CRF1 Not Glucocorticoid Receptors Mediate Prepulse Inhibition Deficits in Mice Overexpressing CRF

Groenink, Lucianne; Dirks, Anneloes; Verdouw, P. Monika; Graaff, Marijke de; Peeters, B.W.M.M.; Millan, Mark J.; Olivier, Berend

doi:10.1016/j.biopsych.2007.06.002

Cited by 32 publications

(19 citation statements)

References 73 publications

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“…These data are consistent with our and others' previous reports showing reduced PPI and habituation following developmental or lifetime CRHOE (Dirks et al, 2002;Groenink et al, 2008;Toth et al, 2014). Pharmacological and genetic manipulation studies reported increased startle and reduced PPI following CRHR1 receptor hypersignaling, whereas CRHR2 receptor stimulation increased PPI (Risbrough et al, 2003(Risbrough et al, , 2004.…”

Section: Discussionsupporting

confidence: 93%

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: 93%

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

Tóth

Flandreau

Deslauriers

et al. 2015

Neuropsychopharmacol

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“…Future clinical research is needed to confirm if early-life stress is specifically associated with poor sensorimotor gating. Mechanisms for the developmental effect of CRFOE on PPI are currently unclear, however, lifetime CRFOE mice showed recovery of PPI after acute CRFR1 receptor antagonist treatments, inferring that the PPI deficits are due to CRFR1 hypersignaling (Groenink et al, 2008). Interestingly, the impact of CRFOE on fear conditioning revealed an opposite effect of exposure period on behavior compared to startle behaviors.…”

Section: Discussionmentioning

confidence: 98%

Forebrain-Specific CRF Overproduction During Development is Sufficient to Induce Enduring Anxiety and Startle Abnormalities in Adult Mice

Tóth

Gresack

Bangasser

et al. 2013

Neuropsychopharmacol

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Corticotropin releasing factor (CRF) regulates physiological and behavioral responses to stress. Trauma in early life or adulthood is associated with increased CRF in the cerebrospinal fluid and heightened anxiety. Genetic variance in CRF receptors is linked to altered risk for stress disorders. Thus, both heritable differences and environmentally induced changes in CRF neurotransmission across the lifespan may modulate anxiety traits. To test the hypothesis that CRF hypersignaling is sufficient to modify anxiety-related phenotypes (avoidance, startle, and conditioned fear), we induced transient forebrain-specific overexpression of CRF (CRFOE) in mice (1) during development to model early-life stress, (2) in adulthood to model adult-onset stress, or (3) across the entire postnatal lifespan to model heritable increases in CRF signaling. The consequences of these manipulations on CRF peptide levels and behavioral responses were examined in adulthood. We found that transient CRFOE during development decreased startle habituation and prepulse inhibition, and increased avoidance (particularly in females) recapitulating the behavioral effects of lifetime CRFOE despite lower CRF peptide levels at testing. In contrast, CRFOE limited to adulthood reduced contextual fear learning in females and increased startle reactivity in males but did not change avoidance or startle plasticity. These findings suggest that forebrain CRFOE limited to development is sufficient to induce enduring alterations in startle plasticity and anxiety, while forebrain CRFOE during adulthood results in a different phenotype profile. These findings suggest that startle circuits are particularly sensitive to forebrain CRFOE, and that the impact of CRFOE may be dependent on the time of exposure.

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“…CRF overexpression under the Thy1 promoter has been shown to induce robust reductions in PPI that are reversible with acute CRF1 receptor antagonist treatment (Groenink et al, 2008). A recent study from our group showed that life-long CRF overexpression restricted to forebrain regions driven by the CamKIIα promotor (no hypothalamic CRF overexpression in contrast to Thy1-CRF-OE and CRF-COE CNS mice) also exhibited reductions in PPI (Toth et al, 2014), indicating that forebrain CRF overexpression is sufficient to induce PPI disruptions.…”

Section: Discussionmentioning

confidence: 99%

“…Studies are ongoing to delineate the compensatory changes in CRF1 and CRF2 expression and binding in response to CRFOE in inhibitory vs. excitatory neurons. The transgenic mouse using the Thy1 promoter to overexpress CRF in postnatal and adult neurons also yielded reduced startle magnitude in some but not all reports (Dirks et al, 2002; Groenink et al, 2008), and these mice have reductions in CRF 1 receptors in thalamus, striatum, cortex, and septum (Korosi et al, 2006). Overexpression of CRF restricted to adulthood also result in alterations in CRF 1 receptor expression and possibly accounts for “paradoxical” anxiolytic effects of CRF overexpression in some reports (Regev et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Cell type-specific modifications of corticotropin-releasing factor (CRF) and its type 1 receptor (CRF1) on startle behavior and sensorimotor gating

Flandreau

Risbrough²,

et al. 2015

Psychoneuroendocrinology

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The corticotropin-releasing factor (CRF) family of peptides and receptors coordinates the mammalian endocrine, autonomic, and behavioral responses to stress. Excessive CRF production has been implicated in the etiology of stress-sensitive psychiatric disorders such as posttraumatic stress disorder (PTSD), which is associated with alterations in startle plasticity. The CRF family of peptides and receptors mediate acute startle response changes during stress, and chronic CRF activation can induce startle abnormalities. To determine what neural circuits modulate startle in response to chronic CRF activation, transgenic mice overexpressing CRF throughout the central nervous system (CNS; CRF-COECNS) or restricted to inhibitory GABAergic neurons (CRF-COEGABA) were compared across multiple domains of startle plasticity. CRF overexpression throughout the CNS increased startle magnitude and reduced ability to inhibit startle (decreased habituation and decreased prepulse inhibition (PPI)), similar to previous reports of exogenous effects of CRF. Conversely, CRF overexpression confined to inhibitory neurons decreased startle magnitude but had no effect on inhibitory measures. Acute CRF receptor 1 (CRF1) antagonist treatment attenuated only the effects on startle induced by CNS-specific CRF overexpression. Specific deletion of CRF1 receptors from forebrain principal neurons failed to alter the effects of exogenous CRF or stress on startle, suggesting that these CRF1 expressing neurons are not required for CRF-induced changes in startle behaviors. These data indicate that the effects of CRF activation on startle behavior utilize an extensive neural circuit that includes both forebrain and non-forebrain regions. Furthermore, these findings suggest that the neural source of increased CRF release determines the startle phenotype elicited. It is conceivable that this may explain why disorders characterized by increased CRF in cerebrospinal fluid (e.g. PTSD and major depressive disorder) have distinct symptom profiles in terms of startle reactivity.

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CRF1 Not Glucocorticoid Receptors Mediate Prepulse Inhibition Deficits in Mice Overexpressing CRF

Cited by 32 publications

References 73 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

Forebrain-Specific CRF Overproduction During Development is Sufficient to Induce Enduring Anxiety and Startle Abnormalities in Adult Mice

Cell type-specific modifications of corticotropin-releasing factor (CRF) and its type 1 receptor (CRF1) on startle behavior and sensorimotor gating

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