Zachary M. Weil, Ph.D. - US grants

Project Summary Children who suffer traumatic brain injuries (TBI) early in life are more likely to suffer from myriad health concerns including neurological and psychiatric ailments, and substance use disorders, including alcohol abuse, as adults. Clinical studies reveal associations between alcohol abuse and TBI onset at a young age, suggesting long- term effects of TBI on developing neural reward pathways. We present both experimental and clinical preliminary data that have uncovered a sexual dimorphism in posttraumatic alcohol abuse. A clinical analysis of TBI patients revealed a striking sex difference in TBI-related alcohol abuse, such that women who suffered a TBI during adolescent development increased drinking behavior relative to women injured at all other ages. Similar increases in drinking behavior were not apparent in males. Moreover, using a mouse model of childhood TBI, our preliminary data indicate that childhood (21 days old) but not adult (60 days old) TBI greatly increases alcohol consumption and conditioned place preference responses, but only in female mice. This leads us to ask whether differences in sex hormone exposure accounts for sex differences in alcohol abuse rates among TBI patients. Indeed, experimental and clinical studies have reported that sex differences in alcohol drinking emerge at puberty, implicating sex steroid hormones as mediators of this phenomenon. The immediate goal of this application is to understand how sex steroid hormones control sex differences in post-traumatic drinking behavior. Our overall goal is to identify which hormones (ovarian vs. testicular steroids) and when during development they act to mediate sex differences in posttraumatic alcohol consumption. Understanding these mechanisms should prove important for refining treatment and rehabilitation to better target the needs of TBI patients of both sexes and open a large avenue of investigation into the mechanisms of steroid control over alcohol reward systems. The hypothesis of this application is that early organizational exposure to androgens and their estrogenic metabolites organizes the male brain and reduces both basal and post-traumatic drinking behavior. We further predict that exposing females to androgenic hormones early in life will reduce their basal and post-traumatic drinking behavior while early hormone deprivation will increase these parameters in males.

Project Summary Traumatic brain injury (TBI) has recently been identified as an independent risk factor for ischemic and hemorrhagic stroke. A history of TBI confers enhanced risk of stroke incidence at a rate similar to other traditional stroke risk factors including smoking and hypertension. In addition, TBI survivors who subsequently have a stroke have increased likelihood of mortality, suggesting that TBI renders brain tissue more vulnerable to ischemic damage. Here we present data generated in mice demonstrating that mild closed head traumatic brain injuries transiently, but significantly, limit central glucose utilization, impair insulin receptor sensitivity and reduce mitochondrial energy production. Furthermore, when ischemic stroke (induced via middle cerebral artery occlusion) occurs one week after TBI, the inflammatory responses, infarct size and functional deficits are all markedly worse than in mice without a history of TBI. Treating metabolic dysfunction pharmacologically attenuated TBI-induced exacerbation of ischemic outcome. The overarching hypothesis of this application is that TBI-induced metabolic dysfunction renders the brain less able to utilize metabolic fuels, and in turn more vulnerable to ischemic damage. The three specific aims will (1) compare the effects of TBI history on stroke-induced CNS inflammation, metabolic physiology, and neuronal death in male and female mice and determine the time course of vulnerability after injury (2) determine whether normalizing insulin signaling during the first several days after prevents the exacerbation of stroke damage and improves mitochondrial respiration and (3) take steps to gain independent funding. Together, these studies will raise awareness of the elevated stroke risk among TBI patients, and by determining the underlying physiological mechanism may offer new directions for TBI treatment that will minimize stroke risk and improve outcomes for individuals who have suffered a TBI.