Pituitary Adenylate Cyclase-Activating Polypeptide Controls Stimulus-Transcription Coupling in the Hypothalamic-Pituitary-Adrenal Axis to Mediate Sustained Hormone Secretion During Stress

Abstract

External and internal stimuli that threaten homeostasis trigger coordinated stress responses through activation of specialised neuroendocrine circuits. In mammals, the hypothalamic-pituitary-adrenal (HPA) axis mediates responses to stressors such as restraint, ultimately enhancing adrenocortical hormone secretion. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in central control of the HPA axis, and we have recently shown PACAP-dependent expression of corticotropin-releasing hormone (CRH) and secretion of corticosterone in response to restraint. We now provide a more detailed analysis of PACAP-dependent HPA axis stimulation in the mouse, indicating that the hypothalamic paraventricular nucleus (PVN) is the primary site of action. We demonstrate by quantitative PCR and in situ hybridisation that upregulation of mRNAs encoding CRH and inducible transcription factors from the Nr4a family (Nur77, Nor1) in the PVN is PACAP-dependent. Furthermore, CRH hnRNA is rapidly upregulated in cultured hypothalamic neurones after treatment with PACAP. Induction of Nr4a factors (Nur77, Nurr1) in response to restraint is attenuated in the pituitary gland of PACAP-deficient mice. In the adrenal glands, restraint elicits a marked PACAP-dependent increase in adrenocortical mRNA levels of all three Nr4a transcription factors, SF-1 (steroidogenic factor 1; Nr5a1), steroidogenic acute regulatory protein (StAR) and steroid 21-hydroxylase. Taken together, our results show that PACAP controls HPA responses to restraint primarily at the level of the hypothalamus by upregulating CRH, possibly involving transcription factors such as Nur77 and Nor1. Subsequent adrenocortical steroidogenesis also appears to involve PACAP-dependent stimulus-transcription coupling, suggesting a mechanism by which PACAP exerts control over HPA axis function during stress.

Impact of PACAP and PAC1 receptor deficiency on the neurochemical and behavioral effects of acute and chronic restraint stress in male C57BL/6 mice

“…If the effects of PACAP neurotransmission at the level of the PVN during stress responding are exerted largely on CRH biosynthesis subsequent to neuronal activation, as previously suggested by Stroth et al (Stroth et al, 2011b), the effects of PACAP deficiency on sustained CORT elevation during chronic stress would be predicted to become progressively more prominent, as initially reported by our laboratory in the context of chronic social defeat (Lehmann et al, 2013). We measured CORT levels prior to the onset of chronic restraint stress (CRS), and on days 1, 4, and 7 during one week of daily (two hours per day) restraint (see Figure 3A for experimental design).…”

“…Furthermore, while HPA axis activation following psychogenic stress (i.e. chronic social defeat, acute restraint stress, open field exploration) is decreased in PACAP-deficient mice, CORT elevation following acute systemic stressors (hypoglycemia, lipopolysaccharide administration, or cold stress) is not (Lehmann et al, 2013; Stroth and Eiden, 2010; Stroth et al, 2011a; Stroth et al, 2011b; Tsukiyama et al, 2011). These studies implicate PACAP and its receptor(s) as possible targets in therapy for stress-related depression, and, along with recent clinical data (Ressler et al, 2011), potentially for depressive behavioral effects occurring in post-traumatic stress disorder (Hammack et al, 2012).…”

“…The PACAP receptor, PAC1, has been implicated in transducing the peripheral effects of PACAP on the adrenal medulla in both acute and chronic stress due to either psychogenic or systemic stressors in mice (Stroth and Eiden, 2010; Stroth et al, 2011a; Stroth et al, 2013; Stroth et al, 2011b). Both PACAP and the PAC1 receptor are also implicated in the anxiogenic effects of PACAP during chronic variate stress, mediated at the level of the extended amygdala, in the rat (Hammack et al, 2010; Roman et al, 2014).…”

Is PACAP the Major Neurotransmitter for Stress Transduction at the Adrenomedullary Synapse?

“…Several laboratories have now firmly implicated PACAP as a major transmitter regulating circadian function in the suprachiasmatic nucleus (co-released with glutamate from retinohypothalamic neurons) (Beaule et al 2009; Colwell and Waschek 2001), hypothalamohypophysial ACTH secretion (Stroth et al 2011), and anxiety responses in the bed nucleus of the stria terminalis (Hammack et al 2010). The high density of expression of the PAC1 receptor in the dentate gyrus of the hippocampus, and in the cerebellum (Zhou et al 2000), suggests that these systems as well may be ones in which PACAP, far from merely modulating transmission, is a primary neurotransmitter under conditions in which LDCV-associated transmitters are selectively deployed by high neuronal firing rates.…”

Molecular Regulation of Corticotropin-Releasing Hormone Gene Expression in Parvocellular Neurons of the Hypothalamic Paraventricular Nucleus

“…Second, pituitary adenylate cyclase activating polypeptide (PACAP), shown to stimulate CRH transcription in hypothalamic neuron primary cultures. Consistent with an important role of PACAP on HPA axis activation, PACAP knockout mice display attenuated HPA axis responses to stress with blunted CRH mRNA responses in the PVN [22]. Third, glucagon-like peptide 1 (GLP-1), released in the PVN by non-catecholaminergic neurons from the nucleus of the solitary tract, is also known to stimulates CRH expression and its blockade inhibits HPA axis activity [23].…”