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      Loss of Cervical Sympathetic Chain Input to the Superior Cervical Ganglia Affects the Ventilatory Responses to Hypoxic Challenge in Freely-Moving C57BL6 Mice

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          Abstract

          The cervical sympathetic chain (CSC) innervates post-ganglionic sympathetic neurons within the ipsilateral superior cervical ganglion (SCG) of all mammalian species studied to date. The post-ganglionic neurons within the SCG project to a wide variety of structures, including the brain (parenchyma and cerebral arteries), upper airway (e.g., nasopharynx and tongue) and submandibular glands. The SCG also sends post-ganglionic fibers to the carotid body (e.g., chemosensitive glomus cells and microcirculation), however, the function of these connections are not established in the mouse. In addition, nothing is known about the functional importance of the CSC-SCG complex (including input to the carotid body) in the mouse. The objective of this study was to determine the effects of bilateral transection of the CSC on the ventilatory responses [e.g., increases in frequency of breathing (Freq), tidal volume (TV) and minute ventilation (MV)] that occur during and following exposure to a hypoxic gas challenge (10% O 2 and 90% N 2) in freely-moving sham-operated (SHAM) adult male C57BL6 mice, and in mice in which both CSC were transected (CSCX). Resting ventilatory parameters (19 directly recorded or calculated parameters) were similar in the SHAM and CSCX mice. There were numerous important differences in the responses of CSCX and SHAM mice to the hypoxic challenge. For example, the increases in Freq (and associated decreases in inspiratory and expiratory times, end expiratory pause, and relaxation time), and the increases in MV, expiratory drive, and expiratory flow at 50% exhaled TV (EF 50) occurred more quickly in the CSCX mice than in the SHAM mice, although the overall responses were similar in both groups. Moreover, the initial and total increases in peak inspiratory flow were higher in the CSCX mice. Additionally, the overall increases in TV during the latter half of the hypoxic challenge were greater in the CSCX mice. The ventilatory responses that occurred upon return to room-air were essentially similar in the SHAM and CSCX mice. Overall, this novel data suggest that the CSC may normally provide inhibitory input to peripheral (e.g., carotid bodies) and central (e.g., brainstem) structures that are involved in the ventilatory responses to hypoxic gas challenge in C57BL6 mice.

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          Respiratory problems and management in people with spinal cord injury

          Spinal cord injury (SCI) is characterised by profound respiratory compromise secondary to the level of loss of motor, sensory and autonomic control associated with the injury. This review aims to detail these anatomical and physiological changes after SCI, and outline their impact on respiratory function. Injury-related impairments in strength substantially alter pulmonary mechanics, which in turn affect respiratory management and care. Options for treatments must therefore be considered in light of these limitations. Key points Respiratory impairment following spinal cord injury (SCI) is more severe in high cervical injuries, and is characterised by low lung volumes and a weak cough secondary to respiratory muscle weakness. Autonomic dysfunction and early-onset sleep disordered breathing compound this respiratory compromise. The mainstays of management following acute high cervical SCI are tracheostomy and ventilation, with noninvasive ventilation and assisted coughing techniques being important in lower cervical and thoracic level injuries. Prompt investigation to ascertain the extent of the SCI and associated injuries, and appropriate subsequent management are important to improve outcomes. Educational aims To describe the anatomical and physiological changes after SCI and their impact on respiratory function. To describe the changes in respiratory mechanics seen in cervical SCI and how these changes affect treatments. To discuss the relationship between injury level and respiratory compromise following SCI, and describe those at increased risk of respiratory complications. To present the current treatment options available and their supporting evidence.
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            Kv2 channel regulation of action potential repolarization and firing patterns in superior cervical ganglion neurons and hippocampal CA1 pyramidal neurons.

