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

项目总结 重复经颅磁刺激(RTMS)是一种非侵入性的脑刺激方法，是FDA- 批准用于严重抑郁症和强迫症的治疗。它在治疗方面也显示出了希望 许多其他神经和精神疾病。高频rTMS靶向前额叶皮质 (PFC)，最原始和最广泛使用的范式，被认为通过增强 大脑皮层兴奋性。然而，HF-rTMS治疗后的临床结果是不同的，详细的 作用机制尚不清楚。以前的机械论研究由于缺乏既定的机制而受到限制。 RTMS动物模型具有较强的表面效度。我们实验室已经获得了第一个啮齿动物TMS线圈 对啮齿动物大脑的个别皮质区域产生局部的、阈值以上的刺激。我要用这个线圈 确定在体慢性HF-rTMS如何改变前额叶兴奋性神经元以及哪些投射类型 这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特异性诱导脑内(IT)回路结构可塑性的假设 这些回路的激活是HF-rTMS引起的行为改变的基础。在目标1中，我将确定如何和 慢性HF-rTMS通过兴奋性神经元的稀疏荧光标记诱导突触变化 在PFC中对树突棘密度进行量化。在目标2中，我将使用化学遗传学方法来确定 前额神经元亚类是HF-rTMS行为效应的基础。这项建议解决了一个紧迫的问题 需要了解哪些回路介导了高频rTMS对行为的影响。这项研究将向 合理设计更有效的rTMS治疗方法，精确地针对潜在的特定缺陷 精神障碍的病理生理学。

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.