? PROJECT 2 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 depression and impulsivity/aggression. The effect of early life adversity interacts with genetic vulnerability to confer heightened risk of psychopathology and adverse health outcomes. The mechanistic links between childhood adversity, genetic risk, molecular/neurobiological pathways, and suicide risk have yet to be established. We propose to investigate key hypotheses regarding: 1) whether childhood adversity interacts with 5-HT1A genotype to generate heightened risk of suicide behavioral; 2) the relationship between environment and genetic risk for suicide on the brain transcriptome and epigenetic variation; 3) the impact on peripheral and brain inflammatory pathways of the combined effects of environmental and genetic vulnerability to suicide behavior and the relationship of these inflammasome measures to risk behavioral phenotypes. We propose to use mouse models as mice are especially well suited to mechanistic studies and transgenic manipulations. Our experiments are designed to parallel the molecular, neurobiological and immune outcomes in 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 (depressive-like, impulsivity/aggression) are heightened through a combination of early life adversity (maternal separation) and a targeted genetic manipulation of the 5-HT1A system that results in elevated expression of 5-HT1A autoreceptors and subsequent decreased 5-HT levels.
Aim 2 determines whether early adversity and elevated 5-HT1A autoreceptor levels in the brain result in an altered hippocampal and prefrontal cortex transcriptome (using RNA-Seq) and variation in DNA methylation within the BDNF and Nr3c1 genes (using bisulfite pyrosequencing).
In Aim 3 we will explore the inflammatory consequences of genetic and environmental vulnerability to suicide behavior and the relationship of these measures to specific suicide behavior phenotypes. To achieve this aim, we will profile cytokine levels within the blood, hippocampus and prefrontal cortex of mice that have experienced postnatal maternal separation combined with elevated expression of 5-HT1A autoreceptors and assess microglial activation within the brain as a consequence of this gene-environment interaction.
| Abreu, L N; Oquendo, M A; Galfavy, H et al. (2018) Are comorbid anxiety disorders a risk factor for suicide attempts in patients with mood disorders? A two-year prospective study. Eur Psychiatry 47:19-24 |
| 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 |
| Ceñido, Joshua F; Itin, Boris; Stark, Ruth E et al. (2017) Characterization of lipid rafts in human platelets using nuclear magnetic resonance: A pilot study. Biochem Biophys Rep 10:132-136 |
| Chesin, Megan S; Galfavy, Hanga; Sonmez, Cemile Ceren et al. (2017) Nonsuicidal Self-Injury Is Predictive of Suicide Attempts Among Individuals with Mood Disorders. Suicide Life Threat Behav 47:567-579 |
| Coleman, Daniel; Lawrence, Ryan; Parekh, Amrita et al. (2017) Narcissistic Personality Disorder and suicidal behavior in mood disorders. J Psychiatr Res 85:24-28 |
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