Norepinephrine modulation of parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) during normoxia and chronic intermittent hypoxia

Abstract

The PVN is important for eliciting the cardiorespiratory reflex responses to a variety of stimuli and stressors. This is accomplished, in part, via reciprocal connections to several nuclei, including the ventrolateral medulla (VLM) and nucleus tractus solitarii (nTS). The PVN receives dense norepinephrine (NE) projections from the VLM and nTS. The α‐1 and α‐2 adrenergic receptors (aAR) are present in PVN, and stimulation of α‐ARs increase blood pressure and sympathetic outflow. Hypoxia is a stressor stimulus that activates PVN, VLM and nTS neurons, including catecholaminergic VLM and nTS neurons. CIH is a model for obstructive sleep apnea (OSA), and like OSA, elevates respiration, induces sympathoexcitation and hypertension and increases circulating NE. The contribution of the PVN, and the role of NE in the PVN, in CIH remains elusive. We determined the electrophysiological properties of PVN parvocellular neurons in response to NE in normoxia and CIH. Male Sprague‐Dawley rats (110–150 g) were exposed to either 10 days normoxia (Norm, FiO2 = 21%, n = 8) or CIH (alternating FiO2 = 21% and 6%, 8 hr/day, n = 5). PVN slices (~280 μm) were generated and cell capacitance (Cm), initial input resistance, holding currents (Ihold) and spontaneous excitatory postsynaptic currents (sEPSCs) were examined by whole cell patch clamp. Ihold and sEPSCs were recorded under aCSF baseline, and following 10 or 100 mM NE (5 min) and/or the α‐1 AR antagonist prazocin (10 mM). Norm and CIH neurons were of similar size [Cm; Norm, 17.7 ± 2.8 pF (n=19) vs CIH, 17.1 ± 1.8 pF (n=15)], but CIH decreased initial input resistance [Rin; Norm, 2.2 ± 0.4 GΩ (n=19) vs CIH, 1.0 ± 0.4 GΩ (n=15)]. Between Norm (n=19) and CIH (n=15), baseline sEPSC frequency (15.9 ± 1.5 vs 13.5 ± 2.5 Hz) and amplitude (11.9 ± 1.4 vs 15.2 ± 2.2 pA) were similar. In Norm cells, 10 mM NE increased, but not significantly, sEPSC frequency (9.1 ± 2.4 to 19.4 ± 4.5 Hz) but did not alter amplitude. Increasing NE to 100 mM significantly increased sEPSC frequency (19.7 ± 0.7 to 32.0 ± 3.4 Hz) and amplitude (8.2 ± 0.5 to 10.3 ± 1.1 pA). Block of the α‐1‐AR with prazosin did not alter sEPSC frequency (aCSF, 17.2 ± 2.9 vs α‐1‐AR block, 17.3 ± 3.2 Hz) or amplitude (aCSF, 9.8 ± 1.3 pA vs α‐1‐AR block, 11.0 ± 1.9 pA). NE (100 mM) in the presence of α‐1‐AR antagonist blocked the increase in sEPSC frequency (14.8 ± 2.9 Hz) and amplitude (7.7 ± 0.7 pA). In contrast to Norm, CIH sEPSC frequency and amplitude were not altered by NE at 10 mM (e.g., 4.7 ± 1.1 to 6.3 ± 1.4 Hz, n=4) or 100 mM (e.g., 19.5 ± 3.1 to 19.0 ± 4.4 Hz, n=5). Prazocin alone did not alter CIH sEPSC frequency or amplitude (e.g., 14.4 ± 4.7 to 15.4 ± 4.6 Hz, n=6). Neither NE nor prazocin altered Norm or CIH Ihold measured 5 min after their application. These results demonstrate that under Norm conditions PVN parvocellular neurons are significantly influenced by NE and α‐1 AR activation. Following CIH, NE responsiveness is reduced, likely as a compensatory mechanism caused by sympathetic hyperactivity. Catecholaminergic activity therefore is likely important in cardiorespiratory reflex modulation under physiological and pathophysiological conditions.Support or Funding InformationHL 098602 and HL128454This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.