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Daskalakis N.P.,Mount Sinai School of Medicine | Daskalakis N.P.,Mental Health Care Center | Binder E.B.,Max Planck Institute of Psychiatry | Binder E.B.,Emory University
Schizophrenia Bulletin | Year: 2015

Many studies have demonstrated that genotype (G) interacts with adverse life experiences (E) to produce individual differences in vulnerability and resilience to mental disorders, including schizophrenia. Genetic susceptibility to stress and the timing of the environmental exposure(s) are relevant for these interactions and represent common risk factors. We take the example of the FKBP5 gene to illustrate G × E interactions that predict pleiotropic psychiatric outcomes, including schizophrenia. © 2015 The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. Source


Daskalakis N.P.,Leiden University | Daskalakis N.P.,Mount Sinai School of Medicine | Daskalakis N.P.,Mental Health Care Center | Diamantopoulou A.,Leiden University | And 8 more authors.
Psychoneuroendocrinology | Year: 2014

Prolonged maternal separation (MS) activates the neonate's hypothalamus-pituitary-adrenal axis causing elevated basal and stress-induced corticosterone levels that may initiate amygdala-dependent fear learning. Here we test the hypothesis that the adult fearful phenotype is programmed by the pup's stressful experience during prolonged MS rather than by prolonged maternal absence per se. For this purpose, Wistar rat pups were exposed, on postnatal-day (pnd) 3, to: (i) repeated-MS in home-environment (HOME-SEP), 8h-MS daily for three days with the pups remaining together in the home-cage; (ii) repeated-MS in a novel-environment (NOVEL-SEP), with the same separation procedure, but now the pups were individually housed in a novel-environment during the 8. h dam's absence; (iii) repeated handling, which consisted of daily brief (15. min instead of 8. h) MS in the home-altogether or in a novel-environment individually (HOME-HAN and NOVEL-HAN, respectively); (iv) no-separation/no-handling (NON-SEP/NON-HAN) control condition, in which pups were left undisturbed in their home-cage. Compared to HOME-SEP rats, the NOVEL-SEP rats showed one day after the last MS enhanced stress-induced amygdala c-Fos expression and ACTH-release, despite of reduced adrenal corticosterone secretion. The higher amygdala c-Fos expression, ACTH-release and reduced corticosterone output observed postnatally, persisted into adulthood of the NOVEL-SEP animals. Behaviorally, NOVEL-SEP juvenile rats displayed deficits in social play, had intact spatial memory in the peri-pubertal period and showed more contextual fear memory compared to HOME-SEP in adulthood. Finally, NOVEL-HAN, compared to HOME-HAN, displayed increased stress-induced corticosterone output, no deficits in social play and reduced contextual fear. In conclusion, programming of an adult fearful phenotype linked to amygdala priming develops if pups are repeatedly isolated from peers in a novel-environment, while away from the dam for a prolonged period of time. © 2013 Elsevier Ltd. Source


Almli L.M.,Emory University | Stevens J.S.,Emory University | Smith A.K.,Emory University | Kilaru V.,Emory University | And 15 more authors.
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2015

Genetic factors appear to be highly relevant to predicting differential risk for the development of post-traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome-wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N=147) that was designed as a case-controlled sample of highly exposed, recently returning veterans with and without combat-related PTSD. A genome-wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N=147, β=31.34, P=1.28×10-8) was found to associate with the gold-standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow-up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N=2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N=2006, P=0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N=157, P=0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N=53, P<0.05) in the GTP replication sample. These data identify a genome-wide significant polymorphism conferring risk for PTSD, which was associated with differential epigenetic regulation and with differential cortical responses to fear in a replication sample. These results may provide new insight into understanding genetic and epigenetic regulation of PTSD and intermediate phenotypes that contribute to this disorder. © 2015 Wiley Periodicals, Inc. Source


Bowers M.E.,Mount Sinai School of Medicine | Yehuda R.,Mount Sinai School of Medicine | Yehuda R.,Mental Health Care Center | Yehuda R.,The New School
Neuropsychopharmacology | Year: 2016

The hypothesis that offspring are affected by parental trauma or stress exposure, first noted anecdotally, is now supported empirically by data from Holocaust survivor offspring cohorts and other populations. These findings have been extended to less extreme forms of stress, where differential physical, behavioral, and cognitive outcomes are observed in affected offspring. Parental stress-mediated effects in offspring could be explained by genetics or social learning theory. Alternatively, biological variations stemming from stress exposure in parents could more directly have an impact on offspring, a concept we refer to here as 'intergenerational transmission', via changes to gametes and the gestational uterine environment. We further extend this definition to include the transmission of stress to offspring via early postnatal care, as animal studies demonstrate the importance of early maternal care of pups in affecting offsprings' long-term behavioral changes. Here, we review clinical observations in offspring, noting that offspring of stress- or trauma-exposed parents may be at greater risk for physical, behavioral, and cognitive problems, as well as psychopathology. Furthermore, we review findings concerning offspring biological correlates of parental stress, in particular, offspring neuroendocrine, epigenetic, and neuroanatomical changes, in an attempt to determine the extent of parental stress effects. Although understanding the etiology of effects in offspring is currently impeded by methodological constraints, and limitations in our knowledge, we summarize current information and conclude by presenting hypotheses that have been prompted by recent studies in the field. © 2016 American College of Neuropsychopharmacology. All rights reserved. Source


Daskalakis N.P.,Mount Sinai School of Medicine | Daskalakis N.P.,Mental Health Care Center | Yehuda R.,Mount Sinai School of Medicine | Yehuda R.,Mental Health Care Center | And 2 more authors.
Psychoneuroendocrinology | Year: 2013

Understanding the neurobiological mechanisms of post-traumatic stress disorder (PTSD) is of vital importance for developing biomarkers and more effective pharmacotherapy for this disorder. The design of bidirectional translational studies addressing all facets of PTSD is needed. Animal models of PTSD are needed not only to capture the complexity of PTSD behavioral characteristics, but also to address experimentally the influence of variety of factors which might determine an individual's vulnerability or resilience to trauma, e.g., genetic predisposition, early-life experience and social support. The current review covers recent translational approaches to bridge the gap between human and animal PTSD research and to create a framework for discovery of biomarkers and novel therapeutics. © 2013. Source

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