Hypothalamic PVN contributes to acute intermittent hypoxia-induced sympathetic but not phrenic long-term facilitation

Abstract

Blackburn MB, Andrade MA, Toney GM. Hypothalamic PVN contributes to acute intermittent hypoxia-induced sympathetic but not phrenic long-term facilitation. J Appl Physiol 124: 1233-1243, 2018. First published December 19, 2017; doi: 10.1152/japplphysiol.00743.2017 .- Acute intermittent hypoxia (AIH) repetitively activates the arterial chemoreflex and triggers a progressive increase of sympathetic nerve activity (SNA) and phrenic nerve activity (PNA) referred to as sympathetic and phrenic long-term facilitation (S-LTF and P-LTF), respectively. Neurons of the hypothalamic paraventricular nucleus (PVN) participate in the arterial chemoreflex, but their contribution to AIH-induced LTF is unknown. To determine this, anesthetized rats were vagotomized and exposed to 10 cycles of AIH, each consisting of ventilation for 3 min with 100% O followed by 3 min with 15% O. Before AIH, rats received bilateral PVN injections of artificial cerebrospinal fluid (aCSF; vehicle) or the GABA-A receptor agonist muscimol (100 pmol in 50 nl) to inhibit neuronal activity. Thirty minutes after completing the AIH protocol, during which rats were continuously ventilated with 100% O, S-LTF and P-LTF were quantified from recordings of integrated splanchnic SNA and PNA, respectively. PVN muscimol attenuated increases of SNA during hypoxic episodes occurring in later cycles (6-10) of AIH ( P < 0.03) and attenuated post-AIH S-LTF ( P < 0.001). Muscimol, however, did not consistently affect peak PNA responses during hypoxic episodes and did not alter AIH-induced P-LTF. These findings indicate that PVN neuronal activity contributes to sympathetic responses during AIH and to subsequent generation of S-LTF. NEW & NOTEWORTHY Neural circuits mediating acute intermittent hypoxia (AIH)-induced sympathetic and phrenic long-term facilitation (LTF) have not been fully elucidated. We found that paraventricular nucleus (PVN) inhibition attenuated sympathetic activation during episodes of AIH and reduced post-AIH sympathetic LTF. Neither phrenic burst patterning nor the magnitude of AIH-induced phrenic LTF was affected. Findings indicate that PVN neurons contribute to AIH-induced sympathetic LTF. Defining mechanisms of sympathetic LTF could improve strategies to reduce sympathetic activity in cardiovascular and metabolic diseases.

CRHR2 (Corticotropin-Releasing Hormone Receptor 2) in the Nucleus of the Solitary Tract Contributes to Intermittent Hypoxia-Induced Hypertension

“…In comparison, after IH exposure, the transcription factor Δ FosB was elevated in the PVN to mediate neuronal activation 8 ; unfortunately, the CeA wasn’t examined in that study. Functional studies have demonstrated that PVN neurons contribute to IH-induced sympathetic activation and hypertension 6,41 . Based on these studies, it is likely that the descending CRH pathway from the PVN to the NTS plays an important role in IH-induced hypertension.…”

A projection from the hypothalamic paraventricular nucleus to the nucleus tractus solitarii is critical for cardiorespiratory responses to hypoxia

“…The PVN plays an important role in respiratory modulation and PVN activation increases respiratory frequency and tidal volume (58,196,247). Furthermore, PVN lesion or inhibition blunts responses to cyanide-evoked chemoreceptor activation and intermittent hypoxia (22,156,174). The current data confirm and extend these studies by showing that inhibition of PVN neurons also attenuates the increase in respiratory frequency and tidal volume due to progressive acute hypoxia.…”

Pentobarbital Anesthesia Suppresses the Glucose Response to Acute Intermittent Hypoxia in Rat

“…In the face of severe stress, the PVN and VLM are critical areas for mediating the hyperglycemic response ( Zhao et al, 2017 ). Another important area of the hypothalamus for glucose homeostasis is the ventromedial hypothalamus (VMH) which projects to a wide range of sympathetic targets, including the PVN, the VLM and the NTS ( Lindberg et al, 2013 ), which are all involved in the responses to intermittent hypoxia as described above ( Mifflin et al, 2015 ; Shell et al, 2016 ; Blackburn et al, 2018 ; Maruyama et al, 2019 ). While there is no clear evidence of the neurocircuitry involved in the glycemic response to acute IHx, there is substantial knowledge of the effects of GABA on the glucoregulatory neurons in the VMH and the sympathoadrenal glucoregulatory reflex.…”

“…The sympathetic effects of OSA are well accepted, with patients presenting with increased daytime muscle sympathetic activity (Narkiewicz and Somers, 1997). IHx in anesthetized rodent models (Dick et al, 2007;Xing and Pilowsky, 2010;Blackburn et al, 2018;Kakall et al, 2018b;Kim et al, 2018;Roy et al, 2018;Farnham et al, 2019) and conscious humans (Louis and Punjabi, 2009;Gilmartin et al, 2010;Tamisier et al, 2011) also both demonstrate persistent increases in sympathetic nerve activity. In the case of chronic IHx, conscious rodent models develop increases in blood pressure (Sharpe et al, 2013) and glucose dysregulation (Polak et al, 2013;Fu et al, 2015).…”