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, CRHOE dev ) 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 CRHOE dev 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 CRHOE dev exposed and unexposed mice were examined 7 days after predator stress. CRHOE dev 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 CRHOE dev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOE dev , males developed significant avoidance only when exposed to both CRHOE dev and stress. Quantitative real-time-PCR analysis indicated that CRHOE dev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOE dev did not. Similar to CRHOE dev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOE dev 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.

Investigating Individual Pre-trauma Susceptibility to a PTSD-Like Phenotype in Animals

“…To study susceptibility empirically, research focuses on using preclinical rodent models to assess a PTSD-like phenotype (Milad et al, 2006;Yehuda and LeDoux, 2007;Goswami et al, 2012). Many animal models of PTSD with face and construct validity have been developed (Hartmann et al, 2012;Toth et al, 2016;Deslauriers et al, 2019). The purpose of this review is not to review these, but to identify those models that are suitable for investigating individual differences in susceptibility.…”

“…(3) Models with construct validity (e.g., knockout of FKBP5, COMT, or CRH overexpression in early life) do not produce a complex PTSD-like phenotype (Hartmann et al, 2012;Toth et al, 2016;Deslauriers et al, 2019). (4) Animal models can inform about some, but not all, aspects of the PTSD phenomenon.…”

Early maturational emergence of adult-like emotional reactivity and anxiety after brief exposure to an obesogenic diet

“…The CRHR1 is abundantly expressed in fear-modulating corticolimbic circuits, including the mPFC (Steckler and Holsboer, 1999). Studies in humans and rodents indicate that CRH-CRHR1 hyper-signaling represents a candidate mechanism for PTSD risk (Bremner et al, 1997;Jovanovic et al, 2020;Rajbhandari et al, 2015;Toth et al, 2016). CRHR1 hyper-signaling alters brain structural integrity (Chen et al, 2004;Kolber et al, 2010;Toth et al, 2014) and has long-lasting consequences in stress susceptibility (Uribe-Mariño et al, 2016), mainly when it is triggered early in life (Toth et al, 2016).…”

Sex differences in corticotropin releasing factor-evoked behavior and activated networks

“…Collectively, these studies suggest widespread sex differences in CRF receptors at the cellular level. However, systems level sex differences in CRF-mediated behaviors and activated circuitry have been largely underexplored because the majority of previous studies assessed systems level effects of CRF only in male rodents (but see, Toth et al, 2015; Toth et al, 2014). …”