Consequences of Brain Injury on Glia-Neuron Dynamics, Neuropathology, and Neuropsychiatric Illness
Abstract
This Focused Program Award proposal is aligned with studying both TBI and Psychological Health. This Focused Program will target Focus Area 1, Understand, to address knowledge gaps in foundational science and etiology of psychological health conditions and TBI. Our team’s preclinical work fits the call of Focus Area 1 to increase understanding of risk, protective and biological factors contributing to an individual’s vulnerability to, response to, and long-term outcomes of…TBI. Critical problem: A critical problem after Traumatic brain injury (TBI) is that over 70% of brain-injured individuals continue to have significant neuropsychiatric and cognitive complications that negatively affect health and life span. TBI is associated with a higher risk for the development of neurodegenerative disorders. Neuroinflammatory processes persist well after the initial TBI and can continue to disrupt brain homeostasis and cause neuropsychiatric complications. Chronic neuroinflammation after TBI is likely mediated by microglia, a specialized tissue macrophage of the brain. The mechanism that drives this dysfunction after TBI is unclear. The overarching goal of this project is to define the contribution of microglia priming to the onset and maintenance of brain and behavioral dysfunction after TBI. Microglia become primed after TBI, which is an increase in readiness to respond to a challenge. This dysregulated response by microglia can negatively impact normal glial/neuron interactions, neurophysiology, and behavior/cognition. Our collective data after TBI in rodents point to microglia-mediated chronic inflammation that disrupts normal glia/neuron interactions, impairs neural connectivity and neurotransmitter balance, and causes deficits in mood, cognition and behavior. These novel and interdisciplinary studies will lead to better understanding of the influence of microglia priming and immune reactivity after TBI on neuronal plasticity (profile, homeostasis, and physiology) and functional recovery (cognitive and behavioral). Central Approach: Four projects will each contribute a unique perspective to the overarching question of how microglia priming contributes to the long-term consequences of TBI. All projects will use rodent models, targeted intervention strategies to test specific hypotheses related to microglia priming and analyses from the transcriptomic, neuroanatomical, and electrophysiological to the behavioral level to comprehensively increase understanding of the mechanism through which TBI influences brain and behavioral outcomes over time. The specific focus of the subprojects will be to understand microglia influences on TBI-related behavioral outcomes in the context of several clinically relevant contexts: Project 1. How do primed microglia and interleukin IL-1 receptor signaling after TBI induce neural pathology and cognitive disruptions? Project 2. How does early life stress-induced microglia priming influence vulnerability to pediatric TBI? Project 3. How do primed microglia influence impulsivity after TBI? Project 4. How do primed microglia interact in the context of sleep disruption stress after TBI? Impact and Relevance to Military Health: The study of microglia priming as a common mechanistic mediator of vulnerability related to TBI is a clinically relevant area of focus. While only a few people suffer from multiple brain injuries, everyone is exposed to adversity, stress, and infections over the course of their life span. Understanding risk for TBI-related negative psychological health sequalae will benefit Service Members pre- and post-deployment as well as the American public at large, since over 414,000 Military Service Members from 2000-19 and 1.5 million Americans each year suffer from TBI. One third of people that suffer a TBI will go on to have an affective disorder, but depression rates are 5x higher, and PTSD rates are 15x higher in the military than in the gen
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311003
Entities
People
- Jonathan Godbout
Organizations
- Ohio State University
- United States Army