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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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          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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            Kv2 channel regulation of action potential repolarization and firing patterns in superior cervical ganglion neurons and hippocampal CA1 pyramidal neurons.

             Pin Liu,  Bruce Bean (2014)
            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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              The sensory and sympathetic innervation of guinea-pig lung and trachea as studied by retrograde neuronal tracing and double-labelling immunohistochemistry.

              The sympathetic and sensory innervation of guinea-pig trachea and lung were studied by means of retrograde neuronal tracing using fluorescent dyes, and double-labelling immunofluorescence. Sympathetic neurons supplying the lung were located in stellate ganglia and in thoracic sympathetic chain ganglia T2-T4; those supplying the trachea resided in the superior cervical and stellate ganglia. Retrogradely labelled sympathetic neurons were usually immunoreactive to tyrosine hydroxylase; the majority also contained neuropeptide Y immunoreactivity. However, a small number were non-catecholaminergic (i.e. tyrosine hydroxylase negative), but neuropeptide Y immunoreactive. Within the airways, tyrosine hydroxylase/neuropeptide Y-immunoreactive axons were found in the smooth muscle layer, around blood vessels including the pulmonary artery and vein, and to a lesser extent in the lamina propria. Periarterial axons contained in addition dynorphin immunoreactivity. Sensory neurons supplying the lung were located in jugular and nodose vagal ganglia as well as in upper thoracic dorsal root ganglia; those supplying the trachea were most frequently found bilaterally in the nodose ganglia and less frequently in the jugular ganglia. A spinal origin of tracheal sensory fibres could not be consistently demonstrated. With regard to their immunoreactivity to peptides, three types of sensory neurons projecting to the airways could be distinguished: (i) substance P/dynorphin immunoreactive; (ii) substance P immunoreactive but dynorphin negative; and (iii) negative to all peptides tested. Substance P-immunoreactive neurons innervating the airways invariably contained immunoreactivity to neurokinin A and calcitonin gene-related peptide. Retrogradely labelled neurons located in the nodose ganglia belonged almost exclusively (greater than or equal to 99%) to the peptide-negative group, whereas the three neuron types each represented about one-third of retrogradely labelled neurons in jugular and dorsal root ganglia. Within the airways, axons immunoreactive to substance P/neurokinin A and substance P/calcitonin gene-related peptide were distributed within the respiratory epithelium of trachea and large bronchi, in the lamina propria and smooth muscle from the trachea down to the smallest bronchioli (highest density at the bronchial level), in the alveolar walls, around systemic and pulmonary blood vessels, and within airway ganglia. Those axons also containing dynorphin immunoreactivity were restricted to the lamina propria and smooth muscle. The origin of nerve fibres immunoreactive for vasoactive intestinal polypeptide, of which a part were also neuropeptide Y immunoreactive, could not be determined by retrograde tracing experiments. Vasoactive intestinal polypeptide-immunoreactive fibres terminating within airway ganglia may be of preganglionic parasympathetic origin, whereas others (e.g. those found in smooth muscle) may arise from intrinsic ganglia.(ABSTRACT TRUNCATED AT 400 WORDS)
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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
                Affiliations
                1Department of Pediatrics, Division of Pulmonology, Allergy and Immunology, Case Western Reserve University , Cleveland, OH, United States
                2The Department of Physiology and Biophysics, Case Western Reserve University , Cleveland, OH, United States
                3Division of Pulmonary, Critical Care and Sleep Medicine, University Hospitals Case Medical Center, Case Western Reserve University , Cleveland, OH, United States
                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
                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.

                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

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