Consequences of spinal cord injury on the sympathetic nervous system.

Spinal cord injury (SCI) damages multiple structures at the lesion site, including ascending, descending, and propriospinal axons; interrupting the conduction of information up and down the spinal cord. Additionally, axons associated with the autonomic nervous system that control involuntary physiological functions course through the spinal cord. Moreover, sympathetic, and parasympathetic preganglionic neurons reside in the spinal cord.

Maladaptation of renal hemodynamics contributes to kidney dysfunction resulting from thoracic spinal cord injury in mice.

Renal dysfunction is a hallmark of spinal cord injury (SCI). Several SCI sequalae are implicated; however, the exact pathogenic mechanism of renal dysfunction is unclear. Herein, we found that T3 (T3Tx) or T10 (T10Tx) complete thoracic spinal cord transection induced hypotension, bradycardia, and hypothermia immediately after injury.

The use of viral vectors to promote repair after spinal cord injury.

Spinal cord injury (SCI) is a devastating event that can permanently disrupt multiple modalities. Unfortunately, the combination of the inhibitory environment at a central nervous system (CNS) injury site and the diminished intrinsic capacity of adult axons for growth results in the failure for robust axonal regeneration, limiting the ability for repair. Delivering genetic material that can either positively or negatively modulate gene expression has the potential to counter the obstacles that hinder axon growth within the spinal cord after injury.

Peripheral Immune Dysfunction: A Problem of Central Importance after Spinal Cord Injury.

Individuals with spinal cord injuries (SCI) exhibit increased susceptibility to infection, with pneumonia consistently ranking as a leading cause of death. Despite this statistic, chronic inflammation and concurrent immune suppression have only recently begun to be explored mechanistically. Investigators have now identified numerous changes that occur in the peripheral immune system post-SCI, including splenic atrophy, reduced circulating lymphocytes, and impaired lymphocyte function.

Pharmacological Inhibition of Soluble Tumor Necrosis Factor-Alpha Two Weeks after High Thoracic Spinal Cord Injury Does Not Affect Sympathetic Hyperreflexia.

After a severe, high-level spinal cord injury (SCI), plasticity to intraspinal circuits below injury results in heightened spinal sympathetic reflex activity and detrimentally impacts peripheral organ systems. Such sympathetic hyperreflexia is immediately apparent as an episode of autonomic dysreflexia (AD), a life-threatening condition characterized by sudden hypertension and reflexive bradycardia following below-level sensory inputs; for example, pressure sores or impacted fecal matter. Over time, plasticity within the spinal sympathetic reflex (SSR) circuit contributes to the progressive intensification of AD events, as the frequency and severity of AD events increase greatly beginning ∼2 weeks post-injury (wpi).

Spinal Dopaminergic Mechanisms Regulating the Micturition Reflex in Male Rats with Complete Spinal Cord Injury.

Traumatic spinal cord injury (SCI) often causes micturition dysfunction. We recently discovered a low level of spinally-derived dopamine (DA) that regulates recovered bladder and sphincter reflexes in SCI female rats. Considering substantial sexual dimorphic features in the lower urinary tract, it is unknown if the DA-ergic mechanisms act in the male.

Neuroimmune System as a Driving Force for Plasticity Following CNS Injury.

Following an injury to the central nervous system (CNS), spontaneous plasticity is observed throughout the neuraxis and affects multiple key circuits. Much of this spontaneous plasticity can elicit beneficial deleterious functional outcomes, depending on the context of plasticity and circuit affected. Injury-induced activation of the neuroimmune system has been proposed to be a major factor in driving this plasticity, as neuroimmune and inflammatory factors have been shown to influence cellular, synaptic, structural, and anatomical plasticity.

Attenuating Neurogenic Sympathetic Hyperreflexia Robustly Improves Antibacterial Immunity After Chronic Spinal Cord Injury.

