Endogenous oxytocin inhibits hypothalamic corticotrophin‐releasing hormone neurones following acute hypernatraemia

Abstract

Significant prior evidence indicates that centrally acting oxytocin robustly modulates stress responsiveness and anxiety‐like behaviour, although the neural mechanisms behind these effects are not entirely understood. A plausible neural basis for oxytocin‐mediated stress reduction is via inhibition of corticotrophin‐releasing hormone (CRH) neurones in the paraventricular nucleus of the hypothalamus (PVN) that regulate activation of the hypothalamic‐pituitary‐adrenal axis. Previously, we have shown that, following s.c. injection of 2.0 mol L−1 NaCl, oxytocin synthesising neurones are activated in the rat PVN, an oxytocin receptor (Oxtr)‐dependent inhibitory tone develops on a subset of parvocellular neurones and stress‐mediated increases in plasma corticosterone levels are blunted. In the present study, we utilised transgenic male CRH‐reporter mice to selectively target PVN CRH neurones for whole‐cell recordings. These experiments reveal that acute salt loading produces tonic inhibition of PVN CRH neurones through a mechanism that is largely independent of synaptic activity. Further studies reveal that a subset of CRH neurones within the PVN synthesise mRNA for Oxtr(s). Salt induced Oxtr‐dependent inhibitory tone was eliminated in individual PVN CRH neurones filled with GDP‐β‐S. Additional electrophysiological studies suggest that reduced excitability of PVN CRH neurones in salt‐loaded animals is associated with increased activation of inwardly rectifying potassium channels. Nevertheless, substantial effort to recapitulate the core effects of salt loading by activating Oxtr(s) with an exogenous agonist produced mixed results. Collectively, these results enhance our understanding of how oxytocin receptor‐mediated signalling modulates the function of CRH neurones in the PVN.

An Angiotensin-Responsive Connection from the Lamina Terminalis to the Paraventricular Nucleus of the Hypothalamus Evokes Vasopressin Secretion to Increase Blood Pressure in Mice

“…P. Li and Pan, 2005). Crosstalk among the neuronal phenotypes residing within the PVN may also contribute to the increased blood pressure that accompanies activation of AT1aR(s), and recent reports demonstrate paracrine signaling within the PVN resulting from dendritic release of neuropeptides (Son et al, 2013;Stern, 2015;Brown et al, 2020;Pati et al, 2020). Finally, it is likely that neurons in the MnPO/OVLT that express AT1aRs make connections beyond the PVN that mediate the autonomic and behavioral effects of Ang-II.…”

“…While completing these studies, we also tested for optogenetic stimulation evoked EPSCs in parvocellular PVN neurons (n = 11) that lacked and I A but exhibited a low threshold spike, a common characteristic of preautonomic neurons with direct projections to the RVLM that control sympathetic outflow to cardiovascular tissues (Luther and Tasker, 2000;Luther et al, 2002). We also recorded from an additional 18 PVN neurons that lacked both I A and low threshold spike, a phenotype observed in corticotrophin-releasing hormone neurosecretory neurons (Wamsteeker Cusulin et Pati et al, 2020). Notably, none of these 29 neurons exhibited an EPSC in response to blue light.…”

Roles of Oxytocin in Stress Responses, Allostasis and Resilience

“…Oxytocin has also been reported to decrease the activity of corticotrophin-releasing hormone (CRH) neurons in the PVN following stress in voles [ 118 ]. The oxytocin receptor is expressed in CRH neurons of the PVN, and oxytocin released by acute salt loading has been suggested to tonically inhibit PVN CRH neurons via the oxytocin receptor [ 119 ].…”

Dendritic osmosensors modulate activity-induced calcium influx in oxytocinergic magnocellular neurons of the mouse PVN

“…It is complicated by the fact that there are both magnocellular and parvocellular hypothalamic OT synthesizing neurons 67 (OT-MCNs, OT-PCNs), and by the fact that OT-MCNs can release peptide both from their axon terminals and from their dendrites. The current study focuses on dendritic physiology of PVN OT-MCNs because 1) OT-MCNs substantially outnumber OT-PCNs (Althammer and Grinevich, 2017), 2) most axons of OT-MCNs project through the median eminence to the posterior pituitary 71 where activity (action potential) dependent release into the vasculature increases peripheral (and 72 not central) OT concentration (Guzek, 1987;Robinson et al, 1989;Falke, 1991), 3) a large portion of 73 OT available for release into the CNS exists in dendritic rather than axonal vesicles that are subject 74 to activity, and calcium, dependent exocytosis (Pow and Morris, 1989;Ludwig et al, 2002;Ludwig 75 and Leng, 2006), 4) such exocytosis supports functionally important peptide mediated paracrine 76 signaling within the hypothalamus (Son et al, 2013;Smith et al, 2015;Pati et al, 2020), and 5) 77 likely also drives volume transmission to increase functional activation of OTRs in a variety of extrahypothalamic cortical and limbic areas (Veening et al, 2010;Fuxe et al, 2012;Ludwig and 79 Stern, 2015;Brown et al, 2020). Indeed, this mechanism seems likely to work in concert with 80 limited/targeted release from centrally projecting axon collaterals of OT neurons, as has been 81…”