Colocalized neurotransmitters in the hindbrain cooperate in adaptation to chronic hypernatremia

Abstract

Chronic hypernatremia activates the central osmoregulatory mechanisms and inhibits the function of the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline (NE) release into the periventricular anteroventral third ventricle region (AV3V), the supraoptic (SON) and hypothalamic paraventricular nuclei (PVN) from efferents of the caudal ventrolateral (cVLM) and dorsomedial (cDMM) medulla has been shown to be essential for the hypernatremia-evoked responses and for the HPA response to acute restraint. Notably, the medullary NE cell groups highly coexpress prolactin-releasing peptide (PrRP) and nesfatin-1/NUCB2 (nesfatin), therefore, we assumed they contributed to the reactions to chronic hypernatremia. To investigate this, we compared two models: homozygous Brattleboro rats with hereditary diabetes insipidus (DI) and Wistar rats subjected to chronic high salt solution (HS) intake. HS rats had higher plasma osmolality than DI rats. PrRP and nesfatin mRNA levels were higher in both models, in both medullary regions compared to controls. Elevated basal tyrosine hydroxylase (TH) expression and impaired restraint-induced TH, PrRP and nesfatin expression elevations in the cVLM were, however, detected only in HS, but not in DI rats. Simultaneously, only HS rats exhibited classical signs of chronic stress and severely blunted hormonal reactions to acute restraint. Data suggest that HPA axis responsiveness to restraint depends on the type of hypernatremia, and on NE capacity in the cVLM. Additionally, NE and PrRP signalization primarily of medullary origin is increased in the SON, PVN and AV3V in HS rats. This suggests a cooperative action in the adaptation responses and designates the AV3V as a new site for PrRP's action in hypernatremia.

Brain RFamide Neuropeptides in Stress-Related Psychopathologies

“…Neuropeptides are coexpressed with classic neurotransmitters, monoamines, and other neuropeptides. They are released under challenged conditions and help to fine-tune cellular activity [17][18][19]. The expression of neuropeptides is usually restricted to a small population of neurons, and they bind to their receptors with high affinity and specificity.…”

“…Practically, no PrRP fibers are detected in the median eminence [130,177,189] confirming that PrRP does not function as a neurohormone. Non-hypothalamic PrRP efferents target stress-related emotional and autonomic centers: the BNST, the septal nuclei, the central AMY, the paratenial thalamic nucleus, the AP, and the NTS [19,130,177]. PrRP axon terminals form close contacts with CRH, oxytocin, and somatostatin neurons in the PVN [130,177].…”

“…High or moderate PrRPR expression has been detected in the BNST, HTH (preoptic nuclei, AV3V, DMN, PeN, PVN), AMY, LC, NTS, and AP (Figure 3). Several other brain areas, such as the perifornical area, the LHA, and the PBN show lower levels of PrRPR expression [19,179,190,194,195].…”

“…Nesfatin-1/NUCB2 is also a stress molecule; it activates the HPA, and its expression is increased after restraint stress in the A1 and A2 cell groups [242]. The cooperative function of PrRP and nesfatin-1/NUCB2 in A1/A2 cell groups occurs during chronic stress, which may be important for maintaining the NA capacity of the cells [19].…”

“…Therefore, the PrRP-NA coexpressing neurons in the NTS are in a gating position between the vagus-mediated visceral signals and the brain. However, the medullary PrRP-NA neurons and the noncatecholaminergic PrRP cells in the DMN contribute almost equally to the innervation of different hypothalamic regions, including the PVN [19]. This suggests that PrRP neurons in the DMN play an important role in homeostatic regulation, including the control of stress response.…”