Impaired adaptation to repeated restraint and decreased response to cold in urocortin 1 knockout mice

Abstract

) is a corticotropin-releasing factor (CRF)-like peptide whose role in stress is not well characterized. To study the physiological role of UCN1 in the response of the hypothalamic-pituitary-adrenal (HPA) axis to stress, we generated UCN1-knockout (KO) mice and examined their adaptation to repeated restraint and to cold environment. Wild-type (WT) and UCN1-KO animals were restrained hourly for 15 min from 9 AM to 2 PM, and blood samples were obtained for corticosterone measurement. WT animals adapted to repeated restraint with a decreased corticosterone response; the restraint-stimulated corticosterone levels fell from 215 Ϯ 31 ng/ml in naïve animals to 142 Ϯ 50 ng/ml in mice subjected to repeated restraint (P Ͻ 0.01) and from 552 Ϯ 98 to 314 Ϯ 58 ng/ml (P Ͻ 0.001) in males and females, respectively. Male UCN1-KO mice did not show any adaptation to repeated restraint; instead, restraint-stimulated corticosterone levels were increased from 274 Ϯ 80 ng/ml in naïve animals to 480 Ϯ 75 ng/ml in mice subjected to repeated restraint (P Ͻ 0.001). Female UCN1-KO mice showed only a partial adaptation to repeated restraint, with a decrease in the restraint-stimulated corticosterone response from 631 Ϯ 102 ng/ml in naïve animals to 467 Ϯ 78 ng/ml in mice subjected to repeated restraint (P Ͻ 0.01). In addition, UCN1-KO mice showed no corticosterone response to 2-h cold environment. These data demonstrate an important role for UCN1 in the HPA axis adaptation to repeated restraint and in the corticosterone response to a cold environment. corticosterone; stress; mice CORTICOTROPIN-RELEASING FACTOR (CRF) plays a critical role in the physiology of the central nervous system and the regulation of hypothalamic-pituitary-adrenal (HPA) axis activity. CRF is a 41-amino acid peptide that stimulates the secretion of adrenocorticotropic hormone (ACTH) (28). Several studies (7,14) have shown that CRF is the major regulator of the basal and stress-induced activation of the HPA-axis and is involved in several other physiological and behavioral responses. Three CRF receptors have been characterized: CRFR1, CRFR2, and CRFR3. CRFR1 and CRFR2 have been found in mammalian species (8, 10) and Xenopus (12), whereas CRFR3 has been found only in fish (4). The CRF receptors couple to the stimulatory G protein (G s ), which activates adenylate cyclase, leading to accumulation of cAMP in the target cells. The CRF receptors have also been shown to couple to several other G proteins, such as G i , G q , G o , and G z (9,15). CRF binds to CRFR1 with high affinity and to CRFR2 minimally (24).Recently, three CRF-like peptides, urocortin (UCN)1 (29), UCN2 (25), and UCN3 (20), have been discovered in different species. UCN2 and UCN3 bind to CRFR2 with a high affinity, but only UCN2 can activate CRFR1 at higher concentrations. UCN1 has equal affinity to both receptors (24); however, this peptide binds to CRFR1 with an affinity that is similar to that of CRF. The high-affinity interaction between UCN1 and CRFR1 suggests a physiological role for UCN1 in stress ...

Association of HPA axis-related genetic variation with stress reactivity and aggressive behaviour in pigs

“…Urocortin is thought to be involved in the autonomic stress response [53] but so far studies with knockout mouse models have revealed no consistent evidence for an involvement of urocortin in the HPA axis response to acute stress (reviewed in [54]). The study of Zalutskaya et al [55] on the response of urocortin knockout mice to repeated restraint indicates that urocortin may play a role in the adaptation of the HPA axis to chronic stress. Little is known about the function of urocortin in the pig.…”

Urocortins: CRF's siblings and their potential role in anxiety, depression and alcohol drinking behavior

“…Whereas Wang and colleagues (Wang et al, 2002) reported no differences in anxiety-like behaviors, Vetter and colleagues (Vetter et al, 2002) reported increased anxiety-like behaviors in the EPM and OF, but not in the DLT, tests. In a more recently developed Ucn1-KO line a slightly increased glucocorticoid response to an intermittent restraint stress in male (but not female) mice was reported (Zalutskaya et al, 2007). …”

Effects of maternal separation on dynamics of urocortin 1 and brain‐derived neurotrophic factor in the rat non‐preganglionic Edinger‐Westphal nucleus

“…An increasing body of evidence indicates that Ucn1 plays a role in stress adaptation (Skelton et al, 2000; Gysling et al, 2004; Kozicz, 2007): (1) acute stress recruits npEW‐Ucn1 neurons in a stressor‐specific fashion (Weninger et al, 1999, 2000; Kozicz et al, 2001; Gaszner et al, 2004); (2) chronic stress elicits a non‐habituating activation of npEW neurons concomitant with strong down‐regulation of Ucn1 expression (Korosi et al, 2005); (3) one of two Ucn1‐deficient mouse lines show increased anxiety‐like behavior, (Vetter et al, 2002), however, another transgenic animal strain displays normal stress‐induced anxiety with increased acoustic startle (Wang et al, 2002). More recently in a third Ucn1 knock‐out mouse line impaired adaptation to repeated restraint and cold stress has been described (Zalutskaya et al, 2007); (4) interestingly the neurochemical make‐up of the npEW in human patients with major depression who had committed suicide appears to be sex‐specifically affected (Kozicz et al, 2008); (5) and finally, CRF‐over‐expressing mice show decreased Ucn1 expression in the npEW (Kozicz et al, 2004), whereas Weninger et al (2000) reported up‐regulation of Ucn1 mRNA in the npEW of CRF‐knockout mice. Interestingly, in both mutant mice, the stress response by the npEW is intact (Weninger et al, 2000; Kozicz et al, 2004).…”