Transient forebrain over-expression of CRF induces plasma corticosterone and mild behavioural changes in adult conditional CRF transgenic mice

Vicentini, Elena; Arban, Roberto; Angelici, Ornella; Maraia, G.; Perico, MariaElisa; Mugnaini, Manolo; Ugolini, Annarosa; Large, Charles H.; Domenici, Enrico; Gerrard, Philip; Bortner, Donna M.; Mansuy, Isabelle M.; Mangiarini, Laura; Merlo‐Pich, Emilio

doi:10.1016/j.pbb.2009.03.015

Cited by 27 publications

(22 citation statements)

References 36 publications

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“…Second, these findings support the importance of early-life CRF hypersignaling in the development of heightened anxiety-like traits by showing increased anxiety in mice exposed to developmental CRFOE but not in mice exposed to adult-onset CRFOE. Consistently, embryonic-developmental (embryonic day 0 to PD21) or lifetime but not adult forebrainspecific CRFOE increased avoidance in most previous CRFOE models (Kolber et al, 2010;Stenzel-Poore et al, 1994;Vicentini et al, 2009), but see (Groenink et al, 2003). Several developmental studies have reported significant alterations in CRF activity in the forebrain following maternal separation and low maternal care as well as elevated CRF levels in the cerebrospinal fluid in these animals (Coplan et al, 1996;Ladd et al, 1996;Plotsky et al, 2005).…”

Section: Discussionmentioning

confidence: 61%

“…To achieve temporal control of CRF expression in the forebrain, we crossed two genetically modified mouse lines (backcrossed on C57BL/6J background to N48 generations) carrying a CaMKIIa promoter-driven rtTA2 transgene (Michalon et al, 2005) and a doxycycline-regulated tetO promoter fused to the CRF gene (Vicentini et al, 2009) to produce double mutant mice. Genotyping was carried out by quantitative polymerase chain reaction (Transnetyx, Memphis Tennessee, USA).…”

Section: Generation Of Mice With Inducible Forebrain-specific Crf Ovementioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 61%

Section: Generation Of Mice With Inducible Forebrain-specific Crf Ovementioning

confidence: 99%

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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“…CRF application and to mimic CRF hyperactivity observed in depressed patients (Nemeroff et al, 1984). These mouse lines have proven extremely valuable given their ability to reflect different degrees of the activating, arousing and anxiogenic-like properties of CRF (Dedic et al, 2012; Dirks et al, 2002; Kolber et al, 2010; Lu et al, 2008; Refojo et al, 2011; Stenzel-Poore et al, 1994; Vicentini et al, 2009). However, a direct comparison of different CRF overexpressing mouse models reveals substantial discrepancies and inconsistencies, which are largely related to differences in the design of these animal models, including the expression level and the spatio-temporal properties of the utilized promoters driving CRF overexpression (reviewed in: Laryea et al, 2012).…”

Section: Dissecting Crh-controlled Neurocircuitries Of Stress and mentioning

confidence: 99%

Evidence for the role of corticotropin-releasing factor in major depressive disorder

Waters

Rivalan

Bangasser

et al. 2015

Neuroscience & Biobehavioral Reviews

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Major depressive disorder (MDD) is a devastating disease affecting over 300 million people worldwide, and costing an estimated 380 billion Euros in lost productivity and health care in the European Union alone. Although a wealth of research has been directed toward understanding and treating MDD, still no therapy has proved to be consistently and reliably effective in interrupting the symptoms of this disease. Recent clinical and preclinical studies, using genetic screening and transgenic rodents, respectively, suggest a major role of the CRF1 gene, and the central expression of CRF1 receptor protein in determining an individual’s risk of developing MDD. This gene is widely expressed in brain tissue, and regulates an organism’s immediate and long-term responses to social and environmental stressors, which are primary contributors to MDD. This review presents the current state of knowledge on CRF physiology, and how it may influence the occurrence of symptoms associated with MDD. Additionally, this review presents findings from multiple laboratories that were presented as part of a symposium on this topic at the annual 2014 meeting of the International Behavioral Neuroscience Society (IBNS). The ideas and data presented in this review demonstrate the great progress that has been made over the past few decades in our understanding of MDD, and provide a pathway forward toward developing novel treatments and detection methods for this disorder.

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“…To induce CRHOE in spatio-temporally restricted manner, we used double-mutant mice carrying CamkIIα promoterdriven rtta2 transgene (Michalon et al, 2005) and doxycycline (DOX)-regulated tetO promoter fused to the Crh gene (Vicentini et al, 2009) on a C57BL/6J background as previously described (Toth et al, 2014). The Crh transgene was turned on by DOX administration in breeder chow (Harlan Laboratories, Indianapolis, IN) to 'single-mutant' dams from postnatal day 2 for 3 weeks (PND2-PND23).…”

Section: Generation Of Mice With Inducible Forebrain-specific Crhoementioning

confidence: 99%

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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Transient forebrain over-expression of CRF induces plasma corticosterone and mild behavioural changes in adult conditional CRF transgenic mice

Cited by 27 publications

References 36 publications

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

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

Evidence for the role of corticotropin-releasing factor in major depressive disorder

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

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