Mice Deficient for Both Corticotropin-Releasing Factor Receptor 1 (CRFR1) and CRFR2 Have an Impaired Stress Response and Display Sexually Dichotomous Anxiety-Like Behavior

Bale, Tracy L.; Picetti, Roberto; Contarino, Angelo; Koob, George F.; Vale, Wylie; Lee, Kuo‐Fen

doi:10.1523/jneurosci.22-01-00193.2002

Cited by 267 publications

(183 citation statements)

References 43 publications

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“…These data must be interpreted with caution, however, as specific manipulation of Fkbp51 and Crhr2 expression is required to confirm any causal relationship between expression changes and PTSD-like phenotypes observed. Overall, the differential pattern of Crhr2 vs Fkbp51 expression changes in female and male mice supports the hypothesis that sex significantly modulates adaptive responses in CRH signaling during development (Bale et al, 2002;Bangasser et al, 2010).…”

Section: Discussionsupporting

confidence: 70%

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Tóth

Flandreau

Deslauriers

et al. 2015

Neuropsychopharmacol

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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.

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Section: Discussionsupporting

confidence: 70%

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Tóth

Flandreau

Deslauriers

et al. 2015

Neuropsychopharmacol

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“…In particular female, but not male, urocortin 2-deficient mice show decreased immobility levels in the forced swim and in the tail suspension tests as well as altered HPA axis activity as compared with wild-type mice (Chen et al, 2006). Moreover, male, but not females, mice born to CRF 2 +/ − or CRF 2 − / − mothers display higher anxiety-like behavior than mice born to wild-type mothers, independently of their CRF 2 genotype (Bale et al, 2002). However, a direct comparison between the latter and the present study is difficult to make.…”

Section: Summary Of the Resultsmentioning

confidence: 89%

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

Morisot

Rouibi

Contarino

2015

Neuropsychopharmacol

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Vulnerability to stressful life events is a hallmark of drug dependence that may persist long after cessation of drug intake and dramatically fuel key clinical features, such as deregulated up-shifted motivational states and craving. However, to date, no effective therapy is available for reducing vulnerability to stressful events in former drug users and drug-dependent patients, mostly because of poor knowledge of the mechanisms underlying it. In this study, we report that genetic inactivation of the stress-responsive corticotropin-releasing factor receptor-2 (CRF 2 − / − ) completely eliminates the reemergence of increased nonrewarded nose-pokes, reflecting up-shifted motivational states, triggered by ethological environmental stressors long after cessation of morphine administration in mice. Accordingly, CRF 2 receptor deficiency completely abolishes the increase in biomarkers of synthesis of major brain motivational substrates, such as ventral tegmental area (VTA) dopamine (DA) and amygdala γ-aminobutyric acid (GABA) systems, associated with the stress-induced reemergence of upshifted motivational states long after opiate withdrawal. Nevertheless, neither CRF 2 receptor deficiency nor long-term opiate withdrawal affects amygdala CRF or hypothalamus CRF expression, indicating preserved brain stress-coping systems. Moreover, CRF 2 receptor deficiency does not influence the locomotor or the anxiety-like effect of long-term opiate withdrawal. Thus, the present results reveal an essential and specific role for the CRF 2 receptor in the stress-induced reemergence of up-shifted motivational states and related alterations in brain motivational systems long after opiate withdrawal. These findings suggest new strategies for the treatment of the severe and longlasting vulnerability that inexorably follows drug withdrawal and hinder drug abstinence.

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“…For example, male mice deficient in both corticotropin releasing hormone (CRH) receptors 1 and 2 exhibit increased anxiety-like behavior in the elevated plus maze, while double mutant females exhibit decreased anxiety-like behavior. 62 Furthermore, human studies have indicated that stressful life events precipitate depressive episodes differentially in women and men. 63 In addition, there is also a sex difference in the heritability of major depression in humans.…”

Section: Discussionmentioning

confidence: 99%

Depressive-like behavior and stress reactivity are independent traits in a Wistar Kyoto × Fisher 344 cross

et al. 2003

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Depression is a heritable disorder that is often precipitated by stress. Abnormalities of the stress-reactive hypothalamic-pituitary-adrenal (HPA) axis are also common in depressed patients. In animal models, the forced swim test (FST) is the most frequently used test of depressive-like behavior. We have used a proposed animal model of depression, the Wistar Kyoto (WKY) rat, to investigate the relationship as well as the mode of inheritance of FST behaviors and HPA measures. Through reciprocal breeding of WKY and F344 parent strains and brother-sister breeding of the F1 generation, we obtained 486 F2 animals. Parent, F1 and F2 animals were tested in the FST. Blood samples were collected for determination of basal and stress (10-min restraint) plasma corticosterone (CORT) levels, and adrenal weights were measured. We found that all measures were heritable to some extent and that this heritability was highly sex dependent. Both correlation and factor analyses of the F2 generation data demonstrate that FST behavior and HPA axis measures are not directly related. Thus, the underlying genetic components of depressive-like behavior and HPA axis abnormalities are likely to be disparate in the segregating F2 generation of a WKY3F344 cross.

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Mice Deficient for Both Corticotropin-Releasing Factor Receptor 1 (CRFR1) and CRFR2 Have an Impaired Stress Response and Display Sexually Dichotomous Anxiety-Like Behavior

Cited by 267 publications

References 43 publications

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

Depressive-like behavior and stress reactivity are independent traits in a Wistar Kyoto × Fisher 344 cross

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