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Inadequate tongue muscle activation contributes to dysarthria, dysphagia, and obstructive sleep apnea. Thus, treatments which increase tongue muscle activity have potential clinical benefit. We hypothesized that lingual injection of an adeno-associated virus (AAV) encoding channelrhodopsin-2 (ChR2) would enable light-induced activation of tongue motor units during spontaneous breathing. An AAV serotype 9 vector (pACAGW-ChR2-Venus-AAV9, 8.29 × 10 11 vg) was injected to the posterior tongue in adult C57BL/6J mice. After 12 weeks, mice were anesthetized and posterior tongue electromyographic (EMG) activity was recorded during spontaneous breathing; a light source was positioned near the injection site. Light-evoked EMG responses increased with the intensity and duration of pulses. Stimulus trains (250 ms) evoked EMG bursts that were comparable to endogenous (inspiratory) tongue muscle activation. Histology confirmed lingual myofiber transgene expression. We conclude that intralingual AAV9-ChR2 delivery enables light evoked lingual EMG activity. These proof-of-concept studies lay the groundwork for clinical application of this novel approach to lingual therapeutics., Competing Interests: Conflict of interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The spiny mouse (Acomys) is a precocial mammal with unique regenerative abilities. We used whole-body plethysmography to describe the breathing patterns and CO 2 production (VCO 2 ) of adult spiny mice (n = 10 male, 10 female) and C57BL/6 mice (n = 9 male, 11 female). During quiet breathing, female but not male spiny mice had lower tidal volumes and CO 2 production vs. C57BL/6 mice. During extended hypoxia (30 min), male and female spiny mice decreased VCO 2 and tidal volume to a greater degree than C57BL/6 mice. During an acute hypoxic-hypercapnic respiratory challenge (10% O 2 , 7% CO 2 ), male and female spiny mice had blunted ventilatory responses as compared to C57BL/6 mice, primarily from a diminished increase in respiratory rate. These data establish a baseline for studies of respiratory physiology and neurobiology in spiny mice in the context of their remarkable regenerative capacity and their unique background of a desert dwelling species., Competing Interests: Conflict of interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ampakines are synthetic molecules that allosterically modulate AMPA-type glutamate receptors. We tested the hypothesis that delivery of ampakines to the intrathecal space could stimulate neural drive to the diaphragm. Ampakine CX717 (20 mM, dissolved in 10 % HPCD) or an HPCD vehicle solution were delivered via a catheter placed in the intrathecal space at the fourth cervical segment in urethane-anesthetized, mechanically ventilated adult male Sprague-Dawley rats. The electrical activity of the phrenic nerve was recorded for 60-minutes following drug application. Intrathecal application of CX717 produced a gradual and sustained increase in phrenic inspiratory burst amplitude (n = 10). In contrast, application of HPCD (n = 10) caused no sustained change in phrenic motor output. Phrenic burst rate, heart rate, and mean arterial pressure were similar between CX717 and HPCD treated rats. We conclude that intrathecally delivered ampakines can modulate phrenic motor output. This approach may have value for targeted induction of spinal neuroplasticity in the context of neurorehabiliation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Intraspinal microstimulation (ISMS) can effectively activate spinal motor circuits, but the impact on the endogenous respiratory pattern has not been systematically evaluated. Here we delivered ISMS in spontaneously breathing adult rats while simultaneously recording diaphragm and external intercostal electromyography activity. ISMS pulses were delivered from C2-T1 along two rostrocaudal tracts located 0.5 or 1 mm lateral to midline. A tungsten electrode was incrementally advanced from the dorsal spinal surface and 300μs biphasic pulses (10-90 μA) were delivered at depth increments of 600 μm. Dorsal ISMS often produced fractionated inspiratory bursting or caused early termination of the inspiratory effort. Conversely, ventral stimulation had no discernable impact on respiratory resetting. We conclude that ISMS targeting the ventral spinal cord is unlikely to directly alter the respiratory rhythm. Dorsal ISMS, however, may terminate the inspiratory burst through activation of spinobulbar pathways. We suggest that respiratory patterns should be included as an outcome variable in preclinical studies of ISMS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Spinal interneuron (IN) networks can facilitate respiratory motor recovery after spinal cord injury (SCI). We hypothesized that excitatory synaptic connectivity between INs located immediately caudal to unilateral cervical SCI would be most prevalent in a contra- to ipsilateral direction. Adult rats were studied following chronic C2 spinal cord hemisection (C2Hx) injury. Rats were anesthetized and ventilated and a multi-electrode array was used to simultaneously record INs on both sides of the C4-5 spinal cord. The temporal firing relationship between IN pairs was evaluated using cross-correlation with directionality of synaptic connections inferred based on electrode location. During baseline recordings, the majority of detectable excitatory IN connections occurred in a contra- to- ipsilateral direction. However, acute respiratory stimulation with hypoxia abolished this directionality, while simultaneously increasing the detectable inhibitory connections within the ipsilateral cord. We conclude that propriospinal networks caudal to SCI can display a contralateral-to-ipsilateral directionality of synaptic connections and that these connections are modulated by acute exposure to hypoxia., (Copyright © 2019 Elsevier B.V. All rights reserved.)