TY - JOUR

T1 - Phasic inhibition as a mechanism for generation of rapid respiratory rhythms

AU - Cregg, Jared M

AU - Chu, Kevin A

AU - Dick, Thomas E

AU - Landmesser, Lynn T

AU - Silver, Jerry

PY - 2017/11/28

Y1 - 2017/11/28

N2 - Central neural networks operate continuously throughout life to control respiration, yet mechanisms regulating ventilatory frequency are poorly understood. Inspiration is generated by the pre-Bötzinger complex of the ventrolateral medulla, where it is thought that excitation increases inspiratory frequency and inhibition causes apnea. To test this model, we used an in vitro optogenetic approach to stimulate select populations of hindbrain neurons and characterize how they modulate frequency. Unexpectedly, we found that inhibition was required for increases in frequency caused by stimulation of Phox2b-lineage, putative CO2-chemosensitive neurons. As a mechanistic explanation for inhibition-dependent increases in frequency, we found that phasic stimulation of inhibitory neurons can increase inspiratory frequency via postinhibitory rebound. We present evidence that Phox2b-mediated increases in frequency are caused by rebound excitation following an inhibitory synaptic volley relayed by expiration. Thus, although it is widely thought that inhibition between inspiration and expiration simply prevents activity in the antagonistic phase, we instead propose a model whereby inhibitory coupling via postinhibitory rebound excitation actually generates fast modes of inspiration.

AB - Central neural networks operate continuously throughout life to control respiration, yet mechanisms regulating ventilatory frequency are poorly understood. Inspiration is generated by the pre-Bötzinger complex of the ventrolateral medulla, where it is thought that excitation increases inspiratory frequency and inhibition causes apnea. To test this model, we used an in vitro optogenetic approach to stimulate select populations of hindbrain neurons and characterize how they modulate frequency. Unexpectedly, we found that inhibition was required for increases in frequency caused by stimulation of Phox2b-lineage, putative CO2-chemosensitive neurons. As a mechanistic explanation for inhibition-dependent increases in frequency, we found that phasic stimulation of inhibitory neurons can increase inspiratory frequency via postinhibitory rebound. We present evidence that Phox2b-mediated increases in frequency are caused by rebound excitation following an inhibitory synaptic volley relayed by expiration. Thus, although it is widely thought that inhibition between inspiration and expiration simply prevents activity in the antagonistic phase, we instead propose a model whereby inhibitory coupling via postinhibitory rebound excitation actually generates fast modes of inspiration.

KW - Animals

KW - Carbon Dioxide/metabolism

KW - Exhalation/drug effects

KW - Female

KW - Hypoglossal Nerve/drug effects

KW - Inhalation/drug effects

KW - Male

KW - Medulla Oblongata/cytology

KW - Mice

KW - Neurons/cytology

KW - Optogenetics/methods

KW - Phrenic Nerve/drug effects

KW - Picrotoxin/pharmacology

KW - Prazosin/pharmacology

KW - Propranolol/pharmacology

KW - Respiratory Center/cytology

KW - Respiratory Rate/drug effects

KW - Spinal Nerve Roots/drug effects

KW - Strychnine/pharmacology

KW - Substance P/pharmacology

U2 - 10.1073/pnas.1711536114

DO - 10.1073/pnas.1711536114

M3 - Journal article

C2 - 29133427

VL - 114

SP - 12815

EP - 12820

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 48

ER -