Nucleus tractus solitarii is required for the development and maintenance of phrenic and sympathetic long-term facilitation after acute intermittent hypoxia

Abstract

Exposure to acute intermittent hypoxia (AIH) induces prolonged increases (long term facilitation, LTF) in phrenic and sympathetic nerve activity (PhrNA, SNA) under basal conditions, and enhanced respiratory and sympathetic responses to hypoxia. The mechanisms and neurocircuitry involved are not fully defined. We tested the hypothesis that the nucleus tractus solitarii (nTS) is vital to augmentation of hypoxic responses and the initiation and maintenance of elevated phrenic (p) and splanchnic sympathetic (s) LTF following AIH. nTS neuronal activity was inhibited by nanoinjection of the GABAA receptor agonist muscimol before AIH exposure or after development of AIH-induced LTF. AIH but not sustained hypoxia induced pLTF and sLTF with maintained respiratory modulation of SSNA. nTS muscimol before AIH increased baseline SSNA with minor effects on PhrNA. nTS inhibition also markedly blunted hypoxic PhrNA and SSNA responses, and prevented altered sympathorespiratory coupling during hypoxia. Inhibiting nTS neuronal activity before AIH exposure also prevented the development of pLTF during AIH and the elevated SSNA after muscimol did not increase further during or following AIH exposure. Furthermore, nTS neuronal inhibition after the development of AIH-induced LTF substantially reversed but did not eliminate the facilitation of PhrNA. Together these findings demonstrate that mechanisms within the nTS are critical for initiation of pLTF during AIH. Moreover, ongoing nTS neuronal activity is required for full expression of sustained elevations in PhrNA following exposure to AIH although other regions likely also are important. Together, the data indicate that AIH-induced alterations within the nTS contribute to both the development and maintenance of pLTF.

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

“…These data support previous studies showing that PVN neurons appear to alter cardiorespiratory output without changes in sympathorespiratory coupling in a variety of circumstances, including acute intermittent hypoxia (Xing & Pilowsky, 2010), dehydration (Holbein et al, 2014), increased osmolality (Holbein & Toney, 2015) and hypertension (Holbein et al, 2018). These data further indicate that although the nTS plays a role in sympathorespiratory coupling (Molkov et al, 2014;Ostrowski et al, 2023), this coupling likely utilizes mechanisms other than those mediated by projections from the PVN to the nTS. Thus, the PVN-nTS pathway enhances cardiorespiratory responses to hypoxia without altering sympathorespiratory coupling, as does the PVN globally.…”

“…Coupling of sympathetic nervous system activity to respiration is necessary for overall cardiovascular function, likely indicates interactions among cardiovascular and respiratory neurons, and may be associated with cardiovascular disease (Molkov et al., 2014; Ostrowski et al., 2023). Manipulation of the PVN‐nTS projection influenced both sympathetic and phrenic nerve activity responses to hypoxia and possibly their coupling.…”

“…Manipulation of the PVN‐nTS projection influenced both sympathetic and phrenic nerve activity responses to hypoxia and possibly their coupling. Therefore, in rats with confirmed activity in both sympathetic and phrenic nerves, we next examined whether the PVN‐nTS pathway is associated with changes in sympathorespiratory coupling, which is altered by hypoxia and changes in nTS activity (Ostrowski et al., 2023). The coupling pattern of SSNA to PhrNA during early and late inspiration (I1, I2) and expiration (E1, E2) was analysed at baseline (BL) and during exposure to 12% O 2 (Hx; Cre‐mCherry, n = 3; Cre‐GqDREADD, n = 6) and 10% O 2 (Cre‐mCherry, n = 2; Cre‐GiDREADD, n = 4).…”

“…Therefore, to analyse specifically the pattern of sympathorespiratory coupling independent of the magnitude of SSNA, we normalized PhrNA‐triggered averages of SSNA to the total activity within a given cycle, and values of SSNA during I1, I2, E1 and E2 are presented as a percentage of the total cycle activity. As previously (Ostrowski et al., 2023), data were analysed at BL (normoxia) and during hypoxia (Hx; at the peak increase in SSNA) both under Ctrl conditions and 60 min after nTS nanoinjection of C21. Coupling analysis typically included 15–20 PhrNA cycles in each respiratory phase.…”

Chronic intermittent hypoxia promotes glomerular hyperfiltration and potentiates hypoxia-evoked decreases in renal perfusion and PO2

“…Studies in SA patients have shown persistent increases in sympathetic nerve activity (SNA) ( Maier et al, 2022 ), decreased renal plasma flow ( Kinebuchi et al, 2004 ), glomerular hyperfiltration ( Kinebuchi et al, 2004 ), increased activity of the renin angiotensin aldosterone system (RAAS) ( Di Murro et al, 2010 ; Zalucky et al, 2015 ), as well as systemic inflammation ( Unnikrishnan et al, 2015 ; Perrini et al, 2017 ; Orrù et al, 2020 ) and evidence of oxidative stress ( Orrù et al, 2020 ; Hu et al, 2022 ). Previous studies have shown that the chronic intermittent hypoxia (CIH) associated with SA results in tonic increases in afferent carotid body chemoreflex (CBC) activity ( Peng et al, 2003 ; Rey et al, 2004 ; Roy et al, 2018 ; Prabhakar et al, 2023 ) as well as changes in central chemoreflex sensitivity, both of which contribute to elevated efferent SNA ( Prabhakar et al, 2023 ; Ostrowski et al, 2023 ; Gilmartin et al, 2010 ; Huang et al, 2009 ; Marcus et al, 2010 ; Molkov et al, 2011 ). Acute activation of the CBC with hypoxia has previously been shown to increase renal SNA and decrease renal blood flow (RBF) in healthy animals ( Huang et al, 2009 ; Marcus et al, 2015 ; Pügge et al, 2016 ; Kious et al, 2022 ), an effect exacerbated by conditions with enhanced chemoreceptor sensitivity ( Huang et al, 2009 ; Marcus et al, 2015 ; Pügge et al, 2016 ; Kious et al, 2022 ).…”