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Neuropsychopharmacology (2016) 41, 16811690 2016 American College of Neuropsychopharmacology. All rights reserved 0893-133X/16
http://www.neuropsychopharmacology.org
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Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood
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Mate Toth1,2, Elizabeth I Flandreau1,2, Jessica Deslauriers1,2, Mark A Geyer1,2, Isabelle M Mansuy3, Emilio Merlo Pich4 and Victoria B Risbrough*,1,2
1Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; 2Center of Excellence for Stress and Mental Health, Veterans Affairs, La Jolla, CA, USA; 3Laboratory of Neuroepigenetics, Center for Neuroscience Zrich, Brain Research Institute, University of Zrich and ETH Zrich, Zrich, Switzerland; 4Division of Brain Sciences, Department of Medicine, Imperial College, London, UK
Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOEdev) in double-mutant mice (Camk2a-rtta2 tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOEdev exposed and unexposed mice, avoidance and arousal behaviors were examined 715 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2, and Fkbp51 in forebrain of CRHOEdev exposed and unexposed mice were examined 7 days after predator stress. CRHOEdev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOEdev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOEdev, males developed significant avoidance only when exposed to both CRHOEdev and stress. Quantitative real-time-PCR analysis indicated that CRHOEdev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOEdev did not. Similar to CRHOEdev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and...