Spinal cord injury (SCI) disrupts critical physiological systems, including the cardiovascular and immune system. Plasticity of spinal circuits below the injury results in abnormal, heightened sympathetic responses, such as extreme, sudden hypertension that hallmarks life-threatening autonomic dysreflexia. Moreover, such sympathetic hyperreflexia detrimentally impacts other effector organs, including the spleen, resulting in spinal cord injury-induced immunodeficiency.

Knockdown of Fidgetin Improves Regeneration of Injured Axons by a Microtubule-Based Mechanism.

Fidgetin is a microtubule-severing protein that pares back the labile domains of microtubules in the axon. Experimental depletion of fidgetin results in elongation of the labile domains of microtubules and faster axonal growth. To test whether knockdown assists axonal regeneration, we plated dissociated adult rat DRGs transduced using AAV5-shRNA- on a laminin substrate with spots of aggrecan, a growth-inhibitory chondroitin sulfate proteoglycan.

Development of Cardiovascular Dysfunction in a Rat Spinal Cord Crush Model and Responses to Serotonergic Interventions.

Selection of a proper spinal cord injury (SCI) rat model to study therapeutic effects of cell transplantation is imperative for research in cardiovascular functional recovery, due to the local harsh milieu inhibiting cell growth. We recently found that a crushed spinal cord lesion can minimize fibrotic scarring and grafted cell death compared with open-dura injuries. To determine if this SCI model is applicable for studying cardiovascular recovery, we examined hemodynamic consequences following crushed SCI and tested cardiovascular responses to serotonin (5-HT) or dopamine (DA) receptor agonists.

Transsynaptic tracing to dissect supraspinal serotonergic input regulating the bladder reflex in rats.

Aims: This study was designed to determine specific cell groups of the raphe nuclei (RN) that give rise to supraspinal serotonergic projections regulating the bladder reflex.

Methods: Anesthetized rats underwent surgery to open the abdomen and expose the bladder. A total of 6 µL transsynaptic neuronal tracer pseudorabies virus (PRV-152), encoding for green fluorescent protein (GFP), was injected into the bladder detrusor.

Soluble TNFα Signaling within the Spinal Cord Contributes to the Development of Autonomic Dysreflexia and Ensuing Vascular and Immune Dysfunction after Spinal Cord Injury.

Cardiovascular disease and susceptibility to infection are leading causes of morbidity and mortality for individuals with spinal cord injury (SCI). A major contributor to these is autonomic dysreflexia (AD), an amplified reaction of the autonomic nervous system (hallmarked by severe hypertension) in response to sensory stimuli below the injury. Maladaptive plasticity of the spinal sympathetic reflex circuit below the SCI results in AD intensification over time.

Combining Constitutively Active Rheb Expression and Chondroitinase Promotes Functional Axonal Regeneration after Cervical Spinal Cord Injury.

After spinal cord injury (SCI), severed axons in the adult mammalian CNS are unable to mount a robust regenerative response. In addition, the glial scar at the lesion site further restricts the regenerative potential of axons. We hypothesized that a combinatorial approach coincidentally targeting these obstacles would promote axonal regeneration.

Surgical techniques influence local environment of injured spinal cord and cause various grafted cell survival and integration.

Background: Cellular transplantation to repair a complete spinal cord injury (SCI) is tremendously challenging due to the adverse local milieu for graft survival and growth. Results from cell transplantation studies yield great variability, which may possibly be due to the surgical techniques employed to induce an SCI. In order to delineate the influence of surgery on such inconsistency, we compared lesion morphology and graft survival as well as integration from different lesion methodologies of SCI.

Local delivery of minocycline from metal ion-assisted self-assembled complexes promotes neuroprotection and functional recovery after spinal cord injury.

Many mechanisms contribute to the secondary injury cascades following traumatic spinal cord injury (SCI). However, most current treatment strategies only target one or a few elements in the injury cascades, and have been largely unsuccessful in clinical trials. Minocycline hydrochloride (MH) is a clinically available antibiotic and anti-inflammatory drug that has been shown to target a broad range of secondary injury mechanisms via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties.

