Deficiency of Antinociception and Excessive Grooming Induced by Acute Immobilization Stress in Per1 Mutant Mice

Jing Zhang,Huajing Teng,Zhong Sheng Sun,Zhouqiao Wu,Linglin Zhou,Wei Dai,Yongqing Wang,Huili Li,Paul A Bartell

doi:10.1371/journal.pone.0016212

Abstract

Acute stressors induce changes in numerous behavioral parameters through activation of the hypothalamic-pituitary-adrenal (HPA) axis. Several important hormones in paraventricular nucleus of the hypothalamus (PVN) play the roles in these stress-induced reactions. Corticotropin-releasing hormone (CRH), arginine-vasopressin (AVP) and corticosterone are considered as molecular markers for stress-induced grooming behavior. Oxytocin in PVN is an essential modulator for stress-induced antinociception. The clock gene, Per1, has been identified as an effecter response to the acute stresses, but its function in neuroendocrine stress systems remains unclear. In the present study we observed the alterations in grooming and nociceptive behaviors induced by acute immobilization stress in Per1 mutant mice and other genotypes (wild types and Per2 mutant). The results displayed that stress elicited a more robust effect on grooming behavior in Per1 mutant mice than in other genotypes. Subsequently, the obvious stress-induced antinociception was observed in the wild-type and Per2 mutant mice, however, in Per1 mutant, this antinociceptive effects were partially-reversed (mechanical sensitivity), or over-reversed to hyperalgesia (thermal sensitivity). The real-time qPCR results showed that in PVN, there were stress-induced up-regulations of Crh, Avp and c-fos in all of genotypes; moreover, the expression change of Crh in Per1 mutant mice was much larger than in others. Another hormonal gene, Oxt, was up-regulated induced by stress in wild-type and Per2 mutant but not in Per1 mutant. In addition, the stress significantly elevated the serum corticosterone levels without genotype-dependent differences, and accordingly the glucocorticoid receptor gene, Nr3c1, expressed with a similar pattern in PVN of all strains. Taken together, the present study indicated that in acute stress treated Per1 mutant mice, there are abnormal hormonal responses in PVN, correlating with the aberrant performance of stress-induced behaviors. Therefore, our findings suggest a novel functional role of Per1 in neuroendocrine stress system, which further participates in analgesic regulation.

Highlights

When an individual experiences stressful events, the state of disharmony or threatened homeostasis and various physiological and behavioral changes are triggered
Grooming behaviors after exposure to immobilization stress in different genotype mice At the basal level, there were no significant difference in both the grooming bouts and grooming durations between the Mutant and wild-type (M-WT) and other mutant mice (Per1 mutant and Per2 mutant) (Figure 1A and 1B), indicating that under non-stressed state, the normal grooming behaviors are kept at the same level in these genotypes
Since our data have shown the genotype-depended divergences of stress-induced behaviors in the mixed back-ground wild type, Per1 mutant and Per2 mutant mice, we further investigated the mRNA expression profiles of several stress-related genes (Crh, Avp, Oxt, c-fos and Nr3c1, which is the encoding gene of glucocorticoid receptor) and Per genes in paraventricular nucleus of the hypothalamus (PVN) of all strains

Summary

Introduction

When an individual experiences stressful events, the state of disharmony or threatened homeostasis and various physiological and behavioral changes are triggered. Stress induces alterations of brain activity and promotes the changes in various function of brain [1,2,3]. As an important part of rodent behavioral repertoire, grooming is often related to dearousal following various stressors, and plays a critical role in behavioral adaptation to stress. It has been demonstrated that in PVN of mouse, the level of several hormones, such as corticotropin-releasing hormone (Crh), argininevasopressin (Avp) and corticosterone, are important influence factors to the intensity of stress-induced abnormal grooming behavior [12,15,16,17]. Previous studies have shown that physical and psychological stresses are the robust influencers in the abnormality of circadian rhythm [18,19]. There could be anatomical and functional interactions of neural mechanisms between the systems of stress, circadian rhythm and nociception

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Results

Conclusion