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Prefrontal circuit mechanisms of repetitive transcranial magnetic stimulation

重复经颅磁刺激的前额电路机制

基本信息

批准号：
10649292
负责人：
Scott Allen Wilke
金额：
$ 23.4万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649292
关键词：
Action Potentials Acute Address Affect Animal Model Brain Brain region Calcium Signaling Cells Chemosensitization Chronic Clinical Collaborations Disinhibition Electromagnetics Equilibrium Excitatory Synapse FDA approved Face Fiber Frequencies Functional disorder Future Head Hour Human Interneurons Investigation Long-Term Potentiation Major Depressive Disorder Measures Mediating Mental disorders Methods Modeling Motor Mus National Institute of Mental Health Neurons Neurosciences Obsessive-Compulsive Disorder Pathologic Photometry Physiologic pulse Prefrontal Cortex Protocols documentation Research Rodent Stress Synapses Synaptic plasticity System Techniques Testing Thalamic structure Therapeutic Therapeutic Effect Time Treatment Protocols United States National Institutes of Health awake cell cortex cell type clinical effect clinical efficacy design effective intervention effective therapy excitatory neuron experimental study in vivo inhibitory neuron nervous system disorder neural neurotransmission noninvasive brain stimulation novel off-label use optogenetics permissiveness rational design redshift repetitive transcranial magnetic stimulation response targeted delivery therapeutic target tool

项目摘要

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.

项目概要重复经颅磁刺激（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，也用于治疗多种神经和精神疾病。临床高频 (HF) rTMS 通常针对前额叶皮质（PFC），被认为可以增强皮质兴奋性。然而，对活性和临床疗效的影响是变化很大，详细的作用机制尚不清楚。主要障碍物限制调查细胞类型和电路特异性机制的研究缺乏具有强大表面有效性的已建立的动物模型。我们的实验室已获得第一个啮齿动物 TMS 线圈，能够对皮质产生局灶性超阈值刺激次区域。我们将使用该线圈来解决 HF-rTMS 修改的细胞类型特定机制体内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，我们将检验以下假设：HF-rTMS 通过快速抑制前额叶的活动来增强前额叶的兴奋性。抑制性神经元导致主要神经元活动的随后增强。在目标 1 中，我们将使用纤维光度测定法记录兴奋性 (Emx1+) 和抑制性 (PV+) 前额叶网络产生的钙信号临床 HF-rTMS 交付之前、期间和之后。在目标 2 中，我们将结合这些细胞类型特定的记录通过长程皮质输入的光遗传学刺激来分析神经活动，以确定 HF-rTMS 如何修改兴奋性与抑制性皮质网络中的突触诱发活动。该提案解决了一个紧迫的问题需要了解介导 rTMS 对皮质影响的细胞类型和电路特定机制功能。我们的研究可以为合理设计更有效的 rTMS 治疗提供信息，这些治疗精确靶向精神疾病病理生理学基础上的特定缺陷。这些基础研究将支持未来的项目旨在确定慢性经颅磁刺激如何逆转啮齿动物应激的病理回路变化模型。