Cervical spinal V2a neurons pattern respiratory muscle activity and enhance ventilation

Abstract

Our prior studies suggested that one subset of V2a neurons activates accessory respiratory muscles whereas another subset of V2a neurons actively prevents their activation at rest. However, since these studies altered V2a neuron excitability throughout the spinal cord and brainstem, it was not clear whether the V2a neurons that activate accessory respiratory muscles are located in the same region of the neuraxis as V2a neurons that prevent activation of accessory respiratory muscles at rest. Therefore, we used a Cre‐dependent AAV virus injected into a Chx10Cre/+ mouse to selectively target either the excitatory (Gq)‐ or inhibitory (Gi)‐DREADD receptor to cervical spinal V2a neurons on one side or both sides of the cord in order to alter V2a neuron excitability. Whole breath plethysmography (WBP) and electromyography (EMG) were recorded in conscious mice at rest to measure ventilation and respiratory muscle activity before and after altering V2a neuron excitability. We found that bilaterally increasing the excitability of cervical spinal V2a neurons increases accessory respiratory muscle (scalene) activity, diaphragm EMG peak amplitude, and ventilation. Although V2a neurons project ipsilaterally, increasing their excitability on one side of the cord is able to synchronously activate scalene muscles on both sides of the body. Bilaterally silencing cervical spinal V2a neurons also activates scalene muscle activity, but does not impair diaphragm function. Our results are consistent with the hypothesis that one subset of V2a neurons in the cervical spinal cord activates accessory respiratory muscles whereas another subset of cervical V2a neurons inhibits accessory respiratory muscles at rest. Support or Funding Information 1RO1NS112255T32NS5007453University of Cincinnati Dean’s Dissertation Completion Fellowship

V2a neurons restore diaphragm function in mice following spinal cord injury

“…For example, activating V2a neurons is unlikely to impact brainstem control of breathing (e.g., chemosensation) because V2a neurons appear to increase activity of the diaphragm without increasing respiratory drive. This data is consistent with our prior studies showing that altering the activity of V2a neurons does not impair breathing in healthy adult mice, despite the fact that V2a neurons provide excitatory drive to brainstem rhythm generating neurons necessary for regular breathing rhythm during the neonatal period ( 29 , 30 , 65 , 71 ). Further, activating V2a neurons does not appear to adversely affect other motor functions, like walking ( 22 , 29 , 30 , 71 ).…”

“…This data is consistent with our prior studies showing that altering the activity of V2a neurons does not impair breathing in healthy adult mice, despite the fact that V2a neurons provide excitatory drive to brainstem rhythm generating neurons necessary for regular breathing rhythm during the neonatal period ( 29 , 30 , 65 , 71 ). Further, activating V2a neurons does not appear to adversely affect other motor functions, like walking ( 22 , 29 , 30 , 71 ). Future experiments to identify druggable molecules expressed by V2a neurons and/or develop improved methods (e.g., electrical stimulation) to target these neurons in humans could lead to advances in the treatment of respiratory insufficiency following spinal cord injury.…”