Alpha adrenergic receptor signaling in the hypothalamic paraventricular nucleus is diminished by the chronic intermittent hypoxia model of sleep apnea

Domingos-Souza, Gean; Martínez, Diana; Sinkler, Steven; Heesch, Cheryl M.; Kline, David D.

doi:10.1016/j.expneurol.2020.113517

Cited by 11 publications

(6 citation statements)

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“…Despite this low fidelity, exposure to moderate (≤12% O 2 ) hypoxia is a sufficient stimulus to activate brainstem catecholaminergic neurons that project to the PVN (King et al., 2012; King et al., 2013) and also PVN neurons (Smith et al., 1995). Furthermore, noradrenaline has multiple effects on PVN neurons (Domingos‐Souza et al., 2021; Li et al., 2005; Milanick et al., 2019) and lesioning brainstem catecholaminergic neurons that project to PVN blunts hypoxic ventilatory responses (King et al., 2015). Thus, a catecholaminergic projection from nTS to PVN appears critical to normal peripheral chemoreflex function.…”

Section: Discussionmentioning

confidence: 99%

Paraventricular nucleus projections to the nucleus tractus solitarii are essential for full expression of hypoxia‐induced peripheral chemoreflex responses

Ruyle,

Lima‐Silveira,

Martinez

et al. 2023

The Journal of Physiology

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The hypothalamic paraventricular nucleus (PVN) is essential to peripheral chemoreflex neurocircuitry, but the specific efferent pathways utilized are not well defined. The PVN sends dense projections to the nucleus tractus solitarii (nTS), which exhibits neuronal activation following a hypoxic challenge. We hypothesized that nTS‐projecting PVN (PVN‐nTS) neurons contribute to hypoxia‐induced nTS neuronal activation and cardiorespiratory responses. To selectively target PVN‐nTS neurons, rats underwent bilateral nTS nanoinjection of retrogradely transported adeno‐associated virus (AAV) driving Cre recombinase expression. We then nanoinjected into PVN AAVs driving Cre‐dependent expression of Gq or Gi designer receptors exclusively activated by designer drugs (DREADDs) to test the degree that selective activation or inhibition, respectively, of the PVN‐nTS pathway affects the hypoxic ventilatory response (HVR) of conscious rats. We used immunohistochemistry for Fos and extracellular recordings to examine how DREADD activation influences PVN‐nTS neuronal activation by hypoxia. Pathway activation enhanced the HVR at moderate hypoxic intensities and increased PVN and nTS Fos immunoreactivity in normoxia and hypoxia. In contrast, PVN‐nTS inhibition reduced both the HVR and PVN and nTS neuronal activation following hypoxia. To further confirm selective pathway effects on central cardiorespiratory output, rats underwent hypoxia before and after bilateral nTS nanoinjections of C21 to activate or inhibit PVN‐nTS terminals. PVN terminal activation within the nTS enhanced tachycardic, sympathetic and phrenic (PhrNA) nerve activity responses to hypoxia whereas inhibition attenuated hypoxia‐induced increases in nTS neuronal action potential discharge and PhrNA. The results demonstrate the PVN‐nTS pathway enhances nTS neuronal activation and is necessary for full cardiorespiratory responses to hypoxia. imageKey points The hypothalamic paraventricular nucleus (PVN) contributes to peripheral chemoreflex cardiorespiratory responses, but specific PVN efferent pathways are not known. The nucleus tractus solitarii (nTS) is the first integration site of the peripheral chemoreflex, and the nTS receives dense projections from the PVN. Selective GqDREADD activation of the PVN‐nTS pathway was shown to enhance ventilatory responses to hypoxia and activation (Fos immunoreactivity (IR)) of nTS neurons in conscious rats, augmenting the sympathetic and phrenic nerve activity (SSNA and PhrNA) responses to hypoxia in anaesthetized rats. Selective GiDREADD inhibition of PVN‐nTS neurons attenuates ventilatory responses, nTS neuronal Fos‐IR, action potential discharge and PhrNA responses to hypoxia. These results demonstrate that a projection from the PVN to the nTS is critical for full chemoreflex responses to hypoxia.

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Section: Discussionmentioning

confidence: 99%

Paraventricular nucleus projections to the nucleus tractus solitarii are essential for full expression of hypoxia‐induced peripheral chemoreflex responses

Ruyle,

Lima‐Silveira,

Martinez

et al. 2023

The Journal of Physiology

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“…3.2 HFS-induced NMDAR-independent LTP of PVN MNCs in acute stress rats was mediated by β-AR AR subtypes are abundantly expressed in the hypothalamic PVN, and contributes to modulation the PVN neuronal synaptic transmission [44,45], we then examined whether the HFS induced LTP of PVN MNCs in acute stress rats was mediated by ARs. In the presence D-APV (50 µM), application a selective α-AR antagonist, phentolamine (100 µM) failed to prevent the HFS-induced LTP of PVN MNCs in acute stress rats (Fig.…”

