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Neuronal HIF-1α in the nucleus tractus solitarius contributes to ventilatory acclimatization to hypoxia.

ABSTRACT:

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We hypothesized that hypoxia inducible factor 1α (HIF-1α) in CNS respiratory centres is necessary for ventilatory acclimatization to hypoxia (VAH); VAH is a time-dependent increase in baseline ventilation and the hypoxic ventilatory response (HVR) occurring over days to weeks of chronic sustained hypoxia (CH). Constitutive deletion of HIF-1α in CNS neurons in transgenic mice tended to blunt the increase in HVR that occurs in wild-type mice with CH. Conditional deletion of HIF-1α in glutamatergic neurons of the nucleus tractus solitarius during CH significantly decreased ventilation in acute hypoxia but not normoxia in CH mice. These effects are not explained by changes in metabolic rate, nor CO₂ , and there were no changes in the HVR in normoxic mice. HIF-1α mediated changes in gene expression in CNS respiratory centres are necessary in addition to plasticity of arterial chemoreceptors for normal VAH.

Abstract

Chronic hypoxia (CH) produces a time-dependent increase of resting ventilation and the hypoxic ventilatory response (HVR) that is called ventilatory acclimatization to hypoxia (VAH). VAH involves plasticity in arterial chemoreceptors and the CNS [e.g. nucleus tractus solitarius (NTS)], although the signals for this plasticity are not known. We hypothesized that hypoxia inducible factor 1α (HIF-1α), an O₂ -sensitive transcription factor, is necessary in the NTS for normal VAH. We tested this in two mouse models using loxP-Cre gene deletion. First, HIF-1α was constitutively deleted in CNS neurons (CNS-HIF-1α^-/- ) by breeding HIF-1α floxed mice with mice expressing Cre-recombinase driven by the calcium/calmodulin-dependent protein kinase IIα promoter. Second, HIF-1α was deleted in NTS neurons in adult mice (NTS-HIF-1α^-/- ) by microinjecting adeno-associated virus that expressed Cre-recombinase in HIF-1α floxed mice. In normoxic control mice, HIF-1α deletion in the CNS or NTS did not affect ventilation, nor the acute HVR (10-15 min hypoxic exposure). In mice acclimatized to CH for 1 week, ventilation in hypoxia was blunted in CNS-HIF-1α^-/- and significantly decreased in NTS-HIF-1α^-/- compared to control mice (P < 0.0001). These changes were not explained by differences in metabolic rate or CO₂ . Immunofluorescence showed that HIF-1α deletion in NTS-HIF-1α^-/- was restricted to glutamatergic neurons. The results indicate that HIF-1α is a necessary signal for VAH and the previously described plasticity in glutamatergic neurotransmission in the NTS with CH. HIF-1α deletion had no effect on the increase in normoxic ventilation with acclimatization to CH, indicating this is a distinct mechanism from the increased HVR with VAH.

SUBMITTER: Moya EA

PROVIDER: S-EPMC7230006 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The nucleus tractus solitarius (NTS) receives subdiaphragmatic visceral sensory information via vagal A- or C-fibers. We have recently shown that, in contrast to cardiovascular NTS medialis neurons, which respond to either purinergic or vanilloid agonists, the majority of esophageal NTS centralis (cNTS) neurons respond to vanilloid agonists, whereas a smaller subset responds to both vanilloid and purinerigic agonists. The present study aimed to further investigate the neurochemical and synaptic characteristics of cNTS neurons using whole cell patch-clamp, single cell RT-PCR and immunohistochemistry. Excitatory postsynaptic currents (EPSCs) were evoked in cNTS by tractus solitarius stimulation, and in 19 of 64 neurons perfusion with the purinergic agonist αβ-methylene ATP (αβMeATP) increased the evoked EPSC amplitude significantly. Furthermore, neurons with αβMeATP-responsive synaptic inputs had different probabilities of release compared with nonresponsive neurons. Single cell RT-PCR revealed that 8 of 13 αβMeATP-responsive neurons expressed metabotropic glutamate receptor 8 (mGluR8) mRNA, which our previous studies have suggested is a marker of glutamatergic neurons, whereas only 3 of 13 expressed glutamic acid dehydroxylase, a marker of GABAergic neurons. A significantly lower proportion of αβMeATP-nonresponsive neurons expressed mGluR8 (2 of 30 neurons), whereas a greater proportion expressed glutamic acid dehydroxylase (12 of 30 neurons). Esophageal distension significantly increased the number of colocalized mGluR8- and c-Fos-immunoreactive neurons in the cNTS from 8.0 ± 4% to 20 ± 2.5%. These data indicate that cNTS comprises distinct neuronal subpopulations that can be distinguished based on their responses to purinergic agonists and that these subpopulations have distinct neurochemical and synaptic characteristics, suggesting that integration of sensory inputs from the esophagus relies on a discrete organization of synapses between vagal afferent fibers and cNTS neurons.

