title: Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood.
abstract: 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 7-15 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 CRHOEdev exposure in males, but not in females. These findings indicate that forebrain CRH hyper-signaling in early-life is sufficient to increase enduring effects of adult trauma and attenuate Crhr2 expression changes in response to stress in males. These data support growing evidence for significant sex differences in response to trauma, and support further study of CRHR2 as a candidate mechanism for PTSD risk.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.|Center of Excellence for Stress and Mental Health, Veterans Affairs, La Jolla, CA, USA.
authors.forename: Mate
authors.initials: M
authors.lastname: Toth
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.|Center of Excellence for Stress and Mental Health, Veterans Affairs, La Jolla, CA, USA.
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Flandreau
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.|Center of Excellence for Stress and Mental Health, Veterans Affairs, La Jolla, CA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Deslauriers
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.|Center of Excellence for Stress and Mental Health, Veterans Affairs, La Jolla, CA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
authors.affiliation: Laboratory of Neuroepigenetics, Center for Neuroscience Zürich, Brain Research Institute, University of Zürich and ETH Zürich, Zürich, Switzerland.
authors.forename: Isabelle M
authors.initials: IM
authors.lastname: Mansuy
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College, London, UK.
authors.forename: Emilio
authors.initials: E
authors.lastname: Merlo Pich
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.|Center of Excellence for Stress and Mental Health, Veterans Affairs, La Jolla, CA, USA.
authors.forename: Victoria B
authors.initials: VB
authors.lastname: Risbrough
mesh_terms: D000367:Age Factors; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000502:physiology; D016548:Prosencephalon / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D018019:Receptors, Corticotropin-Releasing Hormone / Q000502:physiology; D013216:Reflex, Startle / Q000502:physiology; D013313:Stress Disorders, Post-Traumatic / Q000209:etiology / Q000503:physiopathology; D013315:Stress, Psychological / Q000209:etiology / Q000503:physiopathology*; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone