Rapid ReportStress hormone synthesis in mouse hypothalamus and adrenal gland triggered by restraint is dependent on pituitary adenylate cyclase-activating polypeptide signaling
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.
References (33)
- et al.
Pituitary adenylate cyclase-activating polypeptide (PACAP) mimics neuroendocrine and behavioral manifestations of stress: evidence for PKA-mediated expression of the corticotropin-releasing hormone (CRH) gene
Mol Brain Res
(2005) - et al.
Neuronal localization of pituitary adenylate cyclase-activating polypeptide 38 in the adrenal medulla and growth-inhibitory effect on chromaffin cells
Neuroscience
(1995) - et al.
Effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on corticotropin-releasing hormone (CRH) gene expression in the rat hypothalamic paraventricular nucleus
Brain Res
(1997) - et al.
Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): roles for PACAP in anxiety-like behavior
Psychoneuroendocrinology
(2009) - et al.
Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis
Trends Neurosci
(1997) - et al.
Chronic stress plasticity in the hypothalamic paraventricular nucleus
Prog Brain Res
(2008) - et al.
Neuropeptides: opportunities for drug discovery
Lancet Neurol
(2003) - et al.
Induction of multiple immediate early genes in rat hypothalamic paraventricular nucleus after stress
Brain Res Mol Brain Res
(1994) - et al.
Pituitary adenylate cyclase-activating polypeptide-nerve terminals densely innervate corticotropin-releasing hormone-neurons in the hypothalamic paraventricular nucleus of the rat
Neurosci Lett
(1998) - et al.
Behavioral effects of local microinfusion of pituitary adenylate cyclase activating polypeptide (PACAP) into the paraventricular nucleus of the hypothalamus (PVN)
Regul Pept
(2005)
Regulation of vertebrate corticotropin-releasing factor genes
Gen Comp Endocrinol
Negative regulation of corticotropin releasing factor expression and limitation of stress response
Stress
Hypothalamic and brainstem sources of pituitary adenylate cyclase-activating polypeptide nerve fibers innervating the hypothalamic paraventricular nucleus in the rat
J Comp Neurol
PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo
Am J Physiol Regul Integr Comp Physiol
Evolution of concepts of stress
Stress
Adrenomedullary, adrenocortical, and sympathoneural responses to stressors: a meta-analysis
Endocr Regul
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