PROJECT SUMMARY/ABSTRACT Traumatic brain injury (TBI) impacts millions of Americans each year and can lead to cognitive dysfunction, difficulty with sensory processing, sleep disruption, and the development of epilepsy. One common neural outcome of TBI is the development of electrophysiological abnormalities that can lead to post-traumatic epilepsy (PTE) or disruptions in sleep architecture. However, the mechanisms by which these neurological deficits arise as a consequence of TBI remain poorly understood. Preliminary evidence indicates that inflammation contributes to the electrophysiological abnormalities that underlie PTE and sleep disruption in a mouse model of moderate TBI. Indeed, TBI is characterized by both the activation of glial cells like astrocytes and microglia and by the infiltration of peripheral immune cells like monocyte-derived macrophages and T-cells. While neuroinflammation occurs immediately in the cortical region of acute injury, secondary neuroinflammation develops slowly in the ipsilateral thalamus, presumably as a result of loss of intimate reciprocal connections between cortex and thalamus. Because the cortico-thalamo- cortical (CTC) circuit plays a key role in cognition, sleep, and seizures, which are all impacted by TBI, the delayed neural plasticity in this circuit is a good model for teasing apart the interaction between the immune cells and neural circuits after TBI. The role of peripheral immune cells is particularly understudied in the context of TBI-derived electrophysiological deficits like PTE and sleep disruption. Here we use a controlled-cortical impact mouse model of moderate TBI to determine the role of delayed infiltration of monocyte-derived macrophages and CD4+ T cells in secondary neuronal loss (Aim 1), excitation/inhibition imbalance in the cortico-thalamic circuit (Aim 2), and the development of electrographic abnormalities such as sleep disruption and PTE (Aim 3). To do so, we combine cutting-edge tools from both neuroscience and immunology, including genetic manipulations, flow cytometry, 3D imaging of immune-neural interactions, synaptic physiology in brain slices, and chronic wireless EEG recordings. This study will enable us to understand how the immune system interacts with neural circuits after TBI to cause the development of neurological deficits. During the work proposed in this supplement request, Ms. Chatterjee will be involved in a team project that focuses on the neurobiology of TBI, and will study the role of CD4+ T cells in cognitive, motor and sensory behavioral deficits using a cutting-edge deep learning approach. Ms. Chatterjee will also participate in the Post-Bac Program for Equity and Learning (PROPEL) curriculum activities, on which PI Jeanne Paz serves as a mentor. Through PROPEL, Ms. Chatterjee will participate in career development programs.