            Kv2 family "delayed-rectifier" potassium channels are widely expressed in mammalian neurons. Kv2 channels activate relatively slowly and their contribution to action potential repolarization under physiological conditions has been unclear. We explored the function of Kv2 channels using a Kv2-selective blocker, Guangxitoxin-1E (GxTX-1E). Using acutely isolated neurons, mixed voltage-clamp and current-clamp experiments were done at 37°C to study the physiological kinetics of channel gating and action potentials. In both rat superior cervical ganglion (SCG) neurons and mouse hippocampal CA1 pyramidal neurons, 100 nm GxTX-1E produced near-saturating block of a component of current typically constituting ∼60-80% of the total delayed-rectifier current. GxTX-1E also reduced A-type potassium current (IA), but much more weakly. In SCG neurons, 100 nm GxTX-1E broadened spikes and voltage clamp experiments using action potential waveforms showed that Kv2 channels carry ∼55% of the total outward current during action potential repolarization despite activating relatively late in the spike. In CA1 neurons, 100 nm GxTX-1E broadened spikes evoked from -70 mV, but not -80 mV, likely reflecting a greater role of Kv2 when other potassium channels were partially inactivated at -70 mV. In both CA1 and SCG neurons, inhibition of Kv2 channels produced dramatic depolarization of interspike voltages during repetitive firing. In CA1 neurons and some SCG neurons, this was associated with increased initial firing frequency. In all neurons, inhibition of Kv2 channels depressed maintained firing because neurons entered depolarization block more readily. Therefore, Kv2 channels can either decrease or increase neuronal excitability depending on the time scale of excitation.
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              A protocol for high-throughput phenotyping, suitable for quantitative trait analysis in mice.

              Whole-genome genetic association studies in outbred mouse populations represent a novel approach to identifying the molecular basis of naturally occurring genetic variants, the major source of quantitative variation between inbred strains of mice. Measuring multiple phenotypes in parallel on each mouse would make the approach cost effective, but protocols for phenotyping on a large enough scale have not been developed. In this article we describe the development and deployment of a protocol to collect measures on three models of human disease (anxiety, type II diabetes, and asthma) as well as measures of mouse blood biochemistry, immunology, and hematology. We report that the protocol delivers highly significant differences among the eight inbred strains (A/J, AKR/J, BALBc/J, CBA/J, C3H/HeJ, C57BL/6 J, DBA/2 J, and LP/J), the progenitors of a genetically heterogeneous stock (HS) of mice. We report the successful collection of multiple phenotypes from 2000 outbred HS animals. The phenotypes measured in the protocol form the basis of a large-scale investigation into the genetic basis of complex traits in mice designed to examine interactions between genes and between genes and environment, as well as the main effects of genetic variants on phenotypes.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                22 April 2021
                2021
                : 12
                : 619688
                Affiliations
                [1] 1Department of Pediatrics, Division of Pulmonology, Allergy and Immunology, Case Western Reserve University , Cleveland, OH, United States
                [2] 2The Department of Physiology and Biophysics, Case Western Reserve University , Cleveland, OH, United States
                [3] 3Division of Pulmonary, Critical Care and Sleep Medicine, University Hospitals Case Medical Center, Case Western Reserve University , Cleveland, OH, United States
                [4] 4Department of Pharmacology, Case Western Reserve University , Cleveland, OH, United States
                Author notes

                Edited by: Gregory D. Funk, University of Alberta, Canada

                Reviewed by: Nephtali Marina, University College London, United Kingdom; Kevin James Cummings, University of Missouri, United States

                *Correspondence: Stephen J. Lewis, sjl78@ 123456case.edu

                This article was submitted to Respiratory Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2021.619688
                8100345
                33967819
                144ba839-53fd-47ec-bcc4-b13df1b0eca9
                Copyright © 2021 Getsy, Coffee, Hsieh and Lewis.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 20 October 2020
                : 30 March 2021
                Page count
                Figures: 10, Tables: 2, Equations: 0, References: 197, Pages: 23, Words: 0
                Funding
                Funded by: Foundation for the National Institutes of Health 10.13039/100000009
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                cervical sympathetic chain transection,superior cervical ganglion,hypoxic gas challenge,ventilatory parameters,c57bl6 mice

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