Hypoxia activates nucleus tractus solitarii neurons projecting to the paraventricular nucleus of the hypothalamus

Abstract

<jats:p>Peripheral chemoreceptor afferent information is sent to the nucleus tractus solitarii (nTS), integrated, and relayed to other brain regions to alter cardiorespiratory function. The nTS projects to the hypothalamic paraventricular nucleus (PVN), but activation and phenotype of these projections during chemoreflex stimulation is unknown. We hypothesized that activation of PVN-projecting nTS neurons occurs primarily at high intensities of hypoxia. We assessed ventilation and cardiovascular parameters in response to increasing severities of hypoxia. Retrograde tracers were used to label nTS PVN-projecting neurons and, in some rats, rostral ventrolateral medulla (RVLM)-projecting neurons. Immunohistochemistry was performed to identify nTS cells that were activated (Fos-immunoreactive, Fos-IR), catecholaminergic, and GABAergic following hypoxia. Conscious rats underwent 3 h normoxia ( n = 4, 21% O<jats:sub>2</jats:sub>) or acute hypoxia (12, 10, or 8% O<jats:sub>2</jats:sub>; n = 5 each). Hypoxia increased ventilation and the number of Fos-IR nTS cells (21%, 13 ± 2; 12%, 58 ± 4; 10%, 166 ± 22; 8%, 186 ± 6). Fos expression after 10% O<jats:sub>2</jats:sub>was similar whether arterial pressure was allowed to decrease (−13 ± 1 mmHg) or was held constant. The percentage of PVN-projecting cells activated was intensity dependent, but contrary to our hypothesis, PVN-projecting nTS cells exhibiting Fos-IR were found at all hypoxic intensities. Notably, at all intensities of hypoxia, ∼75% of the activated PVN-projecting nTS neurons were catecholaminergic. Compared with RVLM-projecting cells, a greater percentage of PVN-projecting nTS cells was activated by 10% O<jats:sub>2</jats:sub>. Data suggest that increasing hypoxic intensity activates nTS PVN-projecting cells, especially catecholaminergic, PVN-projecting neurons. The nTS to PVN catecholaminergic pathway may be critical even at lower levels of chemoreflex activation and more important to cardiorespiratory responses than previously considered.</jats:p>

AMP-activated Protein Kinase Deficiency Blocks the Hypoxic Ventilatory Response and Thus Precipitates Hypoventilation and Apnea

“…This is consistent with optogenetic and pharmacological interventions at the NTS (16,33) and the proposal that NTS neurons lie on the sensory side of the central respiratory network (34,35). Observed right-left asymmetry of brainstem activation during hypoxia (Figure 4) may provide for specialization sufficient to prevent delays in respiratory responses to hypoxic stress by limiting conflicting outputs from each side of the brain (36) as for cognitive performance (37).…”

“…The caudal location relative to the bregma of the DAR is consistent with areas of the NTS that are activated by hypoxia and which represent the primary site of receipt of carotid body afferent input (13,16,24). Here AMPK deletion selectively attenuated c-fos expression during hypoxia by mixed subpopulations of C2 neurons and A2 neurons (SubP, SolM) within the SolM proximal to the midline and the SubP, which are activated during hypoxia (21).…”

“…The caudal location relative to the bregma of the DAR ( Figure 4C) is consistent with that of the NTS, within which poorly defined subgroups of A2 catecholaminergic neurons receive carotid body afferent inputs (24) and are activated during hypoxia (16,21). The location of the VAR aligns well with the C1/A1 catecholaminergic neurons of the ventrolateral medulla, which are activated during hypoxia via afferent inputs from both carotid bodies and the NTS (21,28,29).…”

“…The present study demonstrates conclusively that AMPK deficiency attenuates the HVR, and thus precipitates hypoventilation and apnea, by blocking the activation of hypoxia-responsive nuclei within the caudal brainstem (15,16), even where carotid body afferent inputs are normal. Some of these results were previously reported in the form of an abstract (17).…”

“…Catecholaminergic and other neurons of the nucleus tractus solitarius (NTS) and ventrolateral medulla receive inputs from the carotid body (21,24,25), are activated by central nervous system hypoxia, and may independently regulate rCPGs in a manner dependent on continued basal (normoxic) afferent input from the carotid bodies (13,16,26). Brainstem activity during hypoxia was therefore assessed by fMRI in anesthetized mice in light of the fact that 9% or less O 2 induces cerebral vasodilation sufficient to eliminate the blood oxygen-level dependent (BOLD) signal driven, under normoxia, by increases in cerebral blood flow in response to sensory stimulation (27).…”