Urocortin-Deficient Mice Display Normal Stress-Induced Anxiety Behavior and Autonomic Control but an Impaired Acoustic Startle Response

Wang, Xiaozhong; Su, Hua; Copenhagen, Leslie D.; Vaishnav, Sukishi; Pieri, Fredalina; Shope, Cynthia; Brownell, William E.; Biasi, Mariella De; Paylor, Richard; Bradley, Allan

doi:10.1128/mcb.22.18.6605-6610.2002

Cited by 71 publications

(50 citation statements)

References 38 publications

(41 reference statements)

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“…In previous studies, it has been described that Ucn1 KO mice display normal hormonal responses to acute stress (Vetter et al 2002, Wang et al 2002. In accordance with these findings, we demonstrated that the structure of the inner adrenal cortex as well as the expression levels of the enzymes involved in corticosterone and catecholamine synthesis remained unchanged.…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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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“…Ucn1 (56,57), Ucn2 (58), and Ucn3 (59) individual KO mouse models have not indicated a clear anxious phenotype, perhaps because of differences in the time points of assessment following the stress exposure. Because the CRFR2 system was suggested to mediate restoration of allostasis (1,12), further testing individual urocortin-KO models at time points that better reflect recovery processes, combined with the use of site-specific manipulations of those genes in adult mice (to avoid developmental compensatory changes), may promote further understanding of the role of each urocortin gene product in regulating the central stress response.…”

Section: Discussionmentioning

confidence: 99%

A triple urocortin knockout mouse model reveals an essential role for urocortins in stress recovery

Neufeld-Cohen

Tsoory²,

Evans³

et al. 2010

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

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Responding to stressful events requires numerous adaptive actions involving integrated changes in the central nervous and neuroendocrine systems. Numerous studies have implicated dysregulation of stress-response mechanisms in the etiology of stress-induced psychopathophysiologies. The urocortin neuropeptides are members of the corticotropin-releasing factor family and are associated with the central stress response. In the current study, a tripleknockout (tKO) mouse model lacking all three urocortin genes was generated. Intriguingly, these urocortin tKO mice exhibit increased anxiety-like behaviors 24 h following stress exposure but not under unstressed conditions or immediately following exposure to acute stress. The inability of these mutants to recover properly from the exposure to an acute stress was associated with robust alterations in the expression profile of amygdalar genes and with dysregulated serotonergic function in stress-related neurocircuits. These findings position the urocortins as essential factors in the stress-recovery process and suggest the tKO mouse line as a useful stress-sensitive mouse model. amygdala | anxiety-like behaviors | serotonergic system | corticotropinreleasing factor | corticotropin-releasing factor receptor type 2 D ysregulation of stress-response mechanisms is proposed to underlie a variety of stress-related psychopathologies (1, 2). Corticotropin-releasing factor (CRF) plays a pivotal and wellestablished role in regulating the hypothalamic-pituitary-adrenal (HPA) axis under basal and stress conditions (3, 4) and, via its type 1 receptor (CRFR1), integrates the autonomic, metabolic and behavioral stress responses (5).The CRF peptide family includes also three urocortin (Ucn) peptides (Ucn1, Ucn2, and Ucn3) that bind and activate the CRF receptor type 2 (CRFR2) with high affinity (6-12). CRF has a relatively lower affinity for CRFR2 than for CRFR1; Ucn1 has equal affinities for both; and Ucns 2 and 3 appear to be selective for CRFR2 (6-9). These receptors are distributed differently throughout the brain: CRFR1 is widely expressed in various brain regions, whereas CRFR2 expression is more localized to selected stress-related brain nuclei, such as the amygdala, the bed nucleus of the stria terminalis (BNST), the lateral septum (LS), and the dorsal raphe nucleus (DRN) (13,14).Evidence from studies using competitive peptides or smallmolecule CRF/urocortin receptor antagonists suggested that the brain CRF/urocortin systems play diverse roles in mediating behavioral responses to stress (15). Based on the complementary behavioral phenotypes of CRFR1-and CRFR2-deficient (KO) mice, opposing roles were suggested for the two CRF receptors systems in modulating anxiety-like behaviors. CRFR1KO mice display decreased anxiety-like behaviors coupled with an impaired HPA axis stress response (16, 17), whereas CRFR2KO mice show increased anxiety-like behaviors and an accelerated HPA-axis response to stress (18,19). Thus, the CRF-CRFR1 system has been suggested as critical for initiating str...

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“…However, Ucn 1 is not a likely physiologic regulator of the HPA axis. Unlike CRF-deficient mice [290], Ucn 1-deficient mice exhibit normal basal and stress-induced HPA hormone levels [292,296]. Similarly, unlike CRF antisera, peripheral administration of specific Ucn 1 antisera does not modify basal, stressinduced or adrenalectomy-induced ACTH levels [179,278].…”

Section: Physiologic and Behavioral Effects Of Ucnsmentioning

confidence: 99%

Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: Ancient CRF paralogs

Fekete

Zorrilla

2007

Frontiers in Neuroendocrinology

219

252

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Urocortins, three paralogs of the stress-related peptide corticotropin-releasing factor (CRF) found in bony fish, amphibians, birds and mammals, have unique phylogenies, pharmacologies, and tissue distributions. As a result and despite a structural family resemblance, the natural functions of urocortins and CRF in mammalian homeostatic responses differ substantially. Endogenous urocortins are neither simply counterpoints nor mimics of endogenous CRF action. In their own right, urocortins may be clinically relevant molecules in the pathogenesis or management of many conditions, including congestive heart failure, hypertension, gastrointestinal and inflammatory disorders (irritable bowel syndrome, active gastritis, gastroparesis, rheumatoid arthritis), atopic/ allergic disorders (dermatitis, urticaria, asthma), pregnancy and parturition (preeclampsia, spontaneous abortion, onset and maintenance of effective labor), major depression and obesity. Safety trials for intravenous urocortin treatment have already begun for the treatment of congestive heart failure. Further understanding the unique functions of urocortin 1, urocortin 2 and urocortin 3 action may uncover other therapeutic opportunities. KeywordsUrocortin 1 or urocortin 2 or urocortin 3 or stresscopin or stresscopin-related peptide; corticotropinreleasing factor or CRF or corticotropin-releasing hormone or CRH or corticoliberin; stress response; peptide; anxiety or depression; pregnancy; labor or parturitition; food intake or energy balance or obesity; inflammation or immune system; salt or fluid balance; cardiovascular or hypertension or heart failure; gastrointestinal motility or irritable bowel syndrome

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Urocortin-Deficient Mice Display Normal Stress-Induced Anxiety Behavior and Autonomic Control but an Impaired Acoustic Startle Response

Cited by 71 publications

References 38 publications

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

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

A triple urocortin knockout mouse model reveals an essential role for urocortins in stress recovery

Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: Ancient CRF paralogs

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