This Merit proposal is part of a BLR&D Collaborative Merit Award for TBI (CTBI) proposal (RFP #BX-19-006) involving three separate but integrated proposals that together investigate the mechanisms by which TBI enhances impulsivity and suicidal behavior in Veterans. The rationale for the collaborative project is to combine human biomarker analysis, with human imaging studies, and with neurobiological mechanistic studies in animals, to understand the manner in which TBI influences impulsivity and suicidal behavior. Preventing suicide is a major priority for the VA. The overarching hypothesis is that TBI enhances impulsivity, a risk factor for suicide, particularly in response to stress, through inflammation and dysfunction of the serotonin system and frontal lobe circuitry. At the Indianapolis VA (INDVA) site, in order first to test our overarching hypothesis, and second to gain a more comprehensive understanding, we propose to translationally integrate human studies of subjects with TBI and suicidality with animal model studies of TBI, using blood biomarkers as a bridge. This will be accomplished via the following Aims: Aim 1 is Human biomarker studies. Aim 1.1. will focus on state aspects, by conducting transcriptomic analyses on blood samples collected in Indianapolis. We will have two groups: suicidality with TBI (n= 70) and suicidality without TBI (n= 70). We will not be conducting imaging studies, but rather use a longitudinal design, by testing the subjects first during an acute inpatient psychiatric hospitalization for suicidality (severe ideation, plan, attempt), and then 3-6 months later for a follow-up visit in a low suicidality state. We hypothesize that inflammatory and serotonin related transcripts will be decrease between acute inpatient and non-acute follow-up testing, but less so in suicidality with TBI compared to suicidality without TBI. Aim 1.2. will focus on trait aspects, by conducting transcriptomic analyses on samples from the Bronx VA (JJPVA) (n=140). We hypothesize that inflammatory and serotonin related transcripts will be increased most in suicidality with TBI compared to suicidality without TBI, TBI without suicidality, and non-TBI, non- suicidality. Aim 2 is Animal model brain and blood biomarkers convergence studies. We will conduct transcriptomic analyses of brain and blood samples from the animal model studies (n= 160) at the New Jersey VA (VANJHCS), a more experimentally tractable way of studying TBI and impulsivity. We hypothesize that we will identify biomarkers that are co- directionally changed in brain and blood. Aim 3 is Translational convergence of human and animal model biomarker data, using Convergent Functional Genomics analyses. We hypothesize that the candidate state and trait biomarkers that track suicidality (ideation, attempts) related to TBI (TBI-S) in the human studies will cross- validate with the brain-blood biomarkers from the animal model studies. We will also test hypothesis driven a series o...