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.

NARRATIVE Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method for clinical brain stimulation that can treat psychiatric disorders. However, the mechanism by which rTMS modulates activity in cortical circuits is poorly understood. This project will determine how rTMS modulates the activity of excitatory and inhibitory cell types in the brain, paving the way for more effective treatments.