Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

Neufeld-Cohen, Adi; Evans, Andrew K.; Getselter, Dmitriy; Spyroglou, Ariadni; Hill, Angela L.; Gil, Shosh; Tsoory, Michael; Beuschlein, Felix; Lowry, Christopher A.; Vale, Wylie; Chen, Alon

doi:10.1038/mp.2009.115

Cited by 51 publications

(46 citation statements)

References 96 publications

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“…For CRFR2 in situ hybridization, antisense and sense (control) RNA probes were generated using CRFR2α cDNA and labeled with DIG-11-UTP using a labeling kit (Roche Molecular Biochemicals). In situ hybridization for CRFR2α mRNAs was carried out with the free-floating section method as previously described (51). Doxycycline Administration.…”

Section: Methodsmentioning

confidence: 99%

Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis

Kuperman

Issler²,

Regev³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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In response to physiological or psychological challenges, the brain activates behavioral and neuroendocrine systems linked to both metabolic and emotional outputs designed to adapt to the demand. However, dysregulation of integration of these physiological responses to challenge can have severe psychological and physiological consequences, and inappropriate regulation, disproportional intensity, or chronic or irreversible activation of the stress response is linked to the etiology and pathophysiology of mood and metabolic disorders. Using a transgenic mouse model and lentiviral approach, we demonstrate the involvement of the hypothalamic neuropeptide Urocortin-3, a specific ligand for the type-2 corticotropin-releasing factor receptor, in modulating septal and hypothalamic nuclei responsible for anxiety-like behaviors and metabolic functions, respectively. These results position Urocortin-3 as a neuromodulator linking stress-induced anxiety and energy homeostasis and pave the way toward better understanding of the mechanisms that mediate the reciprocal relationships between stress, mood and metabolic disorders.metabolic disorders | mood disorders | corticotropin-releasing factor (CRF) | CRF receptor type 2 | stress response I n modern Western societies, the high stress load correlates with an increasing incidence of mood disorders and metabolic syndrome, both of which have reached epidemic proportions over the past decades (1, 2). Exposure to acute or chronic stress is associated with derangement of metabolic and behavioral homeostasis that contributes to the clinical presentation of visceral obesity, type 2 diabetes, atherosclerosis, and metabolic syndrome (2-4). The corticotropin-releasing factor (CRF) neuropeptide system is the primary central mediator of the stress response and contributes to the etiology of stress-related psychiatric illness (5-8). Studies conducted using CRF receptor type 2 (CRFR2)-null mice or Urocortin-2 (Ucn2)-null mice provided evidence that, in addition to its role in mediating stress-related behavior, central CRFR2 is important in modulating metabolic rate, appetite, and feeding behaviors (9-12).The Urocortin-3 (Ucn3) neuropeptide selectively binds and activates CRFR2. Ucn3 is expressed predominately within the hypothalamus, in the median preoptic nucleus and the rostral perifornical area (rPFA) (13-15). The major rPFA-Ucn3 terminal fields, the lateral septum (LS) and the ventromedial hypothalamus (VMH), express high levels of CRFR2 (15). Different stressors and homeostatic insults influence Ucn3 expression levels, suggesting its position as a potential modulator of the stress response (13,16).To assess the functional relevance of endogenous rPFA-Ucn3 neuronal pathways, activating the CRFR2 both in the LS and the VMH, in mediating behavioral and metabolic responses to challenge, we used a site-specific and inducible genetic approach in vivo. We report that rPFA-Ucn3 overexpression induces an anxiety-like behavior, increases the respiratory exchange ratio (RER) and heat production, an...

