Immunohistochemical labeling of ongoing axonal degeneration 10 days following cervical contusion spinal cord injury in the rat.

Study Design: Experimental Animal Study.

Objective: To continue validating an antibody which targets an epitope of neurofilament light chain (NF-L) only available during neurodegeneration and to utilize the antibody to describe the pattern of axonal degeneration 10 days post-unilateral C4 contusion in the rat.

Setting: University of Florida laboratory in Gainesville, USA.

The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.

Oncogenic growth places great strain and dependence on the proteostasis network. This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma.

Targeting α- and α-adrenergic receptors as a countermeasure for fentanyl-induced locomotor and ventilatory depression.

This study assessed the ability of α and α-adrenergic drugs to decrease fentanyl-induced locomotor and ventilatory depression. Rats were given saline or fentanyl, followed by: (1) naltrexone, (2) naloxone, (3) nalmefene, (4) α agonist phenylephrine, (5) α antagonist prazosin, (6) α antagonist BMY-7378, (7) α agonist clonidine, (8) α antagonist yohimbine or (9) vehicle. All µ-opioid antagonists dose-dependently reversed fentanyl-induced locomotor and ventilatory depression.

Sex and genotype influence respiratory function under hypoxic and hypoxic-hypercapnic conditions.

The apolipoprotein E () gene has been studied due to its influence on Alzheimer's disease (AD) development and work in an mouse model recently demonstrated impaired respiratory motor plasticity following spinal cord injury (SCI). Individuals with AD often copresent with obstructive sleep apnea (OSA) characterized by cessations in breathing during sleep. Despite the prominence of genotype and sex as factors in AD progression, little is known about the impact of these variables on respiratory control.

Chemogenetic stimulation of phrenic motor output and diaphragm activity.

Impaired respiratory motor output contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We investigated if expressing designer receptors exclusively activated by designer drugs (DREADDs) in the mid-cervical spinal cord could effectively stimulate phrenic motor output to increase diaphragm activation. Two primary questions were addressed: 1) does effective DREADD-mediated diaphragm activation require focal expression in phrenic motoneurons (vs.

Oxygen therapy attenuates neuroinflammation after spinal cord injury.

Acute hyperbaric O (HBO) therapy after spinal cord injury (SCI) can reduce inflammation and increase neuronal survival. To our knowledge, it is unknown if these benefits of HBO require hyperbaric vs. normobaric hyperoxia.

Hematopoietic stem cells preferentially traffic misfolded proteins to aggresomes and depend on aggrephagy to maintain protein homeostasis.

Hematopoietic stem cells (HSCs) regenerate blood cells throughout life. To preserve their fitness, HSCs are particularly dependent on maintaining protein homeostasis (proteostasis). However, how HSCs purge misfolded proteins is unknown.

Optogenetic activation of the tongue in spontaneously breathing mice.

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.

Effects of Hyperbaric Oxygen Preconditioning on Doxorubicin Cardiorespiratory Toxicity.

Cardiorespiratory dysfunction resulting from doxorubicin (DOX) chemotherapy treatment is a debilitating condition affecting cancer patient outcomes and quality of life. DOX treatment promotes cardiac and respiratory muscle pathology due to enhanced reactive oxygen species (ROS) production, mitochondrial dysfunction and impaired muscle contractility. In contrast, hyperbaric oxygen (HBO) therapy is considered a controlled oxidative stress that can evoke a substantial and sustained increase in muscle antioxidant expression.

Breathing patterns and CO production in adult spiny mice (Acomys cahirinus).

The spiny mouse (Acomys) is a precocial mammal with unique regenerative abilities. We used whole-body plethysmography to describe the breathing patterns and CO production (VCO) 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 production vs.

Optogenetic activation of the diaphragm.

Impaired diaphragm activation is common in many neuromuscular diseases. We hypothesized that expressing photoreceptors in diaphragm myofibers would enable light stimulation to evoke functional diaphragm activity, similar to endogenous bursts. In a mouse model, adeno-associated virus (AAV) encoding channelrhodopsin-2 (AAV9-CAG-ChR2-mVenus, 6.

Hyperbaric Oxygen Therapy after Mid-Cervical Spinal Contusion Injury.

