SUMMARY- PROJECT 1 Childhood adversity is associated with greater risk for adulthood depression (MDD), aggressive traits and suicide. The overall goal of Project 1 is to define a biological phenotype for suicide and assess the contribution of reported childhood (before age 16) adversity. In MDD suicides, we find a higher rate of childhood adverse events. The biological basis of this relationship is mostly unknown, but recent studies, including finds from our previous Conte Center of thinner prefrontal cortex (PFC) and smaller hippocampus (HC) volume and reduced BDNF, suggest glucocorticoid excess and impaired trophic effect is a consequence of stress and contributes to suicide risk. Stress and suicide are also associated with fewer cells and dendritic shrinkage in prefrontal cortex (PFC) and hippocampus (HC). The thinner PFC and smaller HC volume may constitute a biological risk factor for stress-related psychopathology. We hypothesize that this neurobiological phenotype may result from neuroinflammation, environment and epigenetic effects. In the new Conte Center, we aim to determine in the PFC and HC, whether inflammatory cytokines are increased, whether neurons, glia or both express those inflammatory markers, and whether the presence of those markers is associated with changes in neuron number or morphology in 5 groups (n=15 per group) of age- and sex-matched MDD suicides and nonpsychiatric controls with and without reported childhood adversity (before 15y) and 10 non suicide MDDs, all with psychological autopsy and brain toxicology. We propose to measure: 1) 62 markers of the inflammasome in the dorsal PFC (dPFC), ACC and HC; we will estimate total number of neurons and glia in HC and neuronal and glial density in the dPFC and ACC, with neurons and glia double-labeled with select cytokines identified from the inflammasome assay; 2) we will count the number of microglia in the HC (at anterior, mid- and posterior levels) and the density of microglia in dPFC and ACC using microglia specific markers; and 3) Determine the dendrite length and branching as indices of neuron morphology. Exploratory aims will: 1) separate the effect of MDD from that of suicide or adversity on neuron and glia expression of select inflammatory markers comparing the suicide and non-suicide MDD groups; 2) compare cytokines from brain and blood; TSPO level in postmortem brain and measured by PET; cortical thickness and HC volume in postmortem brain and measured in vivo by MRI. The proposed studies will provide evidence whether CA and suicide are associated with a neuroinflammatory response. !