Combined hypoxia and hypercapnia, but not hypoxia alone, suppresses neurotransmission from orexin to hypothalamic paraventricular spinally-projecting neurons in weanling rats

Abstract

Both orexin neurons in the lateral hypothalamus and spinally-projecting pre-sympathetic neurons (PSNs) in the paraventricular nucleus of the hypothalamus (PVN) play an important role in the regulation of cardiovascular function under normal conditions and during cardiovascular challenges such as hypoxia and/or hypercapnia. We have previously established, using selective optogenetic excitation of orexin neurons and pathways, there is a heterogeneous neurotransmission from orexin neurons to PSNs in the PVN. This study was undertaken to test whether this pathway is altered by acute exposure to hypoxia alone and/or combined hypoxia and hypercapnia (H/H). To test this hypothesis, we selectively expressed channelrhodopsin-2 (ChR2) in orexin neurons in the lateral hypothalamus and photoactivated ChR2-expressing fibers to evoke postsynaptic currents in spinally-projecting PSNs in an in vitro slice preparation in rats. In accordance with previously published data, two subpopulations of spinally-projecting PSNs were established, including those with glutamatergic or GABAergic inputs from orexin neurons. Hypoxia alone did not alter the peak amplitude of either glutamatergic or GABAergic neurotransmission, however, H/H significantly inhibited both glutamatergic and GABAergic neurotransmission from orexin neurons to SPNs. In conclusion, H/H may modulate cardiovascular function by affecting heterogeneous pathways from orexin neurons to spinally-projecting PSNs in the PVN.

Current Management of Residual Excessive Daytime Sleepiness Due to Obstructive Sleep Apnea: Insights for Optimizing Patient Outcomes

“…In a hypoxia model in cultured rat hippocampal neurons, orexin-A increased intermittent hypoxemia-induced hippocampal neuronal damage by overphosphorylation of extracellular signal-regulated kinase 1/2 through the orexin receptor–phospholipase C-β1 (PLCβ1) pathway [ 43 ]. In addition, chronic exposure to hypoxia/hypercapnia has been shown to compromise neurotransmission from orexin neurons to parasympathetic cardiac vagal neurons [ 37 , 44 , 45 ]. Results from these rat studies suggest that exaggerated inhibitory neurotransmission from the lateral paragigantocellular nucleus to cardiac vagal neurons may lead to a sleep-associated high risk of tachycardia, arrhythmia, and sudden cardiac death in people with OSA [ 44 ].…”

Intermittent hypercapnic hypoxia induces respiratory hypersensitivity to fentanyl accompanied by tonic respiratory depression by endogenous opioids

“…2014; Dergacheva et al . 2016; Dergacheva & Mendelowitz, 2018) or without (Kline et al . 2007; Kc et al .…”

International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology

“…It has also been suggested that the hypoxiastimulated C1 cell group could activate orexin neurons (Kim et al, 2016). In contrast, hypoxia alone (weakly) or combined hypoxia and hypercapnia (more strongly) have been reported to inhibit orexin neurons in rat hypothalamic slice preparations (Dergacheva and Mendelowitz, 2017).…”