Military veterans continue to suffer from a substantially higher burden of depression, alcohol abuse, and suicide than the general civilian population, and the problem is anticipated to get worse. In fact, over the next 10 years, suicide deaths will outnumber combat casualties by more than 20X, and the outlook is even more dire for individuals in the LGBTQ+ community or communities of color. Understanding the contribution of neurobiological substrates that mediate this increased risk is necessary for identifying individuals at highest risk and developing better treatment strategies to treat suffering US veterans. Unfortunately, mechanism(s) mediating this vulnerability remain elusive. Our ongoing research has identified dysfunction of the brain derived neurotrophic factor (BDNF) system in the brain as a genetic risk factor that confers vulnerability to psychosocial or immune stress, and myriad data generated during the initial funding period of the parent VA Merit Award associated with this supplemental project revealed that disruption of BDNF signaling potentiated neuroinflammation and inflammation-induced depressive-like behaviors and cognitive function. While studies examining the role of the BDNF system on microglia are largely the focus of the parent VA Merit Award, there are several important gaps in knowledge that remain and form the basis for the experiments proposed in this supplemental application. The broad objectives of this supplement application are 1) to support a research intensive mentored project that enhances both the scope and impact of the VA Merit Award to which it is associated, 2) to provide a training opportunity for a DEI mentee (Miguel de la Flor) to develop his scientific skillset while increasing diversity within the VA research community, and most importantly, 3) to establish a novel line of investigation that will provide a basis for Dr. de la Flor to prepare a CDA-2 application and transition into an independent research position. More specifically, we propose 3 specific aims that will be carried out over 2 years that will probe important yet unexplored functional consequences of BDNF dysfunction with or without exposure to psychological or immune stress. First, the role of BDNF deficiency as a vulnerability factor that modifies maladaptive cognitive and behavioral responses will be probed. Non-associative learning, namely habituation, is a fundamental cognitive process that impacts virtually all other higher cognitive processes, yet it is often overlooked. Aim 1 will probe this cognitive process in several distinct ways. Next, neuroinflammation is known to increase alcohol-related behaviors, which are a particular problem adversely impacting veterans and increasing the risk for suicide. Aim 2 will investigate the role of BDNF deficiency as an exacerbating factor in the development of alcohol-related behaviors. Finally, epigenetic regulation of microglia gene expression will be explored a mechanism by which genetics may interact with psychological or immune stress (trauma) to create stable, long-lasting dysregulation.

Exposure to risk factors such as stress or inflammation has been shown to be an important predisposing factor to psychiatric disorders and suicide. However, many individuals exposed to adversity maintain normal psychological functioning, and the factors underlying resistance to the deleterious effects of stress remain unknown. We propose that BDNF functions as a modulator of non-neuronal cells responsible for neuroinflammation and kynurenine metabolism in brain, and that it is through this mechanism that BDNF confers resilience to stress.