Urocortin 2-Deficient Mice Exhibit Gender-Specific Alterations in Circadian Hypothalamus–Pituitary–Adrenal Axis and Depressive-Like Behavior

Chen, Alon; Zorrilla, Eric P.; Smith, Sean M.; Rousso, David; Levy, Coree L.; Vaughan, Joan; Donaldson, Cindy; Roberts, Amanda L.; Lee, Kuo‐Fen; Vale, Wylie

doi:10.1523/jneurosci.3955-05.2006

Cited by 92 publications

(82 citation statements)

References 66 publications

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“…These effects were evident only in the female null mice, suggesting a role for Ucn2 in mediating the sex differences observed in the stress response. 37 Both KOM and KOF mice exhibited a stable anxiolytic phenotype along different paradigms ( Figure 2 and Supplementary Figure S2). When subjected to restraint stress before the tests, WTM and WTF mice exhibited an expected increase in anxiety-like behavior (decreasing locomotion and exploration; Figure 3).…”

Section: Discussionmentioning

confidence: 98%

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

et al. 2009

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The urocortin (Ucn) family of neuropeptides is suggested to be involved in homeostatic coping mechanisms of the central stress response through the activation of corticotropin-releasing factor receptor type 2 (CRFR2). The neuropeptides, Ucn1 and Ucn2, serve as endogenous ligands for the CRFR2, which is highly expressed by the dorsal raphe serotonergic neurons and is suggested to be involved in regulating major component of the central stress response. Here, we describe genetically modified mice in which both Ucn1 and Ucn2 are developmentally deleted. The double knockout mice showed a robust anxiolytic phenotype and altered hypothalamic-pituitary-adrenal axis activity compared with wild-type mice. The significant reduction in anxiety-like behavior observed in these mice was further enhanced after exposure to acute stress, and was correlated with the levels of serotonin and 5-hydroxyindoleacetic acid measured in brain regions associated with anxiety circuits. Thus, we propose that the Ucn/ CRFR2 serotonergic system has an important role in regulating homeostatic equilibrium under challenge conditions.

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Section: Discussionmentioning

confidence: 98%

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

et al. 2009

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“…Relatively few behavioral studies implicate the CRF system in sex-linked differences in stress responses. 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).…”

Section: Summary Of the Resultsmentioning

confidence: 87%

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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“…Mice were individually housed for 1 day to minimize disturbance before sampling. Basal CORT levels were measured during the early (0800-0900 hours) and late (1700-1800 hours) phase of the light cycle, when mouse serum CORT levels are expected to be low and high, respectively (Chen et al, 2006;Lechner et al, 2000). Samples for this and all other CORT analyses were collected from trunk blood, following cervical dislocation and rapid decapitation, within 30 s of disturbing the cage.…”

Section: Hpa-axis Profile and Hippocampal Glucocorticoid Receptor Expmentioning

confidence: 99%

Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes

Camp

MacPherson

Lederle

et al. 2012

Neuropsychopharmacol

109

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Mood and anxiety disorders develop in some but not all individuals following exposure to stress and psychological trauma. However, the factors underlying individual differences in risk and resilience for these disorders, including genetic variation, remain to be determined. Isogenic inbred mouse strains provide a valuable approach to elucidating these factors. Here, we performed a comprehensive examination of the extinction-impaired 129S1/SvImJ (S1) inbred mouse strain for multiple behavioral, autonomic, neuroendocrine, and corticolimbic neuronal morphology phenotypes. We found that S1 exhibited fear overgeneralization to ambiguous contexts and cues, impaired context extinction and impaired safety learning, relative to the (good-extinguishing) C57BL/6J (B6) strain. Fear overgeneralization and impaired extinction was rescued by treatment with the front-line anxiety medication fluoxetine. Telemetric measurement of electrocardiogram signals demonstrated autonomic disturbances in S1 including poor recovery of fear-induced suppression of heart rate variability. S1 with a history of chronic restraint stress displayed an attenuated corticosterone (CORT) response to a novel, swim stressor. Conversely, previously stress-naive S1 showed exaggerated CORT responses to acute restraint stress or extinction training, insensitivity to dexamethasone challenge, and reduced hippocampal CA3 glucocorticoid receptor mRNA, suggesting downregulation of negative feedback control of the hypothalamic-pituitary-adrenal axis. Analysis of neuronal morphology in key neural nodes within the fear and extinction circuit revealed enlarged dendritic arbors in basolateral amygdala neurons in S1, but normal infralimbic cortex and prelimbic cortex dendritic arborization. Collectively, these data provide convergent support for the utility of the S1 strain as a tractable model for elucidating the neural, molecular and genetic basis of persistent, excessive fear.

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Urocortin 2-Deficient Mice Exhibit Gender-Specific Alterations in Circadian Hypothalamus–Pituitary–Adrenal Axis and Depressive-Like Behavior

Cited by 92 publications

References 66 publications

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

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

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

Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes

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