Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.74762
Keywords
respiratory rhythm generation; pattern generation; computational modeling; preB0tzinger complex; Mouse
Categories
Funding
- National Institute of Neurological Disorders and Stroke
- National Science Foundation [DMS 1951095, DMS 1724240]
- National Institutes of Health [R01 AT008632, U01 EB021960]
- Georgia State University
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This study experimentally confirmed the roles of neuronal persistent sodium current (I-NaP) and calcium-activated non-selective cation current (I-CAN) in the respiratory oscillator. The results showed that I-NaP is essential for rhythm generation, while I-CAN plays a crucial role in determining the amplitude of rhythmic output.
Previously our computational modeling studies (Phillips et al., 2019) proposed that neuronal persistent sodium current (I-NaP) and calcium-activated non-selective cation current (I-CAN) are key biophysical factors that, respectively, generate inspiratory rhythm and burst pattern in the mammalian preBotzinger complex (preBotC) respiratory oscillator isolated in vitro. Here, we experimentally tested and confirmed three predictions of the model from new simulations concerning the roles of I-NaP and I-CAN: (1) I-NaP and I-CAN blockade have opposite effects on the relationship between network excitability and preBotC rhythmic activity; (2) I-NaP is essential for preBotC rhythmogenesis; and (3) I-CAN is essential for generating the amplitude of rhythmic output but not rhythm generation. These predictions were confirmed via optogenetic manipulations of preBotC network excitability during graded I-NaP or I-CAN blockade by pharmacological manipulations in slices in vitro containing the rhythmically active preBotC from the medulla oblongata of neonatal mice. Our results support and advance the hypothesis that I-NaP and I-CAN mechanistically underlie rhythm and inspiratory burst pattern generation, respectively, in the isolated preBotC.
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