The experience of childhood adversity in the form of neglect/abuse is a major risk factor for future suicidal behavior perhaps via long-term changes in molecular and neurobiological substrates of anxiety, depression, and impulsivity/aggression. The mechanistic links between childhood adversity, molecular/neurobiological pathways, and suicide risk have yet to be established. We propose to investigate key hypotheses regarding: 1) whether childhood adversity is a causal antecedent to suicide behavioral, neurobiological, and molecular phenotypes;2) the time course of adversity-induced effects on gene expression and epigenetic variation within target gene clusters: 3) the degree of concordance between peripheral cell epigenetic marks and those present in the brain;and 4) explore reversal of such effects by """"""""therapeutic"""""""" intervention. We propose to use mouse models as mice are especially well suited to mechanistic studies. Our experiments are designed to parallel the molecular and neurobiological human studies within the center and can thus readily inform the other projects.
In Aim 1, we will investigate whether suicide-relevant phenotypes in mice induced with eariy life adversity are associated with indices of HPA dysregulation, neurobiological changes, and gene expression patterns in the brain. Heightened stress responsivity is risk factor for the emergence of psychopathology and this aim will establish the HPA function of maternally separated mice that exhibit risk phenotypes (anxiety-like, depressive-like, impulsivity/aggression).
This aim will also determine the density of 5-HTT and 5-HT1AR binding in the brain as a function of maternal separation/risk phenotype and assess the expression of genes within serotonergic, HPA, and neurotrophic pathways, as these are biological phenotypes linked to suicide.
In Aim 2, we will determine the role of epigenetic variation in the form of DNA methylation as a potential molecular pathway of maternal separation-induced effects.
Aim 2 determines whether separation-induced epigenetic effects in the brain correspond to changes in blood and whether these peripheral epigenetic changes can be used to predict the later development of a suicide-relevant risk phenotype.
In Aim 3 we will explore the reversibility of maternal-separation induced effects on suicide-relevant phenotypes using pharmacological targeting and environmental manipulations during the juvenile period.
This project seeks mechanistic insight into the causal relationships between early life adversity, epigenetic effects, gene expression and biological and behavioral phenotypes associated with suicidal behavior. The knowledge gained through our research will contribute to the identification of at risk individuals and provide novel approaches for intervention/treatment of the suicide behavior diathesis.
|Chaudhury, Sadia R; Singh, Tanya; Burke, Ainsley et al. (2016) Clinical Correlates of Planned and Unplanned Suicide Attempts. J Nerv Ment Dis 204:806-811|
|Silvers, Jennifer A; Hubbard, Alexa D; Chaudhury, Sadia et al. (2016) Suicide attempters with Borderline Personality Disorder show differential orbitofrontal and parietal recruitment when reflecting on aversive memories. J Psychiatr Res 81:71-8|
|Kumar, J S Dileep; Underwood, Mark D; Simpson, Norman R et al. (2016) Autoradiographic Evaluation of [(18)F]FECUMI-101, a High Affinity 5-HT1AR Ligand in Human Brain. ACS Med Chem Lett 7:482-6|
|Gilead, Michael; Boccagno, Chelsea; Silverman, Melanie et al. (2016) Self-regulation via neural simulation. Proc Natl Acad Sci U S A 113:10037-42|
|Curley, James P; Champagne, Frances A (2016) Influence of maternal care on the developing brain: Mechanisms, temporal dynamics and sensitive periods. Front Neuroendocrinol 40:52-66|
|Schneck, Noam; Miller, Jeffrey M; Delorenzo, Christine et al. (2016) Relationship of the serotonin transporter gene promoter polymorphism (5-HTTLPR) genotype and serotonin transporter binding to neural processing of negative emotional stimuli. J Affect Disord 190:494-8|
|Lawrence, Ryan E; Brent, David; Mann, J John et al. (2016) Religion as a Risk Factor for Suicide Attempt and Suicide Ideation Among Depressed Patients. J Nerv Ment Dis 204:845-850|
|Reeck, Crystal; Ames, Daniel R; Ochsner, Kevin N (2016) The Social Regulation of Emotion: An Integrative, Cross-Disciplinary Model. Trends Cogn Sci 20:47-63|
|Silvers, Jennifer A; Hubbard, Alexa D; Biggs, Emily et al. (2016) Affective lability and difficulties with regulation are differentially associated with amygdala and prefrontal response in women with Borderline Personality Disorder. Psychiatry Res 254:74-82|
|Yin, Honglei; Pantazatos, Spiro P; Galfalvy, Hanga et al. (2016) A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 171B:414-26|
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