Prefrontal circuit mechanisms of repetitive transcranial magnetic stimulation

项目总结 重复经颅磁刺激(RTMS)是FDA批准的一种非侵入性脑刺激方法 治疗重度抑郁症和强迫症，并在标签外用于治疗 神经和精神障碍。临床高频rTMS通常定位于额叶前部。 大脑皮层(PFC)，被认为可以增强大脑皮层的兴奋性。然而，对活动度和临床疗效的影响是 变数很大，详细的作用机制尚不清楚。主要障碍限制调查 对于细胞类型和电路特异性机制的研究，缺乏建立具有较强表面效度的动物模型。我们的 Lab已经获得了第一个啮齿动物TMS线圈，能够产生局灶性、阈值以上的皮层刺激 次区域。我们将使用这个线圈来解决HF-rTMS修改细胞类型的特定机制 活体兴奋性和抑制性前额叶子网络。通过将rTMS与尖端神经科学工具相结合， 我们将检验这一假说，即HF-rTMS通过快速抑制大脑前额叶的活动来增强前额叶兴奋性。 抑制神经元导致随后主神经元活动的增强。在目标1中，我们将使用光纤 用光度法记录兴奋性(Emx1+)和抑制性(Pv+)前额叶网络产生的钙信号 临床HF-rTMS分娩前、中、后。在目标2中，我们将结合这些细胞类型的特定记录 通过对远程皮质输入的光遗传刺激来确定HF-rTMS如何改变神经活动 兴奋性与抑制性大脑皮层网络的突触诱发活性。这项建议解决了一个紧迫的问题 需要了解调节rTMS对大脑皮层影响的细胞类型和电路特定的机制 功能。我们的研究可以为合理设计更有效的rTMS治疗提供参考，这些治疗方法可以精确地针对 精神障碍的病理生理学基础的特定缺陷。这些基础性研究将支持 未来的项目旨在确定慢性rTMS如何逆转啮齿动物应激的病理回路变化 模特们。

PROJECT SUMMARY Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method FDA-approved to treat major depression and obsessive compulsive disorder, and also used off-label for treating numerous neurological and psychiatric disorders. Clinical high frequency (HF) rTMS is typically targeted to the prefrontal cortex (PFC) and is thought to enhance cortical excitability. However, effects on activity and clinical efficacy are highly variable and the detailed mechanisms of action are not known. The primary obstacle limiting investigation of cell-type and circuit-specific mechanisms is lack of established animal models with strong face validity. Our lab has acquired the first rodent TMS coil capable of generating focal, suprathreshold stimulation of a cortical subregion. We will use this coil to address the cell-type specific mechanisms by which HF-rTMS modifies excitatory and inhibitory prefrontal subnetworks in vivo. By combining rTMS with cutting edge neuroscience tools, we will test the hypothesis that HF-rTMS enhances prefrontal excitability by rapidly suppressing activity in inhibitory neurons leading to subsequent enhancement of principal neuron activity. In Aim 1, we will use fiber photometry to record calcium signals arising from excitatory (Emx1+) and inhibitory (PV+) prefrontal networks before, during and after delivery of clinical HF-rTMS. In Aim 2, we will combine these cell-type specific recordings of neural activity with optogenetic stimulation of long-range cortical inputs to determine how HF-rTMS modifies synaptically-evoked activity in excitatory vs. inhibitory cortical networks. This proposal addresses a pressing need to understand the cell-type and circuit specific mechanisms that mediate the effects of rTMS on cortical function. Our research can inform the rational design of more effective rTMS treatments that precisely target specific deficits underlying the pathophysiology of psychiatric disorders. These foundational studies will support future projects aimed at determining how chronic rTMS can reverse pathological circuit changes in rodent stress models.