Early Life Adversity and Microglia Priming as Underlying Risk Factors for TBI-Induced Mood Dysregulation
Abstract
Objectives: We will target Idea Development Award Focus Area 1 Understand: Understanding of pre-exposure risk, injury, and biological factors contributing to an individual’s response, recovery, and long-term outcomes following a brain injury and the role of health demographics, previous injuries or repetitive exposures. Our study will focus on the possibility that the pre-trauma risk factor of early life stress exposure may lead the brain to be oversensitive to adult traumatic brain injury (TBI) and thereby induce heightened susceptibility to post-TBI mood disorders. We will use a rodent model to answer these questions, discovering new pathways, molecules, and cells in the brain that may be involved and predict who is most at risk. Significance: One in three individuals that experience a TBI suffer from major depression within 1 year of the injury. Adverse childhood experiences are linked to an increased risk of adverse outcomes, including post-traumatic stress disorder (PTSD), after concussion or TBI in military Service Members. Adverse childhood experiences are linked to a host of negative health outcomes, including mood disorders, and approximately one in six Americans have experienced over four, is a critical threshold that predicts negative health outcomes later in life. And yet we still know very little about how early life adversity/stress exposure is leading to later vulnerability to TBI-related mood-related outcomes, nor is there currently any way to predict which individuals are at risk for TBI-induced mood-related outcomes based on previous stressful life experiences. Here, we will perform rodent preclinical studies focused on the neurobiology through which two hits – early life adversity and adult TBI exposure – impact mood-related outcomes, with a mechanistic focus on early life adversity induced priming of brain-resident immune cells called microglia. Hypothesis: Early life adversity increases risk for mood-related dysfunction after adult TBI via underlying effects on immune cell-neuron interactions in the brain. Study Design: Male and female mice will be exposed to the repeated maternal separation model of early life adversity, which is a model of parental neglect during the equivalent of their childhood (postnatal days 2-21). Animals will be grown to adulthood, and then undergo a single TBI (lateral fluid percussion injury, which is a highly validated, well replicable model of both focal and diffuse brain injury). We will assess if early life adversity increases future susceptibility to TBI-related mood dysfunction using well validated rodent tests for behaviors of relevance to human anxiety and depression, including a loss of pleasure (anhedonia), a loss of active coping with stress (behavioral despair) and increased anxiety-like behavior in an unfamiliar environment. We will test the key role for microglia as necessary cells for early life stress to increase later risk for mood dysfunction after TBI, and assess blood levels of inflammation prior to TBI to discover potential biomarkers of early life stress exposure that could predict TBI-related behavioral outcomes. Impact/Innovation: Understanding pre-exposure risk for TBI-related negative psychological health sequelae will benefit Service Members pre- and post-deployment as well as the American public at large, since over 414,000 military Service Members from 2000-2019 and 1.5 million Americans each year suffer from TBI. One in three of people that suffer a TBI will go on to have a mood disorder, but it is hard to predict who will experience negative psychological outcomes. Our work will be a step toward the goal of prediction, by offering better understanding of how mechanistically early life adversity may act on the brain to become a pre-TBI risk factor.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210840
Entities
People
- Kathryn M Lenz
Organizations
- Ohio State University
- United States Army