Project Summary Intracortical microstimulation (ICMS) of the sensory cortices is an emerging approach to restore sensation to people who have lost it due to neurological injury or disease. ICMS of somatosensory cortex has been used in clinical trials to restore sensation to the hands of people with spinal cord injury and, more recently, was used to restore vision to a person with blindness. The sensations evoked by ICMS are dependent on the stimulated electrode and selected parameters. Differences in perception of ICMS are likely the result of differences in the structure of the recruited circuit. Two inhibitory subtypes, parvalbumin (PV) and somatostatin (SOM), have recently been shown to play important but often opposing roles in sensory circuits. Understanding the neurophysiology of somatosensory cortex and how this affects neural recruitment by ICMS is important for both basic sensory neuroscience and for clinical approaches. With an improved understanding of the underlying neurophysiology and how it is affected by stimulation, we can create better technologies for brain stimulation and improve clinical outcomes. Studying neural mechanisms of ICMS evoked activity is difficult in humans due to limitations in imaging capabilities and current hardware. Mouse models allow for high-resolution imaging of neural activity in the brain and labeling of specific neuronal types through transgenic lines. I will study mechanisms of ICMS in mouse somatosensory cortex using two-photon microscopy in transgenic mice with fluorescent labeling to measure the activation of excitatory, PV, and SOM neurons. This approach will allow me to measure the activation of the underlying neural circuits by ICMS using high-resolution imaging. In the first specific aim, I will investigate how stimulus amplitude and frequency of ICMS together affect the intensity of cortical activation. I expect that at lower amplitudes, responses will be more homogenous due to a decrease in distant and SOM neuron recruitment. In the second specific aim, I will measure the intensity of evoked activity in response to different ICMS frequencies across cortex. I expect that responses will vary across cortex based on the recruitment of PV and SOM neurons. The goals of this proposal align with multiple priorities of the BRAIN initiative, including understanding cell types and their role in health and disease, understanding neural circuits underlying cortical function, applying methods for large scale neural recording, and interrogating the brain with interventional tools. The proposed training and research experience will prepare me to use techniques, including genetic labeling, two-photon microscopy, and combined in vivo animal electrophysiology, that will complement my graduate work in human electrophysiology to develop me into an independent scientist who can study stimulation therapies in the brains of both animals and humans to advance the goals of the BRAIN initiative.