Project description:The hippocampus is involved in the regulation of the autonomic nervous system, together with the hypothalamus and brainstem nuclei, such as the paraventricular nucleus and nucleus tractus solitarius. The vagus nerve-nucleus tractus solitarius pathway has an important role in cardiovascular reflex regulation. Myocardial ischemia has been shown to cause changes in the autonomic nervous system, affecting the dynamic equilibrium of the sympathetic and vagal nerves. However, it remains poorly understood how the hippocampus communicates with brainstem nuclei to regulate the autonomic nervous system and alleviate myocardial ischemic tissue damage. A rat model of acute myocardial ischemia (AMI) was made by ligating the left anterior descending branch of the coronary artery. Three days before ischemia, the hippocampal CA1 region was damaged. Then, 3 days after ischemia, electroacupuncture (EA) at Shenmen (HT7)-Tongli (HT5) was performed (continuous wave, 1 mA, 2 Hz, duration of 30 minutes). Cluster analysis of firing patterns showed that one type of neuron was found in rats in the sham and AMI groups. Three types of neurons were observed in the AMI + EA group. Six types of neurons were found in the AMI + EA + Lesion group. Correlation analysis showed that the frequency of vagus nerve discharge in each group was negatively correlated with heart rate (HR) (P < 0.05, r = -0.424), and positively correlated with mean arterial pressure (MAP) (P < 0.05, r = 0.40987) and the rate-pressure product (RPP) (P < 0.05, r = 0.4252). The total frequency of the nucleus tractus solitarius discharge in each group was positively correlated with vagus nerve discharge (P < 0.01, r = 0.7021), but not with hemodynamic index (HR: P > 0.05, r = -0.03263; MAP: P > 0.05, r = -0.08993; RPP: P > 0.05, r = -0.03263). Some neurons (Neuron C) were negatively correlated with vagus nerve discharge, HR, MAP and RPP in the AMI + EA group (vagus nerve discharge: P < 0.05, r = -0.87749; HR: P < 0.01, r = -0.91902; MAP: P < 0.05, r = -0.85691; RPP: P < 0.01, r = -0.91902). Some neurons (Neurons C, D and E) were positively correlated with vagus nerve discharge, HR, MAP and RPP in the AMI + EA + Lesion group (vagus nerve discharge: P < 0.01, r = 0.8905, P < 0.01, r = 0.9725, P < 0.01, r = 0.9054; HR: P < 0.01, r = 0.9347, P < 0.01, r = 0.9089, P < 0.05, r = 0.8247; MAP: P < 0.05, r = 0.8474, P < 0.01, r = 0.9691, P < 0.01, r = 0.9027; RPP: P < 0.05, r = 0.8637, P < 0.01, r = 0.9407, P < 0.01, r = 0.9027). These findings show that the hippocampus-nucleus tractus solitarius-vagus nerve pathway is involved in the cardioprotective effect of EA at the heart meridian. Some interneurons in the nucleus tractus solitarius may play a particularly important role in the cardiomodulatory process.

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Neuronal HIF-1α in the nucleus tractus solitarius contributes to ventilatory acclimatization to hypoxia.

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