labeling of excitatory neurons in PFC to quantify dendritic spine density. In Aim 2, I will use chemogenetic approaches to determine whether subclasses of prefrontal neurons underlie behavioral effects of HF-rTMS. This proposal addresses a pressing need to understand which circuits mediate the effects of HF-rTMS on behavior. This research will inform the rational design of more effective rTMS treatments that precisely target specific deficits underlying the pathophysiology of psychiatric disorders.

项目概要 重复经颅磁刺激 (rTMS) 是一种无创脑刺激方法，是 FDA 批准的一种方法。 批准治疗重度抑郁症和强迫症。它还显示出治疗的希望 许多其他神经和精神疾病。针对前额皮质的高频 (HF) rTMS （PFC）是最初且最广泛使用的范式，被认为是通过增强 皮质兴奋性。然而，HF-rTMS 治疗后的临床结果是可变的，详细的 作用机制尚不清楚。先前的机制研究因缺乏既定的证据而受到限制 rTMS 动物模型具有很强的表面效度。我们的实验室获得了第一个啮齿动物 TMS 线圈，能够 对啮齿动物大脑中的各个皮质区域产生局灶性、阈上刺激。我将使用这个线圈 确定体内慢性 HF-rTMS 如何改变前额叶兴奋性神经元以及哪些投射类别 是改善行为结果的基础。通过将 rTMS 与尖端神经科学工具相结合，我将测试 HF-rTMS 特异性诱导端脑内 (IT) 回路的结构可塑性的假设 这些回路的激活是 HF-rTMS 引起的行为变化的基础。在目标 1 中，我将确定如何以及 慢性 HF-rTMS 通过使用兴奋性神经元的稀疏荧光标记来诱导突触变化 在 PFC 中量化树突棘密度。在目标 2 中，我将使用化学遗传学方法来确定是否 前额叶神经元的亚类是 HF-rTMS 行为效应的基础。该提案解决了一个紧迫的问题 需要了解哪些回路介导 HF-rTMS 对行为的影响。这项研究将告知 合理设计更有效的 rTMS 治疗方法，精确针对潜在的特定缺陷 精神疾病的病理生理学。