Dopamine is produced in the rat spinal cord and regulates micturition reflex after spinal cord injury.

Dopamine (DA) neurons in the mammalian central nervous system are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine micturition center. Here we show that DA is produced in the rat spinal cord and modulates the bladder reflex.

Expressing Constitutively Active Rheb in Adult Dorsal Root Ganglion Neurons Enhances the Integration of Sensory Axons that Regenerate Across a Chondroitinase-Treated Dorsal Root Entry Zone Following Dorsal Root Crush.

While the peripheral branch of dorsal root ganglion neurons (DRG) can successfully regenerate after injury, lesioned central branch axons fail to regrow across the dorsal root entry zone (DREZ), the interface between the dorsal root and the spinal cord. This lack of regeneration is due to the limited regenerative capacity of adult sensory axons and the growth-inhibitory environment at the DREZ, which is similar to that found in the glial scar after a central nervous system (CNS) injury. We hypothesized that transduction of adult DRG neurons using adeno-associated virus (AAV) to express a constitutively-active form of the GTPase Rheb (caRheb) will increase their intrinsic growth potential after a dorsal root crush.

Cardiovascular dysfunction following spinal cord injury.

Both sensorimotor and autonomic dysfunctions often occur after spinal cord injury (SCI). Particularly, a high thoracic or cervical SCI interrupts supraspinal vasomotor pathways and results in disordered hemodynamics due to deregulated sympathetic outflow. As a result of the reduced sympathetic activity, patients with SCI may experience hypotension, cardiac dysrhythmias, and hypothermia post-injury.

Expressing Constitutively Active Rheb in Adult Neurons after a Complete Spinal Cord Injury Enhances Axonal Regeneration beyond a Chondroitinase-Treated Glial Scar.

Unlabelled: After a spinal cord injury (SCI), CNS axons fail to regenerate, resulting in permanent deficits. This is due to: (1) the presence of inhibitory molecules, e.g.

Pharmacologically inhibiting kinesin-5 activity with monastrol promotes axonal regeneration following spinal cord injury.

While it is well established that the axons of adult neurons have a lower capacity for regrowth, some regeneration of certain CNS populations after spinal cord injury (SCI) is possible if their axons are provided with a permissive substrate, such as an injured peripheral nerve. While some axons readily regenerate into a peripheral nerve graft (PNG), these axons almost always stall at the distal interface and fail to reinnervate spinal cord tissue. Treatment of the glial scar at the distal graft interface with chondroitinase ABC (ChABC) can improve regeneration, but most regenerated axons need further stimulation to extend beyond the interface.

Partial restoration of cardiovascular function by embryonic neural stem cell grafts after complete spinal cord transection.

High-level spinal cord injury can lead to cardiovascular dysfunction, including disordered hemodynamics at rest and autonomic dysreflexia during noxious stimulation. To restore supraspinal control of sympathetic preganglionic neurons (SPNs), we grafted embryonic brainstem-derived neural stem cells (BS-NSCs) or spinal cord-derived neural stem cells (SC-NSCs) expressing green fluorescent protein into the T4 complete transection site of adult rats. Animals with injury alone served as controls.

Intraspinal AAV Injections Immediately Rostral to a Thoracic Spinal Cord Injury Site Efficiently Transduces Neurons in Spinal Cord and Brain.

In the vast majority of studies utilizing adeno-associated virus (AAV) in central nervous system applications, including those published with spinal cord injury (SCI) models, AAV has been administered at the level of the cell body of neurons targeted for genetic modification, resulting in transduction of neurons in the vicinity of the injection site. However, as SCI interrupts many axon tracts, it may be more beneficial to transduce a diverse pool of supraspinal neurons. We determined if descending axons severed by SCI are capable of retrogradely transporting AAV to remotely transduce a variety of brain regions.