Section: Acute Stress Facilitates Hfs-induced Glutamatergic Ltp Of Pv...mentioning

confidence: 99%

“…In addition, activation of α-and β-ARs modulated the strength of synaptic transmission and long-term plasticity via cAMP /PKA signaling pathway in the brain [37,[40][41][42][43]. Notably, both α-AR and β-AR subtypes are abundantly expressed in the hypothalamic PVN, and contributes to modulation the neuronal activity and synaptic transmission during various stress response [44,45], suggesting that ARs contributes to modulating the long-term synaptic plasticity of the excitatory glutamatergic inputs in the PVN MNCs in response to stressor. Therefore, we here investigated the effect of acute stress on the long-term glutamatergic synaptic plasticity in the PVN MNCs in vitro in rats.…”

Section: Introductionmentioning

confidence: 99%

Acute stress facilitates glutamatergic long-term potentiation in PVN magnocellular neurons through beta-adrenergic receptor/PKA cascade in vitro in rats

Jin,

Zhang,

Liu

et al. 2024

Preprint

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Acute stress alternates the hypothalamic paraventricular nucleus (PVN) magnocellular neuronal activity through modulation of excitatory and inhibitory synaptic inputs, leading to abnormal secretion of oxytocin (OT) and vasopressin (VP). However, mechanism of acute stress modulates the glutamatergic long-term potentiation (LTP) in PVN magnocellular neuroendocrine cells (MNCs) is unclear. We here investigated the effect of acute stress on the glutamatergic LTP of PVN MNCs, by whole-cell patch-clamp recording with biocytin staining and pharmacological methods. Delivery of high frequency stimulation (HFS) induced a glutamatergic LTP accompanied with a decrease in paired-pulse ratio in PVN MNCs, which was significantly enhanced in acute stress rats. Blockade of N-methyl-D-aspartate receptors (NMDAR) activity abolished the LTP of PVN MNCs in control group, but reveal a NMDAR-independent LTP in acute stress group. The NMDAR-independent LTP of PVN MNCs in stress rats was abolished by a β-AR inhibitor, propranolol, but not by an α-AR inhibitor, Phentolamine. The NMDAR-independent LTP of PVN MNCs in stress rats was abolished by bath application of a potent protein kinase A (PKA) inhibitor, KT5720 (200 nM), but not by a PKC inhibitor. Moreover, postsynaptic blockade of PKA completely prevented the HFS-induced glutamatergic LTP in PVN MNCs of stress rats. These results indicate that acute stress triggers an NMDAR-independent glutamatergic LTP of the PVN MNCs through a postsynaptic β-AR/PKA signaling pathway, resulting in an enhancement of an NMDAR-dependent presynaptic LTP in vitro in rats. The results suggest that acute stress upregulates OT and VP secretion by enhancing the excitatory glutamatergic LTP of PVN MNCs.

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“…In contrast, intra-PVN microinjection of prazosin decreased the systolic pressure and heart rate in previously undernourished adult hypertensive rats [ 24 , 93 ] altogether with lowering the spontaneous firing rate in PVN neurons [ 52 ]. In contrast, both noradrenaline and the α 1 -adrenoceptor agonist phenylephrine increased the frequency of spontaneous excitatory postsynaptic currents in PVN slices from normotensive control animals, but not in PVN slices from animals made hypertensive by chronic intermittent hypoxia [ 122 ].…”

Section: Maladaptive Programming Of Paraventricular-coerulear Network...mentioning

confidence: 99%

The Role of the Paraventricular-Coerulear Network on the Programming of Hypertension by Prenatal Undernutrition

Cayupe

Troncoso

Morgan

et al. 2022

IJMS

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A crucial etiological component in fetal programming is early nutrition. Indeed, early undernutrition may cause a chronic increase in blood pressure and cardiovascular diseases, including stroke and heart failure. In this regard, current evidence has sustained several pathological mechanisms involving changes in central and peripheral targets. In the present review, we summarize the neuroendocrine and neuroplastic modifications that underlie maladaptive mechanisms related to chronic hypertension programming after early undernutrition. First, we analyzed the role of glucocorticoids on the mechanism of long-term programming of hypertension. Secondly, we discussed the pathological plastic changes at the paraventricular nucleus of the hypothalamus that contribute to the development of chronic hypertension in animal models of prenatal undernutrition, dissecting the neural network that reciprocally communicates this nucleus with the locus coeruleus. Finally, we propose an integrated and updated view of the main neuroendocrine and central circuital alterations that support the occurrence of chronic increases of blood pressure in prenatally undernourished animals.

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Alpha adrenergic receptor signaling in the hypothalamic paraventricular nucleus is diminished by the chronic intermittent hypoxia model of sleep apnea

Cited by 11 publications

References 57 publications

Paraventricular nucleus projections to the nucleus tractus solitarii are essential for full expression of hypoxia‐induced peripheral chemoreflex responses

Paraventricular nucleus projections to the nucleus tractus solitarii are essential for full expression of hypoxia‐induced peripheral chemoreflex responses

Acute stress facilitates glutamatergic long-term potentiation in PVN magnocellular neurons through beta-adrenergic receptor/PKA cascade in vitro in rats

The Role of the Paraventricular-Coerulear Network on the Programming of Hypertension by Prenatal Undernutrition

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