Abstract
Exposure to acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF). We have shown that nucleus tractus solitarii (nTS) activity is necessary for both the development and maintenance of pLTF. Activation of glutamatergic N-methyl-d-aspartate receptors (NMDARs) and CaMKII contribute to in vitro long-term potentiation, to nTS hypoxic responses, and possibly to pLTF. This study investigated the role of nTS NMDARs and CaMKII in the development and maintenance of AIH-induced pLTF. Phrenic nerve and splanchnic sympathetic nerve activity (PhrNA and sSNA) were recorded in male Sprague-Dawley rats in response to AIH [10 bouts of 10% O(2) (45 s, interspersed by 5 min)]. Time control (TC) rats underwent a single hypoxia bout and were monitored for 2 h afterward. After AIH, PhrNA amplitude increased compared to initial baseline (BL) and TC, indicating induction of pLTF. pLTF development was associated with increased nTS neuronal Ca(2+) and action potential discharge recorded via GCaMP8 fiber photometry and an array probe, respectively. Inhibition of nTS CaMKII activity before AIH exposure attenuated the development of pLTF and elevation of nTS neuronal discharge. In contrast, after pLTF had developed, inhibiting nTS CaMKII activity had no effect on the maintenance of pLTF. Nevertheless, after AIH, blocking NMDARs specifically in the nTS by bilateral nanoinjection of AP5 reduced the magnitude of pLTF. Altogether, these results indicate that increased nTS neuronal activity likely due to activation of NMDARs and their downstream CaMKII signaling complex are critical components for AIH-induced neuroplasticity in central cardiorespiratory output.NEW & NOTEWORTHY Exposure to acute intermittent hypoxia (AIH) induced sustained increases in phrenic nerve activity (phrenic long-term facilitation, pLTF) that were associated with increased nucleus tractus solitarii (nTS) neuronal Ca(2+) and action potential discharge. nTS CaMKII activity was critical for pLTF development and AIH-induced increases in neuronal discharge. In contrast, nTS NMDA receptor (NMDAR) activation, but not CaMKII activity, was required for maintaining AIH-induced pLTF. Increased nTS neuronal activity, NMDAR activation, and CaMKII are critical for AIH-induced neuroplasticity in central cardiorespiratory output.