Dysfunction in BDNF confers vulnerability to psychosocial stress, and myriad data generated during the initial funding period of this project revealed that disruption of BDNF signaling also potentiated neuroinflammation and inflammation-induced depressive-like behaviors. The US veteran population is well known to suffer high rates of psychological stress and chronic inflammatory conditions as well as disproportionately increased risk of depression and suicide. Understanding the contribution of neurobiological substrates that mediate this increased risk is necessary for developing better treatment strategies to treat suffering US veterans. Unfortunately, mechanism(s) mediating this vulnerability remain elusive. Our recent discoveries suggest that dysfunction in the BDNF system represents a genetic vulnerability factor for the development of depression, and preliminary data have identified therapeutically targetable neural substrates that appear to mediate this vulnerability. More specifically, dysregulation of the kynurenine pathway in the brain has been implicated in the pathogenesis of depressive symptomotology. Of functional significance, two metabolic branches of the kynurenine pathway are physically compartmentalized. The neuroprotective branch that forms kynurenic acid resides in astrocytes. The neurotoxic branch that forms 3- hydroxykynurenine and quinolinic acid resides in microglia. A large body of evidence implicates the kynurenine pathway in depression associated with inflammation. However, a role for this pathway in stress- or inflammation-induced depressive behavior has been largely unexplored. We have recently reported that low-level stress, consisting of psychosocial and environmental challenges, increases neuroprotective factors kynurenic acid and the anti-inflammatory cytokine IL-10 in the forebrain of wild-type, but not BDNF+/- mice. In striking contrast, levels of the neurotoxic kynurenine metabolite 3-hydroxykynurenine are markedly increased in BDNF+/- mice. These observations support our contention that protective mechanisms present in wild-type mice are absent in BDNF deficient animals. Mice with genetic disruptions in the BDNF system exhibit pronounced neuroinflammation, oxidative kynurenine metabolism and depressive-like behavior relative to wild-type mice. Our overall hypothesis is that during exposure to depression risk factors (stress or inflammation), the activity-dependent release of BDNF increases IL-10 production, which in turn modulates kynurenine pathway metabolism resulting in increased levels of kynurenic acid. Under conditions of BDNF deficiency or dysfunction, the absence of these neuroprotective mechanisms results in a stress-sensitive phenotype. We will use BDNF heterozygous mice (BDNF+/- mice), which exhibit marked reductions in BDNF expression, to mechanistically explore the aims proposed. To test our hypotheses in a translationally relevant model, we will use transgenic mice carrying the met allele of the human bdnf gene (BDNFmet knock-in mice). This single nucleotide polymorphism (rs6265) is a risk factor associated with depression and suicide. That the kynurenine pathway may play a role in the brain's response to stress is an innovative perspective, which may provide insight into mechanism(s) mediating vulnerability and resilience. The preclinical experiments outlined in this proposal will serve to increase our understanding of the neurobiological mechanisms underlying the sensitivity of certain individuals to depression risk factors. The proposed experiments will also identify potentially novel therapeutic approaches to mitigate depression symptoms and suicidality in suffering veterans.

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 non-neuronal cells responsible for neuroinflammation and kynurenine metabolism in brain, and that it is through this mechanism that BDNF confers resilience to stress.