Childhood adversity is associated with greater risk for adulthood depression (MDD), aggressive traits and suicide. The biological basis of this relationship is mostly unknown but for the interesting finding of DNA methylation/less expression of the glucocorticoid receptor (GR) gene in suicides reporting childhood adversity. Stress and suicide are also associated with fewer cells and dendritic shrinkage in prefrontal cortex (PFC) and hippocampus (HC). Smaller HC volume may constitute a risk factor for stress-related psychopathology. In MDD suicides we find lower serotonin transporter (5-HTT) and higher serotonin IA receptor (5-HTIA) binding in PFC and higher rate of childhood adverse events. We hypothesize that this neurobiological phenotype may result from genes, environment and epigenetic effects.
We aim to determine whether 5-HT1A binding, BDNF, measures of the hypothalamus-pituitary-adrenocortical (HPA) axis and candidate gene expression and methylation levels, correlate with neuron and glia density or number in PFC and HC in 5 groups of age- and sex-matched MDD suicides and nonpsychiatric controls with and without reported childhood adversity (before 15y) and 12 non suicide MDDs, all with psychological autopsy and brain toxicology. We propose to measure: 1) neuronal and glial density in dorsal PFC (dPFC) and ACC and estimate total number in HC; 2) 5-HTT and 5-HTIA binding in dPFC and ACC and number of 5-HT1A-immunoreactive (IR) Axonal Initial Segments in the granule cell layer of the dentate gyrus (DG) of the HC and BDNF-IR neuron density or number in dPFC and ACC and BDNF-IR cell number in HC;3) Determine the effect of childhood adversity on HPA axis indices in dPFC, ACC and HC, and regional correlations with neuron number or density;4) Determine the effect of childhood adversity on neuronal gene expression and methylation levels of 18 candidate genes in dPFC, ACC and HC in the same 5 groups as Aim 1. Exploratory aims will: 1) separate the effect of MDD from that of suicide or adversity on neuron, glia and BDNF-IR cell density, in dPFC and ACC, or number, in HC, comparing the suicide and non-suicide MDD groups;2) test the relationship between lifetime aggression scores and childhood adversity, neuron and glia number or density, serotonin indices, HPA axis indices, gene expression and methylation.
Suicide diathesis may result from the complex interaction of genetic and environmental factors. The PFC and HC are part of the stress-response brain circuit. The proposed studies will compare effect of childhood adversity on neuronal and glial changes in dPFC and HC and the relationship with serotonin indices, BDNF expression, HPA indices, gene expression and methylation levels of 18 candidate genes, in MDD suicides and controls with no psychopathology. Differentiating the determinants of a diathesis and a resilient phenotype, helps identify prevention and treatment targets. Differences related to suicide or MDD will be identified comparing the suicide and non-suicide MDD groups.
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