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.
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| Rizk, Mina M; Rubin-Falcone, Harry; Lin, Xuejing et al. (2018) Gray matter volumetric study of major depression and suicidal behavior. Psychiatry Res Neuroimaging 283:16-23 |
| Daray, Federico M; Mann, J John; Sublette, M Elizabeth (2018) How lipids may affect risk for suicidal behavior. J Psychiatr Res 104:16-23 |
| Rizk, Mina M; Galfalvy, Hanga; Singh, Tanya et al. (2018) Toward subtyping of suicidality: Brief suicidal ideation is associated with greater stress response. J Affect Disord 230:87-92 |
| Rubin-Falcone, Harry; Zanderigo, Francesca; Thapa-Chhetry, Binod et al. (2018) Pattern recognition of magnetic resonance imaging-based gray matter volume measurements classifies bipolar disorder and major depressive disorder. J Affect Disord 227:498-505 |
| Boldrini, Maura; Fulmore, Camille A; Tartt, Alexandria N et al. (2018) Human Hippocampal Neurogenesis Persists throughout Aging. Cell Stem Cell 22:589-599.e5 |
| Youssef, Mariam M; Underwood, Mark D; Huang, Yung-Yu et al. (2018) Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide. Int J Neuropsychopharmacol 21:528-538 |
| Chaudhury, Sadia R; Galfalvy, Hanga; Biggs, Emily et al. (2017) Affect in response to stressors and coping strategies: an ecological momentary assessment study of borderline personality disorder. Borderline Personal Disord Emot Dysregul 4:8 |
| Fitzgerald, Megan L; Kassir, Suham A; Underwood, Mark D et al. (2017) Dysregulation of Striatal Dopamine Receptor Binding in Suicide. Neuropsychopharmacology 42:974-982 |
| Ganança, Licinia; Galfalvy, Hanga C; Oquendo, Maria A et al. (2017) Lipid correlates of antidepressant response to omega-3 polyunsaturated fatty acid supplementation: A pilot study. Prostaglandins Leukot Essent Fatty Acids 119:38-44 |
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