Optogenetic perturbation of preBötzinger complex inhibitory neurons modulates respiratory pattern

Sherman, David; Worrell, Jason W.; Cui, Yan; Feldman, Jack L.

doi:10.1038/nn.3938

Cited by 109 publications

(164 citation statements)

References 43 publications

(70 reference statements)

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“…The Breuer-Hering inhibitory reflex (BHIR) is a powerful lung inflation-induced, vagus nerve-mediated reflex that results in a sustained apnea mediated by fast synaptic inhibition within the preBötC (Janczewski et al, 2013; Sherman et al, 2015). In Dbx1-ChR2 mice, apnea caused by a prolonged BHIR could be broken by bilateral preBötC SPP.…”

Section: Resultsmentioning

confidence: 99%

“…However, synapsin is a pan-neuronal promoter that cannot distinguish among different populations of excitatory and inhibitory neurons. Consequently, the preBötC subpopulations responsible for excitation-mediated rhythm and pattern generation (Greer et al, 1991) and for the roles of GABA- and glycine-mediated postsynaptic inhibition in the Breuer-Hering Inflation Reflex (BHIR) (Janczewski et al, 2013), in modulating breathing frequency, in shaping the pattern of respiratory motor output, and in producing apneas essential for such behaviors as swallowing, phonation, and breathholding (Sherman et al, 2015) must still be specified.…”

Section: Introductionmentioning

confidence: 99%

“…The functional role of various preBötC subpopulations can be elucidated by differentially perturbing their excitability, e.g., for inhibitory neurons (Sherman et al, 2015). To determine the in vivo roles of preBötC Dbx1 + and SST + neurons in rhythm and pattern generation and deconstruct the related neural microcircuits, we employed Cre/loxP transgenic strategies to express ChR2-tdTomato in Dbx1 + neurons (Dbx1-ChR2) or SST + neurons (SST-ChR2).…”

Section: Introductionmentioning

confidence: 99%

“…We conclude that the preBötC is composed of partially overlapping subpopulations that form functionally distinct rhythm and pattern generating microcircuits. We suggest that: i) the onset of activity in preinspiratory Dbx1 + neurons initiates each inspiration (Kam et al, 2013a); ii) Dbx1 + and SST + inspiratory neurons primarily act in a patterning role to transmit activity from rhythmogenic preBötC neurons (Revill et al, 2015; Tan et al, 2010) and ultimately shape inspiratory motoneuronal activity; iii) SST + neuron-mediated inhibitory pathways modulate respiratory activity; and iv) postsynaptic inhibition within the preBötC induces apneas, broadens the dynamic range of inspiratory burst amplitude, and stabilizes the rhythm in the presence of significant perturbations, but is not obligatory for rhythmogenesis (Janczewski et al, 2013; Sherman et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

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Defining preBötzinger Complex Rhythm- and Pattern-Generating Neural Microcircuits In Vivo

Cui

Kam

Sherman

et al. 2016

Neuron

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Summary Normal breathing in rodents requires activity of glutamatergic Dbx1-derived (Dbx1+) preBötzinger Complex (preBötC) neurons expressing somatostatin (SST). We combined in vivo optogenetic and pharmacological perturbations to elucidate the functional roles of these neurons in breathing. In transgenic adult mice expressing channelrhodopsin (ChR2) in Dbx1+ neurons, photoresponsive preBötC neurons had preinspiratory or inspiratory firing patterns associated with excitatory effects on burst timing and pattern. In transgenic adult mice expressing ChR2 in SST+ neurons, photoresponsive preBötC neurons had inspiratory or postinspiratory firing patterns associated with excitatory responses on pattern or inhibitory responses that were largely eliminated by blocking synaptic inhibition within preBötC or by local viral infection limiting ChR2 expression to preBötC SST+ neurons. We conclude that: i) preinspiratory preBötC Dbx1+ neurons are rhythmogenic; ii) inspiratory preBötC Dbx1+ and SST+ neurons primarily act to pattern respiratory motor output, and; iii) SST+ neuron-mediated pathways and postsynaptic inhibition within preBötC modulate breathing pattern.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Defining preBötzinger Complex Rhythm- and Pattern-Generating Neural Microcircuits In Vivo

Cui

Kam

Sherman

et al. 2016

Neuron

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139

186

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show abstract

“…Indeed, these mice have been generated, and the GlyT2-Cre mice are suitable for the selective targeting of floxed genes and transgenes in glycinergic interneurons of brainstem and spinal cord [6,8]. Data recently obtained in these mice are producing relevant information about the role of subpopulations of glycinergic neurons in processing motor and sensory information [6,[9][10][11][12].…”

Section: Introduction: the Building Of A Glycinergic Neuronmentioning

confidence: 99%

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

2016

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Glycinergic neurons are major contributors to the regulation of neuronal excitability, mainly in caudal areas of the nervous system. These neurons control fluxes of sensory information between the periphery and the CNS and diverse motor activities like locomotion, respiration or vocalization. The phenotype of a glycinergic neuron is determined by the expression of at least two proteins: GlyT2, a plasma membrane transporter of glycine, and VIAAT, a vesicular transporter shared by glycine and GABA. In this article, we review recent advances in understanding the role of GlyT2 in the pathophysiology of inhibitory glycinergic neurotransmission. GlyT2 mutations are associated to decreased glycinergic function that results in a rare movement disease termed hyperekplexia (HPX) or startle disease. In addition, glycinergic neurons control pain transmission in the dorsal spinal cord and their function is reduced in chronic pain states. A moderate inhibition of GlyT2 may potentiate glycinergic inhibition and constitutes an attractive target for pharmacological intervention against these devastating conditions.

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Efferent projections of excitatory and inhibitory preBötzinger Complex neurons

Yang

Feldman

2018

J of Comparative Neurology

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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.

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Optogenetic perturbation of preBötzinger complex inhibitory neurons modulates respiratory pattern

Cited by 109 publications

References 43 publications

Defining preBötzinger Complex Rhythm- and Pattern-Generating Neural Microcircuits In Vivo

Defining preBötzinger Complex Rhythm- and Pattern-Generating Neural Microcircuits In Vivo

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

Efferent projections of excitatory and inhibitory preBötzinger Complex neurons

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