Effecting Rhythm and Pattern Generation with Cholinergic Modulation in Rhythmic Medullary Slices of Mice

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Obstructive Sleep Apnea (OSA) is characterized by repeated airway obstructions during sleep leading to cyclic reduced oxygen levels, known as chronic intermittent hypoxia (CIH), and frequent arousals. Insufficient neural control of upper airway muscles, especially the genioglossus, is the causative agent of OSA pathophysiology. Hypoglossal motoneurons (XII MNs) innervate the tongue and maintain airway patency. Airway narrowing during sleep is linked to loss of noradrenergic drive and muscarinic acetylcholine receptor (mAChR) activation. While noradrenergic signaling has been investigated, less is known about mAChR modulation in the inspiratory network. This study's objective is to examine CIH effects on mAChR signaling in the preBötzinger Complex (preBötC, site of inspiratory rhythm generation) and XII MNs. We hypothesize that CIH enhances muscarinic excitatory effects in these regions. In preparation to test the effects of CIH, we tested the effects of cholinergic agonists using rhythmic medullary slice preparations from naïve neonatal mice of both sexes at two postnatal stages (postnatal day (P0-5, P6-8). Bath application of acetylcholine (1 µM, 10 µM, 100 µM, 200 µM) and muscarine (1 µM, 10 µM) was used to evaluate changes in relative peak amplitude of inspiratory bursts and absolute peak frequency in rhythmic medullary slices. In P0-5 slices (n = 4), preliminary data indicated that acetylcholine in the bath increased inspiratory burst amplitude (1 µM: 101 ± 25% 10 µM: 117 ± 55%, 100 µM: 144 ± 85%, 200 µM: 140 ±114%) compared to baseline. Inspiratory burst frequency (bursts/min) may decrease at the highest acetylcholine concentrations (baseline: 24 ± 7, 1 µM: 25 ± 8, 10 µM: 23 ± 5, 100 µM: 22 ± 6, 200 µM: 19 ± 6). In P6-8 slices, preliminary data indicated that acetylcholine had a limited effect on inspiratory burst amplitude (1 µM: 87 ± 16% 10 µM: 94 ± 13%, 100 µM: 98 ± 36%, 200 µM: 98 ± 53%) compared to baseline. In P6-8 slices, inspiratory burst frequency (bursts/min) may decrease at higher acetylcholine concentrations (baseline: 27 ± 10, 1 µM: 27 ± 11, 10 µM: 28 ± 14, 100 µM: 23 ± 7, 200 µM: 21 ± 7). We also tested whether muscarine, an agonist of muscarinic acetylcholine receptors, would affect inspiratory bursting in P6-7 preparations. In a sample of two rhythmic slice preparations, muscarine increased inspiratory burst amplitude (1 µM: 106-156%, 10 µM: 131-207%) and decreased inspiratory burst frequency (bursts/min) (baseline: 20-29, 1 µM: 11-15, 10 µM: 7-11). Preliminary data suggest acetylcholine may have excitatory effects on inspiratory burst amplitude in P0-5 but not in P6-8 preparations and may decrease inspiratory burst frequency. In P6-8 preparations, muscarinic modulation potentiated inspiratory burst amplitude but inhibited inspiratory burst frequency. This data suggests that cholinergic modulation within the medullary slice preparation may undergo developmental changes in its effect early in postnatal maturation. Future experiments will evaluate how CIH alters cholinergic signaling within the rhythmic medullary slice preparation across postnatal maturation. Grant: NIH/NHLBI 1R15HL175526-01 (to ALR) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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