Mechanisms of age-related cognitive impairment in male and female rats after mTBI

Va New Jersey Health Care System, East Orange NJ

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Abstract

? DESCRIPTION (provided by applicant): Over 90% of all traumatic brain injuries (TBI) sustained by military populations are classified as mild TBI or moderate TBI, with the vast majority being mild TBI. Mild or moderate TBI in early life is associated with memory impairments later in life, suggesting that TBI during early adulthood can exacerbate age-related changes that occur later in life. Despite this, the neurobiological mechanisms of memory impairment following TBI are not fully understood, and the long-term effects of mild TBI and moderate TBI on aging are in the very early stages of being characterized. Age-related memory impairments and TBI are associated with similar changes in growth factor signaling and synaptic plasticity, so mild and moderate TBI may exacerbate the normally occurring mechanisms of neurobiological aging. Although sex differences in cognitive and neurobiological aging are known, whether the effects of mild and moderate TBI on aging differs between sexes is unknown. Our long-term goal is to understand the neural mechanisms responsible for cognitive impairment following TBI. The overall objective of this application, which is the next step toward attainment of our long- term goal, is to determine the differential effects of mild versus moderate TBI on growth factor signaling and cognition across the lifespan of male and female rats. Our central hypothesis is that moderate TBI will result in accelerated onset of age-related cognitive impairments compared to mild TBI and that females will be more resistant to these changes. These hypotheses were formulated based on our own published and preliminary data that sex steroid hormones rapidly regulate growth factor signaling in brain regions sensitive to TBI and data demonstrating that even mild TBI results in long-term effects on growth factor signaling in spite of cognitive recovery. Guided by strong preliminary data, our hypotheses will be tested in three specific aims designed to: 1) examine the extent to which age-related changes in cognitive function are exacerbated by mild or moderate TBI and differentially impacted by sex, 2) determine the role of altered growth factor signaling in mediating cognitive impairment following TBI, 3) identify the long-lasting changes in synaptic physiology following mild or moderate TBI. This research is innovative because it represents a fundamental shift from examining one severity of TBI for a short time period in males only, and this research provides a genes to behavior approach. The proposed research is significant because it is the first step in a research program to develop more effective treatments to reduce cognitive dysfunction following TBI. The mechanisms uncovered in the proposed studies will greatly improve the quality of life of millions of Veterans because it will provide sorely needed insights from which novel therapeutic targets will be developed to reduce memory dysfunction in the aging Veteran population. In addition to the scientific objectives, a mentoring program has been developed specifically for Dr. Fortress, taking into account her prior experience. The training program will initially focus on developing expertise in areas that will enhance Dr. Fortress's research studies, such as knowledge of various types of brain injury, molecular assays and manuscript preparation. In subsequent years, Dr. Fortress's training will expand to skills required of independent researchers, including grant writing, grant and manuscript reviews, teaching, mentoring students and committee membership. Together the mentoring program and the proposed scientific study will enhance success in Dr. Fortress's career goals to become a successful independent VA researcher.