Abstract
The rhythm generating network for breathing must continuously adjust to changing metabolic and behavioral demands. Here, we examined network-based mechanisms in the mouse preBötzinger complex using substance P, a potent excitatory modulator of breathing frequency and stability, as a tool to dissect network properties that underlie dynamic breathing. We find that substance P does not alter the balance of excitation and inhibition during breaths or the duration of the resulting refractory period. Instead, mechanisms of recurrent excitation between breaths are enhanced such that the rate that excitation percolates through the network is increased. We propose a conceptual framework in which three distinct phases of inspiration, the burst phase, refractory phase, and percolation phase, can be differentially modulated to control breathing dynamics and stability. Unraveling mechanisms that support this dynamic control may improve our understanding of nervous system disorders that destabilize breathing, many of which involve changes in brainstem neuromodulatory systems.
Highlights
Since substance P (SP) reduced the variability of the inter-burst interval (IBI) at the network level, we examined the relationship between the duration of individual IBIs and the slope of pre-inspiratory spiking activity
Under control conditions and in SP, there was a significant inverse relationship between the duration of a given IBI and the slope of the corresponding pre-inspiratory ramp, such that pre-inspiratory spiking activity at the level of individual neurons can predict the duration between inspiratory bursts at the network level
The rhythm generating network that produces breathing movements must constantly adjust to changing metabolic demands and adapt to overlapping volitional and reflexive behaviors (Feldman et al, 2013, Ramirez and Baertsch, 2018b)
Summary
Rhythmicity is ubiquitous in the brain, important for many high order functions such as consciousness, attention, perception, and memory (Basar and Duzgun, 2016, Basar and Guntekin, 2008, Colgin, 2016, Hanslmayr et al, 2016, Kiehn, 2016, Neske, 2015, Palva and Palva, 2018, Paton and Buonomano, 2018), as well as vital rhythmic motor behaviors including chewing, locomotion, and breathing (Grillner and El Manira, 2015, Kiehn, 2016, Narayanan and DiLeone, 2017, Ramirez and Baertsch, 2018a, Wyart, 2018, Nakamura et al, 2004). Rhythms generated by the brain are diverse, as are the underlying rhythm generating network- and cellular-level mechanisms (Paton and Buonomano, 2018). Understanding principles that allow dynamic control of rhythm generating networks may provide important insights into the regulation of diverse brain functions. Investigations of the networks and cellular mechanisms that generate breathing have provided valuable, generalizable insights into the origins and control of neural rhythmicity (Del Negro et al, 2018, Feldman and Kam, 2015, Ramirez and Baertsch, 2018b, Wyman, 1977, Cohen, 1981, Ezure, 1990, Long and Duffin, 1986, Milsom, 1991). A region that is both necessary and sufficient for inspiration, the pre-Bötzinger Complex (preBötC), is autorhythmic and forms the core of this network (Smith et al, 1991, Tan et al, 2008, Vann et al, 2018)
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