The PVN enhances cardiorespiratory responses to acute hypoxia via input to the nTS

Chemoreflex neurocircuitry includes the paraventricular nucleus (PVN), but the role of PVN efferent projections to specific cardiorespiratory nuclei is unclear. We hypothesized that the PVN contributes to cardiorespiratory responses to hypoxia via projections to the nucleus tractus solitarii (nTS). Rats received bilateral PVN microinjections of adeno-associated virus expressing inhibitory designer receptor exclusively activated by designer drug (GiDREADD) or green fluorescent protein (GFP) control. Efficacy of GiDREADD inhibition by the designer receptor exclusively activated by designer drug (DREADD) agonist Compound 21 (C21) was verified in PVN slices; C21 reduced evoked action potential discharge by reducing excitability to injected current in GiDREADD-expressing PVN neurons. We evaluated hypoxic ventilatory responses (plethysmography) and PVN and nTS neuronal activation (cFos immunoreactivity) to 2 h hypoxia (10% O2) in conscious GFP and GiDREADD rats after intraperitoneal C21 injection. Generalized PVN inhibition via systemic C21 blunted hypoxic ventilatory responses and reduced PVN and also nTS neuronal activation during hypoxia. To determine if the PVN-nTS pathway contributes to these effects, we evaluated cardiorespiratory responses to hypoxia during selective PVN terminal inhibition in the nTS. Anesthetized GFP and GiDREADD rats exposed to brief hypoxia (10% O2, 45 s) exhibited depressor and tachycardic responses and increased sympathetic and phrenic nerve activity. C21 was then microinjected into the nTS, followed after 60 min by another hypoxic episode. In GiDREADD but not GFP rats, PVN terminal inhibition by nTS C21 strongly attenuated the phrenic amplitude response to hypoxia. Interestingly, C21 augmented tachycardic and sympathetic responses without altering the coupling of splanchnic sympathetic nerve activity to phrenic nerve activity during hypoxia. Data demonstrate that the PVN, including projections to the nTS, is critical in shaping sympathetic and respiratory responses to hypoxia.

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Hypoxia activates a neuropeptidergic pathway from the paraventricular nucleus of the hypothalamus to the nucleus tractus solitarii

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00244.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. R1167-R1182 ◽

Cited By ~ 9

Author(s):

Brian C. Ruyle ◽

Paula J. Klutho ◽

Christopher P. Baines ◽

Cheryl M. Heesch ◽

Eileen M. Hasser

Keyword(s):

Paraventricular Nucleus ◽

Fluorescent Protein ◽

Acute Hypoxia ◽

Nucleus Tractus Solitarii ◽

Neuronal Activation ◽

Cardiorespiratory Responses ◽

Efferent Projections ◽

Green Fluorescent ◽

Dense Projections ◽

Peripheral Chemoreflex

The paraventricular nucleus of the hypothalamus (PVN) contributes to both autonomic and neuroendocrine function. PVN lesion or inhibition blunts cardiorespiratory responses to peripheral chemoreflex activation, suggesting that the PVN is required for full expression of these effects. However, the role of efferent projections to cardiorespiratory nuclei and the neurotransmitters/neuromodulators that are involved is unclear. The PVN sends dense projections to the nucleus tractus solitarii (nTS), a region that displays neuronal activation following hypoxia. We hypothesized that acute hypoxia activates nTS-projecting PVN neurons. Using a combination of retrograde tracing and immunohistochemistry, we determined whether hypoxia activates PVN neurons that project to the nTS and examined the phenotype of these neurons. Conscious rats underwent 2 h normoxia (21% O2, n = 5) or hypoxia (10% O2, n = 6). Hypoxia significantly increased Fos immunoreactivity in nTS-projecting neurons, primarily in the caudal PVN. The majority of activated nTS-projecting neurons contained corticotropin-releasing hormone (CRH). In the nTS, fibers expressing the CRH receptor corticotropin-releasing factor receptor 2 (CRFR2) were colocalized with oxytocin (OT) fibers and were closely associated with hypoxia-activated nTS neurons. A separate group of animals that received a microinjection of adeno-associated virus type 2-hSyn-green fluorescent protein (GFP) into the PVN exhibited GFP-expressing fibers in the nTS; a proportion of these fibers displayed OT immunoreactivity. Thus, nTS CRFR2s appear to be located on the fibers of PVN OT neurons that project to the nTS. Taken together, our findings suggest that PVN CRH projections to the nTS may modulate nTS neuronal activation, possibly via OTergic mechanisms, and thus contribute to chemoreflex cardiorespiratory responses.

