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A projection from the hypothalamic paraventricular nucleus (PVN) to nucleus tractus solitarii (nTS) is essential for cardiorespiratory responses to hypoxia

The PVN contributes to cardiorespiratory responses to peripheral chemoreflex activation. We have shown that hypoxia (Hx) activates PVN neurons that project to the nTS but the functional role of this nTS projection is not known. We hypothesized that selective inhibition/activation of the PVN to nTS pathway blunts/augments chemoreflex cardiorespiratory responses. Male SD rats received bilateral microinjections of retrograde AAV‐pgk‐Cre into the nTS. One week later, rats received bilateral PVN injections of Cre‐dependent AAV2‐DIO‐hSyn‐mCherry expressing inhibitory (Gi) or excitatory (Gq) DREADD, or control virus (mCh), and 3–5 weeks allowed for expression in nTS‐projecting PVN neurons. To evaluate the contribution of the PVN to nTS pathway to chemoreflex function, ventilatory responses (plethysmography) to progressive Hx (14–8% O2) were assessed in conscious animals before and after ip injection of saline or the synthetic selective DREADD ligand C21 (1mg/kg). We similarly evaluated Hx‐induced nTS neuronal activation (Fos immunohistochemistry); 60 min after ip saline or C21, conscious mCh (n=6) and Gi (n=4) rats were exposed to Hx (2 hr, 10% O2) and Gq rats were exposed to 12% O2. Saline had no effect on either ventilatory responses or nTS neuronal activation to Hx in any group. In Gi rats, selective inhibition of nTS‐projecting PVN neurons with C21 blunted hypoxic ventilatory responses to 10% and 8% O2 (n=8, p<0.05) and appeared associated with decreased Hx‐induced nTS neuronal activation (581 ± 33 vs. 375 ± 150 cells; saline vs. C21; n=2 each). In contrast, selective activation of the PVN to nTS pathway by C21 in Gq rats (n=8) enhanced Hx ventilatory responses to milder hypoxia (14 and 12% O2, p<0.05), and produced greater Hx‐induced Fos‐IR in the nTS (377 ± 45 vs. 550 ± 23 cells; saline vs. C21, n=3 ea). To confirm that altered cardiorespiratory chemoreflex responses were mediated by PVN terminals in the nTS, anesthetized rats were exposed to brief (45s) Hx episodes (10% O2, mCh and Gi rats; 12% O2, Gq rats) before and after bilateral nTS microinjection of C21 (0.1mM; 90nl/side). Mean arterial pressure (MAP), heart rate (HR), splanchnic sympathetic nerve activity (sSNA) and phrenic nerve activity (PhrNA)] were measured. Under control conditions, Hx decreased MAP and increased HR, sSNA and PhrNA in all groups. Peak responses to 10% O2 were similar in mCh and Gi rats and greater than control responses to 12% O2 in Gq rats. nTS microinjection of C21 had minor baseline effects, which were not different among groups. nTS C21 did not alter the Hx‐induced increase in PhrNA of mCh rats (n=2). In Gi rats (n=3), DREADD‐mediated inhibition of PVN terminals in the nTS blunted both PhrNA (−63 ± 10%; p<0.05) and sSNA (−32 ± 18%; p<0.05) responses to Hx. In contrast, activation of PVN terminals in the nTS enhanced both PhrNA (+51 ± 36%) and sSNA (+166 ± 41%) responses to Hx in Gq rats (n=3). Together, these results suggest that a PVN to nTS pathway directly enhances nTS neuronal activation and cardiorespiratory responses to hypoxia.