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1 Organismal Biology and Anatomy, University of Chicago, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: jcv{at}uchicago.edu.
Pacemakers are found throughout the mammalian central nervous system. Yet, it remains largely unknown how these neurons contribute to network activity. Here we show that for the respiratory network isolated in transverse slices of mice, different functions can be assigned to different types of pacemakers and non-pacemakers. This difference becomes evident in response to norepinephrine (NE). Although NE depolarized 88 % of synaptically isolated inspiratory neurons, this neuromodulator had differential effects on different neuron types. NE increased in cadmium-insensitive pacemakers burst frequency, not burst area and duration, and it increased in cadmium-sensitive pacemakers burst duration and area, but not frequency. NE differentially modulated also non-pacemakers. Two types of non-pacemakers were identified: "Silent non-pacemakers" stop spiking, while "active non-pacemakers" spontaneously spike when isolated from the network. NE induced selectively cadmium-sensitive pacemaker properties in active, but not silent non-pacemakers. Flufenamic acid (FFA), a blocker of ICAN, blocked the induction as well as modulation of cadmium-sensitive pacemaker activity, and blocked at the network level the NE-induced increase in burst area and duration of inspiratory network activity. The frequency modulation was unaffected. We therefore propose that modulation of cadmium-sensitive pacemaker activity contributes at the network level to changes in burst shape, not frequency. Riluzole blocked the frequency modulation of isolated cadmium-insensitive pacemakers. In the presence of riluzole, NE caused disorganized network activity, suggesting that cadmium-insensitive pacemakers are critical for rhythm generation. We conclude that different types of non-pacemaker and pacemaker neurons differentially control different aspects of the respiratory rhythm.
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