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The effects of sevoflurane, isoflurane, and halothane on the pattern of phrenic nerve activity in response to acute hypoxia in rats

European Journal of Anaesthesiology ◽

10.1097/00003643-200805001-00224 ◽

2008 ◽

Vol 25 (Sup 44) ◽

pp. 71

Author(s):

N. Karanovic ◽

R. Pecotic ◽

M. Valic ◽

M. Carev ◽

Z. Dogas

Keyword(s):

Phrenic Nerve ◽

Acute Hypoxia ◽

Nerve Activity ◽

Phrenic Nerve Activity

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Microinjections of glycine into the pre-Bötzinger complex inhibit phrenic nerve activity in the rat

Brain Research ◽

10.1016/s0006-8993(02)02902-5 ◽

2002 ◽

Vol 947 (1) ◽

pp. 25-33 ◽

Cited By ~ 7

Author(s):

V.C Chitravanshi ◽

H.N Sapru

Keyword(s):

Phrenic Nerve ◽

Nerve Activity ◽

Phrenic Nerve Activity ◽

Bötzinger Complex

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Daily acute intermittent hypoxia enhances phrenic motor output and stimulus-evoked phrenic responses in rats

Journal of Neurophysiology ◽

10.1152/jn.00112.2021 ◽

2021 ◽

Author(s):

Raphael Rodrigues Perim ◽

Michael D. Sunshine ◽

Joseph F. Welch ◽

Juliet Santiago ◽

Ashley Holland ◽

...

Keyword(s):

Motor Neurons ◽

Phrenic Nerve ◽

Intermittent Hypoxia ◽

Neural Control ◽

Respiratory Cycle ◽

Evoked Responses ◽

Nerve Activity ◽

Synaptic Inputs ◽

Phrenic Nerve Activity ◽

The Impact

Plasticity is a hallmark of the respiratory neural control system. Phrenic long-term facilitation (pLTF) is one form of respiratory plasticity characterized by persistent increases in phrenic nerve activity following acute intermittent hypoxia (AIH). Although there is evidence that key steps in the cellular pathway giving rise to pLTF are localized within phrenic motor neurons (PMNs), the impact of AIH on the strength of breathing-related synaptic inputs to PMNs remains unclear. Further, the functional impact of AIH is enhanced by repeated/daily exposure to AIH (dAIH). Here, we explored the effects of AIH vs. 2 weeks of dAIH preconditioning on spontaneous and evoked responses recorded in anesthetized, paralyzed (with pancuronium bromide) and mechanically ventilated rats. Evoked phrenic potentials were elicited by respiratory cycle-triggered lateral funiculus stimulation at C2 delivered prior to- and 60 min post-AIH (or an equivalent time in controls). Charge-balanced biphasic pulses (100 µs/phase) of progressively increasing intensity (100 to 700 µA) were delivered during the inspiratory and expiratory phases of the respiratory cycle. Although robust pLTF (~60% from baseline) was observed after a single exposure to moderate AIH (3 x 5 min; 5 min intervals), there was no effect on evoked phrenic responses, contrary to our initial hypothesis. However, in rats preconditioned with dAIH, baseline phrenic nerve activity and evoked responses were increased, suggesting that repeated exposure to AIH enhances functional synaptic strength when assessed using this technique. The impact of daily AIH preconditioning on synaptic inputs to PMNs raises interesting questions that require further exploration.

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Evaluation of a New Valveless all Purpose Ventilator: Effect of Ventilating Frequency PEEP, PACO2 and PAO2 on Phrenic Nerve Activity

Perspectives in High Frequency Ventilation - Developments in Critical Care Medicine and Anesthesiology ◽

10.1007/978-94-009-6711-3_15 ◽

1983 ◽

pp. 140-145 ◽

Cited By ~ 2

Author(s):

M. K. Chakrabarti ◽

J. G. Whitwam

Keyword(s):

Phrenic Nerve ◽

Nerve Activity ◽

Phrenic Nerve Activity

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Effects of hypercapnia and hypoxia on phrenic nerve activity and respiratory timing

Journal of Applied Physiology ◽

10.1152/jappl.1981.51.3.732 ◽

1981 ◽

Vol 51 (3) ◽

pp. 732-738 ◽

Cited By ~ 18

Author(s):

J. F. Ledlie ◽

S. G. Kelsen ◽

N. S. Cherniack ◽

A. P. Fishman

Keyword(s):

Phrenic Nerve ◽

Carotid Sinus ◽

Peak Height ◽

Inspiratory Time ◽

Nerve Activity ◽

Phrenic Nerve Activity ◽

Chemical Stimuli ◽

Proprioceptive Inputs ◽

Spontaneously Breathing ◽

Respiratory Responses

In the spontaneously breathing animal, respiratory responses to chemical stimuli are influenced by phasic proprioceptive inputs from the thorax. We have compared the effects of hypercapnia and hypoxia on the level and timing of phrenic nerve activity while these phasic afferent signals were absent. Progressive hyperoxic hypercapnia and isocapnic hypoxia were produced in anesthetized paralyzed dogs by allowing 3–5 min of apnea to follow mechanical ventilation with 100% O2 or 35% O2 in N2, respectively; during hypoxia, isocapnia was maintained by intravenous infusion of tris(hydroxymethyl)aminomethane buffer. The peak height (P) of nerve bursts, inspiratory time (TI), and expiratory time (TE) were measured from the phrenic neurogram. With the vagi intact or severed, hypoxia decreased TI, whereas hypercapnia did not; both stimuli decreased TE. At the same minute phrenic activity (P x frequency), P, TI, and TE were all less during hypoxia than during hypercapnia. The decreases in TI and TE with hypoxia were significantly less after carotid sinus denervation. The results indicate that the patterns of phrenic nerve activity in response to hypoxia and hypercapnia are different: hypoxia has a greater effect on respiratory timing, whereas hypercapnia has a greater effect on peak phrenic nerve activity. The effect of hypoxia on respiratory timing is largely mediated by the peripheral chemoreceptors.

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