J.david Gladstone Institutes

Role of Myeloid and CD4+ T Immune Cells in Post-traumatic Plasticity - 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. We Propose to 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 Will 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. Funding of This Study Will Enable Us to Better Understand How the Immune System Interacts With Neural Circuits After Tbi to Cause the Development of Neurological Deficits. Given That There Are Treatments Already Available in Clinic to Block CD4+ T Cells and Macrophages, This Study Has the Potential to Rapidly Impact How Tbi Is Treated in Human Patients.