Elsevier

Neuroscience

Volume 165, Issue 4, 17 February 2010, Pages 1025-1030
Neuroscience

Rapid Report
Stress hormone synthesis in mouse hypothalamus and adrenal gland triggered by restraint is dependent on pituitary adenylate cyclase-activating polypeptide signaling

https://doi.org/10.1016/j.neuroscience.2009.11.023Get rights and content

Abstract

Stress responses are elicited by a variety of stimuli and are aimed at counteracting direct or perceived threats to the well-being of an organism. In the mammalian central and peripheral nervous systems, specific cell groups constitute signaling circuits that indicate the presence of a stressor and elaborate an adequate response. Pituitary adenylate cyclase-activating polypeptide (PACAP) is expressed in central and peripheral parts of these circuits and has recently been identified as a candidate for regulation of the stress axis. In the present experiments, we tested the involvement of PACAP in the response to a psychological stressor in vivo. We used a restraint paradigm and compared PACAP-deficient mice (PACAP−/−) to wild-type controls (PACAP+/+). Acute secretion of corticosterone elicited by 1 h of restraint was found to be identical between genotypes, whereas sustained secretion provoked by 6 h of unrelieved restraint was 48% lower in PACAP−/−mice. Within the latter time frame, expression of messenger RNA (mRNA) encoding corticotropin-releasing hormone (CRH) was increased in the hypothalamus of wild type, but not PACAP-deficient mice. Expression of the activity-regulated transcription factors Egr1 (early growth response 1) and Fos (FBJ osteosarcoma oncogene) in the hypothalamus was rapidly and transiently induced by restraint in a PACAP-dependent fashion, a pattern that was also found in the adrenal glands. Here, abundance of transcripts encoding enzymes required for adrenomedullary catecholamine biosynthesis, namely TH (tyrosine hydroxylase) and PNMT (phenylethanolamine N-methyltransferase), was higher in PACAP+/+ mice after 6 h of unrelieved restraint. Our results suggest that sustained corticosterone secretion, synthesis of the hypophysiotropic hormone CRH in the hypothalamus, and synthesis of the enzymes producing the hormone adrenaline in the adrenal medulla, are controlled by PACAP signaling in the mouse. These findings identify PACAP as a major contributor to the stimulus-secretion-synthesis coupling that supports stress responses in vivo.

Section snippets

Animals and restraint paradigm

Male mice (3.4–5.4 months of age) harboring the PACAP−/− allele (Hamelink et al., 2002) were used in the present study and compared to age-matched PACAP+/+ (wild type) mice. All mice represent a full backcross of the knock-out allele into the C57BL/6N strain. They were housed in a temperature- and humidity-controlled facility with 12 h light/dark cycle (lights on at 6:00 am) and had access to chow and water ad libitum. Experiments were conducted in a separate room to which animals were

Results

Restraint caused marked elevation of corticosterone secretion in both genotypes within 1 h (Fig. 1A). However, only PACAP+/+ mice maintained high serum levels during prolonged restraint, while secretion was significantly impaired in PACAP−/− mice (dotted line). Thus, after 6 h of unrelieved restraint (group 6 h), corticosterone levels were reduced by 48% compared with PACAP+/+ (Fig. 1A). Within the same time frame, hypothalamic levels of corticotropin-releasing hormone (CRH) mRNA increased

Discussion

Neuropeptides are preferentially released under conditions of intense neural activation and thus represent “the language of the stressed nervous system” (Hokfelt et al., 2003). Recent evidence has implicated PACAP in the control of stress responses at multiple central and peripheral levels (Vaudry et al., 2009). PACAP-immunoreactive nerve fibers are numerous in the PVN (Hannibal, 2002), where PACAP-containing terminals innervate CRH-positive neurons (Legradi et al., 1998) and i.c.v. injection

Conclusion

Our results provide compelling evidence that PACAP is required for sustained function of the stress axis under conditions of persistent stressor exposure. By controlling corticosterone secretion, transcriptional induction of activity-regulated genes, and key neuroendocrine factors in the hypothalamus and adrenal gland, PACAP could serve as a master integrator of stress signaling in the central and peripheral nervous system.

Acknowledgments

This work was supported by NIMH Intramural Research Program ProjectZ01 MH002386-23.

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