Localization of Vasoactive Intestinal Polypeptide Receptor 1 (VPAC1) in Hypothalamic Neuroendocrine Oxytocin Neurons; A Potential Role in Circadian Prolactin Secretion

Abstract

Prolactin (PRL) is a versatile hormone and serves a broad variety of physiological functions besides lactation. The release of PRL from lactotrophs in the pituitary has in rodents been shown to be released with a circadian pattern depending on the physiological state of the animal. The circadian release of PRL seems to be complex involving tonic inhibition by dopamine (DA) neurons on lactotrophs and one or even several releasing factors. Because of the circadian releasing pattern of PRL, neurons in the suprachiasmatic nucleus (SCN), "the brain clock," and especially the neurons expressing neuropeptide vasoactive intestinal polypeptide (VIP), have been suggested to be involved in the circadian regulation of PRL. In the present study, we used fluorescence immunohistochemistry, in situ hybridization histochemistry, confocal microscopy, threedimensional reconstruction, and highly specific antibodies to visualize the occurrence of VIP receptors 1 and 2 (VPAC1 and VPAC2) in mouse brain hypothalamic sections stained in combination with VIP, oxytocin (OXT), arginine vasopressin (AVP), and DA (tyrosine hydroxylase, TH). We demonstrated that VIP fibers most likely originating from the ventral part of the SCN project to OXT neurons in the magnocellular part of the paraventricular nucleus (PVN). In the PVN, VIP fibers were found in close apposition to OXT neuron exclusively expressing the VPAC1 receptor. Furthermore, we demonstrate that neither OXT neurons nor TH or AVP neurons were expressing the VPAC2 receptor. VPAC1 receptor expression was also found on blood vessels but not in neurons expressing AVP or TH. These findings suggest that VIP signaling from the SCN does not directly target DA neurons involved in PRL secretion. Furthermore, the findings support the notion that VIP from neurons in the SCN could regulate circadian release of OXT in the posterior pituitary or modulate OXT neurons as a releasing factor involved in the circadian regulation of PRL from pituitary lactotrophs.

Phenotyping of light-activated neurons in the mouse SCN based on the expression of FOS and EGR1

“…Other SCN neurons project externally to the anterior and mid-and dorsal hypothalamus, representing output-regulating nerve fibers, being involved in the circadian regulation of physiological rhythms ( Paul et al, 2020 ; Ono et al, 2021 ) such as the HPA- and HPG axis via the VPAC1 and the VPAC2 receptor ( Stangerup and Hannibal, 2020 ). It is likely that signaling pathways initiated by the induction of either EGR1 or FOS or both couple to different functionalities.…”

“…It remains to be shown whether AVP neurons in the SCN are directly innervated from the eyes or indirectly via light-sensitive VIP neurons in the ventral SCN projecting to the dorsal shell region ( Abrahamson and Moore, 2001 ; Stangerup and Hannibal, 2020 ), where the VPAC2 receptor is found on neurons ( Hannibal et al, 2017 ; Hannibal et al, 2019 ), some of which express AVP ( An et al, 2012 ). AVP signaling in the SCN is via the V1a and V1b receptors ( Bedont et al, 2018 ) and https://mouse.brain-map.org/gene/show/33433 and https://mouse.brain-map.org/gene/show/26109 .…”

Sexual dimorphism in the bed nucleus of the stria terminalis, medial preoptic area and suprachiasmatic nucleus in male and female tree shrews

“…Vasoactive intestinal polypeptide (VIP), a 28‐amino acid neuropeptide that is mainly synthesized in the suprachiasmatic nucleus (SCN), plays a role in circadian rhythmicity and synchrony (Aton et al, 2005), the regulation of aggression (Kingsbury, 2015) and the modulation of vasopressin and oxytocin release (Bardrum et al, 1988; Stangerup & Hannibal, 2020). The central part of the BST is innervated by VIP cells (Zhou et al, 1995).…”