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Section: Methodsmentioning

confidence: 99%

Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis

Kuperman

Issler²,

Regev³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Plasma corticosterone levels were measured by ELISA as described previously (Neufeld-Cohen et al, 2010a). New cohorts of AMY-DCR-KO and control mice were single housed 24 h before testing.…”

Section: Corticosterone Measurementsmentioning

confidence: 99%

microRNA as Repressors of Stress-Induced Anxiety: The Case of Amygdalar miR-34

Haramati¹,

Navon²,

Issler³

et al. 2011

J. Neurosci.

228

178

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The etiology and pathophysiology of anxiety and mood disorders is linked to inappropriate regulation of the central stress response. To determine whether microRNAs have a functional role in the regulation of the stress response, we inactivated microRNA processing by a lentiviral-induced local ablation of the Dicer gene in the central amygdala (CeA) of adult mice. CeA Dicer ablation induced a robust increase in anxiety-like behavior, whereas manipulated neurons survive and appear to exhibit normal gross morphology in the time period examined. We also observed that acute stress in wild-type mice induced a differential expression profile of microRNAs in the amygdala. Bioinformatic analysis identified putative gene targets for these stress-responsive microRNAs, some of which are known to be associated with stress. One of the prominent stress-induced microRNAs found in this screen, miR-34c, was further confirmed to be upregulated after acute and chronic stressful challenge and downregulated in Dicer ablated cells. Lentivirally mediated overexpression of miR34c specifically within the adult CeA induced anxiolytic behavior after challenge. Of particular interest, one of the miR-34c targets is the stress-related corticotropin releasing factor receptor type 1 (CRFR1) mRNA, regulated via a single evolutionary conserved seed complementary site on its 3Ј UTR. Additional in vitro studies demonstrated that miR-34c reduces the responsiveness of cells to CRF in neuronal cells endogenously expressing CRFR1. Our results suggest a physiological role for microRNAs in regulating the central stress response and position them as potential targets for treatment of stress-related disorders.

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“…Mouse breeding took place at the Weizmann Institute of Science, Rehovot, Israel. Mice lacking two or all the three Ucn genes (Ucn1, Ucn2, and Ucn3) were generated by crossbreeding of Ucn1, Ucn2, and Ucn3 single KO mice, which has been reported earlier (Vetter et al 2002, Chen et al 2006, Neufeld-Cohen et al 2010a. All mice were on a mixed C57BL/6!129 background.…”

Section: Animals and Housing Conditionsmentioning

confidence: 99%

Urocortin-dependent effects on adrenal morphology, growth, and expression of steroidogenic enzymes in vivo

Riester

Spyroglou²,

Neufeld-Cohen³

et al. 2012

Journal of Molecular Endocrinology

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Urocortin (UCN) 1, 2, and 3 are members of the corticotropin-releasing factor (CRF) family that display varying affinities to the CRF receptor 1 (CRFR1 (CRHR1)) and 2 (CRFR2 (CRHR2)). UCNs represent important modulators of stress responses and are involved in the control of anxiety and related disorders. In addition to the CNS, UCNs and CRFRs are highly expressed in several tissues including the adrenal gland, indicating the presence of UCN-dependent regulatory mechanisms in these peripheral organ systems. Using knockout (KO) mouse models lacking single or multiple Ucn genes, we examined the potential role of the three different Ucns on morphology and function of the adrenal gland. Adrenal morphology was investigated, organ size, cell size, and number were quantified, and growth kinetics were studied by proliferative cell nuclear antigen staining and Ccnd1 expression analysis. Furthermore, mRNA expression of enzymes involved in steroidogenesis and catecholamine synthesis was quantified by real-time PCR. Following this approach, Ucn2, Ucn1/Ucn2 dKO and Ucn1/Ucn2/Ucn3 tKO animals showed a significant cellular hypotrophy of the adrenal cortex and an increase in Ccnd1 expression, whereas in all other genotypes, no changes were observable in comparison to age-matched controls. For steroidogenesis, Ucn2/Ucn3 dKO animals displayed the most pronounced changes, with significant increases in all investigated enzymes, providing indirect evidence for increased stress behavior. Taken together, these data suggest that mainly Ucn2 and Ucn3 could be involved in adrenal stress response regulation while Ucn2 additionally appears to play a role in morphology and growth of the adrenal gland.

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Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

Cited by 51 publications

References 96 publications

Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis

Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis

microRNA as Repressors of Stress-Induced Anxiety: The Case of Amygdalar miR-34

Urocortin-dependent effects on adrenal morphology, growth, and expression of steroidogenic enzymes in vivo

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