Breathing control center neurons that promote arousal in mice

Yackle, Kevin; Schwarz, Lindsay A.; Kam, Kaiwen; Sorokin, Jordan M.; Huguenard, John R.; Feldman, Jack L.; Luo, Liqun; Krasnow, Mark A.

doi:10.1126/science.aai7984

Cited by 214 publications

(201 citation statements)

References 47 publications

Supporting

Mentioning

185

Contrasting

Unclassified

Order By: Relevance

“…While injections into the preBötC of both SST‐Cre and GlyT2‐Cre mice revealed strong projections to discrete nuclei, there were also markedly less dense and diffuse EGFP + processes that did not appear to target specific regions and are not described here. For example, we observed very sparse projections in the cerebellum and raphe nuclei, with a few projections in the locus coeruleus (cf., Yackle et al, ) apparently straying from neighboring parabrachial nuclei.…”

Section: Resultsmentioning

confidence: 99%

Efferent projections of excitatory and inhibitory preBötzinger Complex neurons

Yang

Feldman

2018

J of Comparative Neurology

Self Cite

148

128

View full text Add to dashboard Cite

The preBötzinger Complex (preBötC), a compact medullary region essential for generating normal breathing rhythm and pattern, is the kernel of the breathing central pattern generator (CPG). Excitatory preBötC neurons in rats project to major breathing-related brainstem regions. Here, we provide a brainstem connectivity map in mice for both excitatory and inhibitory preBötC neurons. Using a genetic strategy to label preBötC neurons, we confirmed extensive projections of preBötC excitatory neurons within the brainstem breathing CPG including the contralateral preBötC, Bötzinger Complex (BötC), ventral respiratory group, nucleus of the solitary tract, parahypoglossal nucleus, parafacial region (RTN/pFRG or alternatively, pF /pF ), parabrachial and Kölliker-Füse nuclei, as well as major projections to the midbrain periaqueductal gray. Interestingly, preBötC inhibitory projections paralleled the excitatory projections. Moreover, we examined overlapping projections in the pons in detail and found that they targeted the same neurons. We further explored the direct anatomical link between the preBötC and suprapontine brain regions that may govern emotion and other complex behaviors that can affect or be affected by breathing. Forebrain efferent projections were sparse and restricted to specific nuclei within the thalamus and hypothalamus, with processes rarely observed in cortex, basal ganglia, or other limbic regions, e.g., amygdala or hippocampus. We conclude that the preBötC sends direct, presumably inspiratory-modulated, excitatory and inhibitory projections in parallel to distinct targets throughout the brain that generate and modulate breathing pattern and/or coordinate breathing with other behaviors, physiology, cognition, or emotional state.

show abstract

Section: Resultsmentioning

confidence: 99%

Efferent projections of excitatory and inhibitory preBötzinger Complex neurons

Yang

Feldman

2018

J of Comparative Neurology

Self Cite

148

128

View full text Add to dashboard Cite

show abstract

“…The PBel CGRP neurons provide the main relay for these stimuli to reach forebrain sites to cause wakefulness, which in turn augments airway opening, and permits the individual to survive the apneic event. Although other brainstem cell groups may participate in CO2 responses, such as the serotonergic dorsal raphe (Buchanan and Richerson, 2010;Ray et al, 2011;Ray et al, 2013;Richerson et al, 2005;Smith et al, 2012) and noradrenergic locus coeruleus neurons (Carter et al, 2010;Gargaglioni et al, 2010;Yackle et al, 2017), they clearly cannot cause normal arousal to elevated CO2 without the PBel CGRP neurons. How they participate, presumably in a modulatory role, is the subject of our current investigation.…”

Section: Discussionmentioning

confidence: 99%

A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia

Kaur

Wang

Ferrari

et al. 2017

Neuron

124

179

View full text Add to dashboard Cite

Summary The precise neural circuitry that mediates arousal during sleep apnea is not known. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) play a critical role in arousal to elevated CO2 or hypoxia. Because many of the PBel neurons that respond to CO2 express calcitonin gene-related peptide (CGRP), we hypothesized that CGRP may provide a molecular identifier of the CO2 arousal circuit. Here we report that selective chemogenetic and optogenetic activation of PBelCGRP neurons caused wakefulness, whereas optogenetic inhibition of PBelCGRP neurons prevented arousal to CO2, but not to an acoustic tone or shaking. Optogenetic inhibition of PBelCGRP terminals identified a network of forebrain sites under the control of a PBelCGRP switch that is necessary to arouse animals from hypercapnia. Our findings define a novel cellular target for interventions that may prevent sleep fragmentation and the attendant cardiovascular and cognitive consequences seen in obstructive sleep apnea.

show abstract

“…Chemical ablation of LC neurons results in a significant attenuation of the hypercapnic respiratory effect (Bianciardi et al, 2008;Noronha-de-Souza et al, 2006). Connections from the LC to preinspiratory neurons have also been identified (Dobbins & Feldman, 1994;Yackle et al, 2017). Importantly, because arterial CO 2 levels are known to fluctuate with respiration (Band, Cameron, & Semple, 1969;Band, Wolff, Ward, Cochrane, & Prior, 1980;Honda & Ueda, 1961; see Figure 1), this should induce a corresponding fluctuation of LC tonic 1 Positive hydrogen ions result from CO 2 combining with H 2 O to produce carbonic acid, which is then broken down into bicarbonate, resulting in a surplus H1 ion.…”

Section: Lc and Co 2 Chemosensitivitymentioning

confidence: 99%

Coupling of respiration and attention via the locus coeruleus: Effects of meditation and pranayama

et al. 2018

View full text Add to dashboard Cite

The locus coeruleus (LC) has established functions in both attention and respiration. Good attentional performance requires optimal levels of tonic LC activity, and must be matched to task consistently. LC neurons are chemosensitive, causing respiratory phrenic nerve firing to increase frequency with higher CO levels, and as CO level varies with the phase of respiration, tonic LC activity should exhibit fluctuations at respiratory frequency. Top-down modulation of tonic LC activity from brain areas involved in attentional regulation, intended to optimize LC firing to suit task requirements, may have respiratory consequences as well, as increases in LC activity influence phrenic nerve firing. We hypothesize that, due to the physiological and functional overlaps of attentional and respiratory functions of the LC, this small neuromodulatory nucleus is ideally situated to act as a mechanism of synchronization between respiratory and attentional systems, giving rise to a low-amplitude oscillation that enables attentional flexibility, but may also contribute to unintended destabilization of attention. Meditative and pranayama practices result in attentional, emotional, and physiological enhancements that may be partially due to the LC's pivotal role as the nexus in this coupled system. We present original findings of synchronization between respiration and LC activity (via fMRI and pupil dilation) and provide evidence of a relationship between respiratory phase modulation and attentional performance. We also present a mathematical dynamical systems model of respiratory-LC-attentional coupling, review candidate neurophysiological mechanisms of changes in coupling dynamics, and discuss implications for attentional theory, meditation, and pranayama, and possible therapeutic applications.

show abstract

Breathing control center neurons that promote arousal in mice

Cited by 214 publications

References 47 publications

Efferent projections of excitatory and inhibitory preBötzinger Complex neurons

Efferent projections of excitatory and inhibitory preBötzinger Complex neurons

A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia

Coupling of respiration and attention via the locus coeruleus: Effects of meditation and pranayama

Contact Info

Product

Resources

About