Compensatory changes after spinal cord injury in a remyelination deficient mouse model.

The development of therapeutic strategies to reduce impairments following spinal cord injury (SCI) motivates an active area of research, because there are no effective therapies. One strategy is to address injury-induced demyelination of spared axons by promoting endogenous or exogenous remyelination. However, previously, we showed that new myelin was not necessary to regain hindlimb stepping following moderate thoracic spinal cord contusion in 3-month-old mice.

Direct comparison of Hoxb8-driven reporter distribution in the brains of four transgenic mouse lines: towards a spinofugal projection atlas.

Introduction: Hox genes govern rostro-caudal identity along the developing spinal cord, which has a well-defined division of function between dorsal (sensory) and ventral (motor) halves. Here we exploit developmental Hoxb8 expression, normally restricted to the dorsal cord below the obex, to genetically label spinal cord-to-brain ("spinofugal") axons.

Methods: We crossed two targeted (knock-in) and two non-targeted recombinase-expressing lines (Hoxb8-IRES-Cre and Hoxb8-T2AFlpO; Hoxb8-Cre and Hoxb8-FlpO, respectively) with appropriate tdtomato-expressing reporter strains.

Applying the lessons of design thinking: a unique programme of care for acutely unwell, community-dwelling COVID-19 patients.

Background: The COVID-19 pandemic limited access to primary care and in-person assessments requiring healthcare providers to re-envision care delivery for acutely unwell outpatients. Design thinking methodology has the potential to support the robust evolution of a new clinical model.

Aim: To demonstrate how design thinking methodology can rapidly and rigorously create and evolve a safe, timely, equitable and patient-centred programme of care, and to share valuable lessons for effective implementation of design thinking solutions to address complex problems.

A new Hoxb8FlpO mouse line for intersectional approaches to dissect developmentally defined adult sensorimotor circuits.

Improvements in the speed and cost of expression profiling of neuronal tissues offer an unprecedented opportunity to define ever finer subgroups of neurons for functional studies. In the spinal cord, single cell RNA sequencing studies support decades of work on spinal cord lineage studies, offering a unique opportunity to probe adult function based on developmental lineage. While Cre/Flp recombinase intersectional strategies remain a powerful tool to manipulate spinal neurons, the field lacks genetic tools and strategies to restrict manipulations to the adult mouse spinal cord at the speed at which new tools develop.

Microglial activating transcription factor 3 upregulation: An indirect target to attenuate inflammation in the nervous system.

Activating Transcription Factor 3 (ATF3) is upregulated in reaction to several cellular stressors found in a wide range of pathological conditions to coordinate a transcriptional response. ATF3 was first implicated in the transcriptional reaction to axotomy when its massive upregulation was measured in sensory and motor neuron cell bodies following peripheral nerve injury. It has since been shown to be critical for successful axon regeneration in the peripheral nervous system and a promising target to mitigate regenerative failure in the central nervous system.

Spinal cord injury impairs cardiac function due to impaired bulbospinal sympathetic control.

Spinal cord injury chronically alters cardiac structure and function and is associated with increased odds for cardiovascular disease. Here, we investigate the cardiac consequences of spinal cord injury on the acute-to-chronic continuum, and the contribution of altered bulbospinal sympathetic control to the decline in cardiac function following spinal cord injury. By combining experimental rat models of spinal cord injury with prospective clinical studies, we demonstrate that spinal cord injury causes a rapid and sustained reduction in left ventricular contractile function that precedes structural changes.

Systemic hypoxia mimicry enhances axonal regeneration and functional recovery following peripheral nerve injury.

Despite the ability of peripheral nerves to regenerate after injury, failure occurs due to an inability of supporting cells to maintain growth, resulting in long-term consequences such as sensorimotor dysfunction and neuropathic pain. Here, we investigate the potential of engaging the cellular adaptive response to hypoxia, via inhibiting its negative regulators, to enhance the regenerative process. Under normoxic conditions, prolyl hydroxylase domain (PHD) proteins 1, 2, and 3 hydroxylate the key metabolic regulator hypoxia inducible factor 1α (HIF1α), marking it for subsequent proteasomal degradation.

Beneficial "Pharmaceutical Pleiotropy" of Gabapentinoids in Spinal Cord Injury: A Case for Refining Standard-of-Care.

Spinal cord injury results in devastating neurological deficits accompanied by lifelong disability and significant economic burden. While the development of novel compounds or cell-based interventions for spinal cord injury is unquestionably worthwhile, a complementary approach examines current standards of care and the degree to which these can be optimized to benefit long-term neurological function. Numerous classes of drugs, already in use in the acute phase of spinal cord injury, are intriguing because they (1) readily cross the blood-spinal cord barrier to modulate activity in the central nervous system and (2) are administered during a window of time in which neuroprotection, and even some repair, are feasible.

A Cervical Spinal Cord Hemi-Contusion Injury Model Based on Displacement Control in Non-Human Primates .

Non-human primate (NHP) spinal cord injury (SCI) models can be informative in the evaluation of treatments that show promise in rodent models prior to translation to humans. In the present study, we aimed to establish a cervical spinal hemi-contusion model with controlled displacement and evaluate the abnormalities in behavior, electrophysiology, histology, and magnetic resonance imaging. Twelve adult NHPs were divided into an SCI group ( = 8, 24 and 48 weeks) and a control group ( = 4).