Hyperbaric oxygen (HBO) therapy is frequently used to treat peripheral wounds or decompression sickness. Evidence suggests that HBO therapy can provide neuroprotection and has an anti-inflammatory impact after neurological injury, including spinal cord injury (SCI). Our primary purpose was to conduct a genome-wide screening of mRNA expression changes in the injured spinal cord after HBO therapy.

Ampakines Stimulate Diaphragm Activity after Spinal Cord Injury.

Respiratory compromise after cervical spinal cord injury (SCI) is a leading cause of mortality and morbidity. Most SCIs are incomplete, and spinal respiratory motoneurons as well as proprio- and bulbospinal synaptic pathways provide a neurological substrate to enhance respiratory output. Ampakines are allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are prevalent on respiratory neurons.

Phrenic afferent activation modulates cardiorespiratory output in the adult rat.

Phrenic afferents project to brainstem areas responsible for cardiorespiratory control and the mid-cervical spinal cord containing the phrenic motor nucleus. Our purpose was to quantify the impact of small- and large-diameter phrenic afferent activation on phrenic motor output. Anesthetized and ventilated rats received unilateral phrenic nerve stimulation while contralateral phrenic motor output and blood pressure were recorded.

Spinally delivered ampakine CX717 increases phrenic motor output in adult rats.

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.

Ampakine pretreatment enables a single hypoxic episode to produce phrenic motor facilitation with no added benefit of additional episodes.

Repeated short episodes of hypoxia produce a sustained increase in phrenic nerve output lasting well beyond acute intermittent hypoxia (AIH) exposure (i.e., phrenic long-term facilitation; pLTF).

Automated Classification of Whole Body Plethysmography Waveforms to Quantify Breathing Patterns.

Whole body plethysmography (WBP) monitors respiratory rate and depth but conventional analysis fails to capture the diversity of waveforms. Our first purpose was to develop a waveform cluster analysis method for quantifying dynamic changes in respiratory waveforms. WBP data, from adult Sprague-Dawley rats, were sorted into time domains and principle component analysis was used for hierarchical clustering.

Hsf1 promotes hematopoietic stem cell fitness and proteostasis in response to ex vivo culture stress and aging.

Maintaining proteostasis is key to resisting stress and promoting healthy aging. Proteostasis is necessary to preserve stem cell function, but little is known about the mechanisms that regulate proteostasis during stress in stem cells, and whether disruptions of proteostasis contribute to stem cell aging is largely unexplored. We determined that ex-vivo-cultured mouse and human hematopoietic stem cells (HSCs) rapidly increase protein synthesis.

Daily acute intermittent hypoxia enhances phrenic motor output and stimulus-evoked phrenic responses in rats.

Plasticity is a hallmark of the respiratory neural control system. Phrenic long-term facilitation (pLTF) is one form of respiratory plasticity characterized by persistent increases in phrenic nerve activity following acute intermittent hypoxia (AIH). Although there is evidence that key steps in the cellular pathway giving rise to pLTF are localized within phrenic motor neurons (PMNs), the impact of AIH on the strength of breathing-related synaptic inputs to PMNs remains unclear.

Case Studies in Neuroscience: Neuropathology and diaphragm dysfunction in ventilatory failure from late-onset Pompe disease.

Pompe disease (PD) is a neuromuscular disorder caused by a mutation in the acid alpha-glucosidase (GAA) gene. Patients with late-onset PD retain some GAA activity and present symptoms later in life, with fatality mainly associated with respiratory failure. This case study presents diaphragm electrophysiology and a histological analysis of the brainstem, spinal cord, and diaphragm, from a male PD patient diagnosed with late-onset PD at age 35.

Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation.

Respiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min).

Spiny mouse (Acomys): an emerging research organism for regenerative medicine with applications beyond the skin.

The spiny mouse (Acomys species) has emerged as an exciting research organism due to its remarkable ability to undergo scarless regeneration of skin wounds and ear punches. Excitingly, Acomys species demonstrate scar-free healing in a wide-range of tissues beyond the skin. In this perspective article, we discuss published findings from a variety of tissues to highlight how this emerging research organism could shed light on numerous clinically relevant human diseases.

A micro-LED implant and technique for optogenetic stimulation of the rat spinal cord.

To date, relatively few studies have used optogenetic stimulation to address basic science and therapeutic questions within the spinal cord. Even less have reported optogenetic stimulation in the rat spinal cord. This is likely due to a lack of accessible optogenetic implants.