Dokument

Summary:
Stress is a vital response of all organisms to the demands of life. By adjusting to stimuli from the outside world, and stimuli arising from its internal organs, the body is continually at work to ensure its proper function under a widely variable range of conditions. Thus, acute and adequate responses to such stimuli (stressors) are essential. However, when these responses are either insufficient or excessive, the well-being of the organism is at risk. Furthermore, if stress becomes chronic and the cost of continual adjustment rises, a plethora of illnesses can result. This phenomenon has grown into epidemic proportions, particularly in Western societies, with the physical and mental health of millions severely affected. Despite much research, the mechanisms underlying responses to stressors are still incompletely understood. Our experiments show that the neuropeptide PACAP is required for normal responses to acute stressor exposure. Expanding previous results from our laboratory, evidence is provided for PACAP-dependent regulation of the catecholaminergic system in the adrenal medulla during responses of the ANS. By inducing the expression of enzymes required for epinephrine biosynthesis (tyrosine hydroxylase, phenylethanolamine N-methyltransferase), as well as neuropeptides involved in modulation of adrenal secretory activity (galanin, Tac1, VIP), PACAP appears to provide a mechanism for plasticity during periods of high demand. Our data suggest that this PACAP-dependent stimulus-transcription coupling may proceed via stressor-specific mechanisms, as the induction of a number of transcription factors which are putatively responsible for the regulation of enzymes and neuropeptides (e.g. Egr1, Fos, Nur77) is PACAP-dependent in response to restraint, but not hypoglycemia. Furthermore, PACAP controls upregulation of transcripts encoding potential cytoprotectants (Ier3, Stc1) in the adrenal glands, in response to hypoglycemia and restraint. Most importantly, our present work is the first to show that the endogenous PACAPergic system is required for activation of the HPA axis in response to stressor exposure. This appears to be mediated at the central level, via PACAP-dependent stimulation of hypophysiotropic neurons, as restraint-induced upregulation of CRH mRNA in the PVN is completely abolished in PACAP-deficient mice. Consequently, restraint-induced secretion of ACTH and corticosterone is blunted, particularly when stressor exposure is prolonged, while serum concentrations of both hormones in untreated mice are equivalent to those in wild-types. These PACAP-dependent effects seem to involve PACAP-dependent stimulus-transcription coupling throughout the HPA axis, and possibly rely on inducible transcription factors from the Nr4a family of orphan nuclear receptors. Thus, rapid regulation of Nur77 (Nr4a1), Nurr1 (Nr4a2) and Nor1 (Nr4a3) in the PVN, pituitary gland and adrenal cortex occurs in a PACAP-dependent pattern. The fact that stressor-induced upregulation of transcripts encoding steroidogenic acute regulatory protein (StAR) and steroidogenic factor 1 (SF-1) is significantly attenuated in adrenal glands from PACAP-deficient mice provides a link between PACAP-dependent central control of the HPA axis and peripheral corticosterone production. Beyond the acute regulation of responses to stressor exposure, our results have implications for the understanding, and potentially the treatment, of disease states associated with chronic stress. In this regard, a crucial finding from the present work concerns stressor-induced corticosterone secretion. The initial phase is largely intact in PACAP-deficient animals, while more sustained secretion during prolonged stressor exposure becomes increasingly blunted. This suggests that chronic hypersecretion of glucocorticoids, such as during certain psychiatric illnesses, could be targeted by blockade of the PACAPergic system, without compromising acute HPA responses that are necessary for survival and health. As mentioned, our experiments suggest that PACAP is a central regulator of the HPA axis, controlling activation in response to stressors at the level of the hypothalamic PVN. Future work will address the exact signaling mechanisms employed during PACAP-dependent stress responses, in order to reveal potential avenues for therapeutic intervention. To further clarify the involvement of this neuropeptide in chronic stress-related diseases, the PACAP-deficient mouse model will continue to be used as a valuable tool in experiments concerning the behavioral, physiological, cellular and molecular mechanisms of stress.

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