Skilled reaching deterioration contralateral to cervical hemicontusion in rats is reversed by pregabalin treatment conditional upon its early administration.

Introduction: Gabapentinoids are first-line treatments for painful traumatic and nontraumatic central nervous system disorders. Evidence from a large human study suggests that early use of gabapentinoids after spinal cord injury improves motor scores. The underlying mechanism is unknown.

KIF2A characterization after spinal cord injury.

Axons in the central nervous system (CNS) typically fail to regenerate after injury. This failure is multi-factorial and caused in part by disruption of the axonal cytoskeleton. The cytoskeleton, in particular microtubules (MT), plays a critical role in axonal transport and axon growth during development.

An ATF3-CreERT2 Knock-In Mouse for Axotomy-Induced Genetic Editing: Proof of Principle.

Genome editing techniques have facilitated significant advances in our understanding of fundamental biological processes, and the Cre-Lox system has been instrumental in these achievements. Driving Cre expression specifically in injured neurons has not been previously possible: we sought to address this limitation in mice using a Cre-ERT2 construct driven by a reliable indicator of axotomy, activating transcription factor 3 (ATF3). When crossed with reporter mice, a significant amount of recombination was achieved (without tamoxifen treatment) in peripherally-projecting sensory, sympathetic, and motoneurons after peripheral nerve crush in hemizygotes (65-80% by 16 d) and was absent in uninjured neurons.

Development of a traumatic cervical dislocation spinal cord injury model with residual compression in the rat.

Background: Preclinical spinal cord injury models do not represent the wide range of biomechanical factors seen in human injuries, such as spinal level, injury mechanism, velocity of spinal cord impact, and residual compression. These factors may be responsible for differences observed between experimental and clinical study results, especially related to the controversial issue of timing of surgical decompression.

New Method: Somatosensory Evoked Potentials were used to: a) characterize residual compression depths in a dislocation model, and b) evaluate the physiological effect of whether or not the spinal cord was decompressed following the initial injury, prior to the application of residual compression.

Ecological fallacy as a novel risk factor for poor translation in neuroscience research: A systematic review and simulation study.

Background: Translational neuroscience is largely concerned with establishing causal links between biological processes and functional outcomes. Exciting new methods have emerged and top-tier biomedical journals are placing increasingly high demand for experiments that link outcomes. One pitfall to making these connections is the "ecological fallacy"-establishing a relationship between outcomes based on aggregate (averaged) results (a distinct issue from correlation vs causation).

Preserved Adrenal Function After Lumbar Spinal Cord Transection Augments Low Pressure Bladder Activity in the Rat.

Spinal cord injury (SCI) disconnects supraspinal micturition centers from the lower urinary tract resulting in immediate and long-term changes in bladder structure and function. While cervical and high thoracic SCI have a greater range of systemic effects, clinical data suggest that those with lower (suprasacral) injuries develop poorer bladder outcomes. Here we assess the impact of SCI level on acute changes in bladder activity.

Advillin Is Expressed in All Adult Neural Crest-Derived Neurons.

Promoter-based genetic recombination (via, e.g., Cre-lox) is most useful when all cells of interest express a particular gene.

Neuropathic pain following traumatic spinal cord injury: Models, measurement, and mechanisms.

Neuropathic pain following spinal cord injury (SCI) is notoriously difficult to treat and is a high priority for many in the SCI population. Resolving this issue requires animal models fidelic to the clinical situation in terms of injury mechanism and pain phenotype. This Review discusses the means by which neuropathic pain has been induced and measured in experimental SCI and compares these with human outcomes, showing that there is a substantial disconnection between experimental investigations and clinical findings in a number of features.

Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury.

Following traumatic spinal cord injury, acute demyelination of spinal axons is followed by a period of spontaneous remyelination. However, this endogenous repair response is suboptimal and may account for the persistently compromised function of surviving axons. Spontaneous remyelination is largely mediated by Schwann cells, where demyelinated central axons, particularly in the dorsal columns, become associated with peripheral myelin.

Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism.

The oxygen-sensing prolyl hydroxylase domain proteins (PHDs) regulate cellular metabolism, but their role in neuronal metabolism during stroke is unknown. Here we report that PHD1 deficiency provides neuroprotection in a murine model of permanent brain ischemia. This was not due to an increased collateral vessel network.

Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis.

Background: Tamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans.

Passive Hind-Limb Cycling Reduces the Severity of Autonomic Dysreflexia After Experimental Spinal Cord Injury.

Background: Spinal cord injury (SCI) induces alterations in cardio-autonomic control of which autonomic dysreflexia (AD), a condition characterized by life-threatening hypertension, is arguably the most insidious. Passive hind-limb cycling represents a low-cost therapeutic intervention with demonstrable cardiovascular, sensory, and motor benefits.

Objective: To investigate the effect of passive hind-limb cycling on AD in rodents with T3 SCI.

Restoring function after spinal cord injury: towards clinical translation of experimental strategies.

Spinal cord injury is currently incurable and treatment is limited to minimising secondary complications and maximising residual function by rehabilitation. Improved understanding of the pathophysiology of spinal cord injury and the factors that prevent nerve and tissue repair has fuelled a move towards more ambitious experimental treatments aimed at promoting neuroprotection, axonal regeneration, and neuroplasticity. By necessity, these new options are more invasive.