Normal breathing requires preBötzinger complex neurokinin-1 receptor-expressing neurons.
ABSTRACT The normal breathing rhythm in mammals is hypothesized to be generated by neurokinin-1 receptor (NK1R)-expressing neurons in the preBötzinger complex (preBötC), a medullary region proposed to contain the kernel of the circuits generating respiration. If this hypothesis is correct, then complete destruction of preBötC NK1R neurons should severely perturb and perhaps even fatally arrest breathing. Here we show that specific and near complete bilateral (but not unilateral) destruction of preBötC NK1R neurons results in both an ataxic breathing pattern with markedly altered blood gases and pH, and pathological responses to challenges such as hyperoxia, hypoxia and anesthesia. Thus, these approximately 600 neurons seem necessary for the generation of normal breathing in rats.
Full-textDOI: · Available from: Jack L Feldman, May 28, 2015
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ABSTRACT: Substance P (SP) and its receptor, neurokinin-1 (NK1R), have been shown to be excitatory modulators of respiratory frequency and stabilize breathing regularity. Studies in anesthetized mice suggest that tonic activation of NK1Rs is particularly important when other excitatory inputs to the pre-Bötzinger Complex in the ventral respiratory column (VRC) are attenuated. Consistent with these findings, muscarinic receptor blockade in the VRC of intact goats elicits an increase in breathing frequency associated with increases in SP and serotonin concentrations, suggesting an involvement of these substances in neuromodulator compensation. To gain insight on the contribution to breathing of endogenous SP and NK1R activation, and how NK1R modulates the release of other neurochemicals, we individually dialyzed antagonists to NK1R (133, 267, 500 µM Spantide; 3 mM RP67580) throughout the VRC of awake and sleeping goats. We found that NK1R blockade with either Spantide at any dose or RP67580 had no effect on breathing or regularity. Both antagonists significantly (P<0.001) increased SP, while RP67580 also increased serotonin and glycine and decreased TRH concentrations in the dialysate. Taken together, these data support the concept of neuromodulator interdependence, and we believe that the loss of excitatory input from NK1Rs was locally compensated by changes in other neurochemicals. Copyright © 2014, Journal of Applied Physiology.Journal of Applied Physiology 01/2015; 118(6):jap.00884.2014. DOI:10.1152/japplphysiol.00884.2014 · 3.43 Impact Factor
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ABSTRACT: Breathing in mammals is a seemingly straightforward behavior controlled by the brain. A brainstem nucleus called the preBötzinger Complex sits at the core of the neural circuit generating respiratory rhythm. Despite the discovery of this microcircuit almost 25 years ago, the mechanisms controlling breathing remain elusive. Given the apparent simplicity and well-defined nature of regulatory breathing behavior, the identification of much of the circuitry, and the ability to study breathing in vitro as well as in vivo, many neuroscientists and physiologists are surprised that respiratory rhythm generation is still not well-understood. Our view is that conventional rhythmogenic mechanisms involving pacemakers, inhibition, or bursting are problematic and that simplifying assumptions commonly made for many vertebrate neural circuits ignore consequential detail. We propose that novel emergent mechanisms govern generation of respiratory rhythm. That a mammalian function as basic as rhythm generation arises from complex and dynamic molecular, synaptic, and neuronal interactions within a diverse neural microcircuit highlights the challenges in understanding neural control of mammalian behaviors, many (considerably) more elaborate than breathing. We suggest that the neural circuit controlling breathing is inimitably tractable and may inspire general strategies for elucidating other neural microcircuits.This article is protected by copyright. All rights reservedThe Journal of Physiology 11/2014; 593(1). DOI:10.1113/jphysiol.2014.277632 · 4.54 Impact Factor
Article: Vocal development in dystonic rats[Show abstract] [Hide abstract]
ABSTRACT: Vocal production, which requires the generation and integration of laryngeal and respiratory motor patterns, can be impaired in dystonia, a disorder believed due to dysfunction of sensorimotor pathways in the central nervous system. Herein, we analyze vocal and respiratory abnormalities in the dystonic (dt) rat, a well-characterized model of generalized dystonia. The dt rat is a recessive mutant with haploinsufficiency of Atcay which encodes the neuronally restricted protein caytaxin. Olivocerebellar functional abnormalities are central to the dt rat's truncal and appendicular dystonia and could also contribute to vocal and respiratory abnormalities in this model system. Differences in vocal repertoire composition were found between homozygote and wild-type dt rat pups developing after 3 weeks of life. Those spectro-temporal differences were not paralleled by differences in vocal activity or maximum lung pressures during quiet breathing and vocalization. However, breathing rhythm was slower in homozygote pups. This slower breathing rhythm persisted into adulthood. Given that cerebellectomy eliminates truncal and appendicular dystonia in the dt rat, we hypothesize that the altered breathing patterns stem either from a disturbance in the maturation of respiratory pattern generators or from deficient extracerebellar caytaxin expression affecting normal respiratory pattern generation. The altered breathing rhythm associated with vocal changes in the murine model resembles aspects of vocal dysfunction that are seen in humans with sporadic dystonia. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.04/2015; 3(4). DOI:10.14814/phy2.12350