Chondroitinase ABC promotes recovery of adaptive limb movements and enhances axonal growth caudal to a spinal hemisection.

A number of studies have shown that chondroitinase ABC (Ch'ase ABC) digestion of inhibitory chondroitin sulfate glycosaminoglycans significantly enhances axonal growth and recovery in rodents following spinal cord injury (SCI). Further, our group has shown improved recovery following SCI in the larger cat model. The purpose of the current study was to determine whether intraspinal delivery of Ch'ase ABC, following T10 hemisections in adult cats, enhances adaptive movement features during a skilled locomotor task and/or promotes plasticity of spinal and supraspinal circuitry. Here, we show that Ch'ase ABC enhanced crossing of a peg walkway post-SCI and significantly improved ipsilateral hindlimb trajectories and integration into a functional forelimb-hindlimb coordination pattern. Recovery of these complex movements was associated with significant increases in neurofilament immunoreactivity immediately below the SCI in the ipsilateral white (p = 0.033) and contralateral gray matter (p = 0.003). Further, the rubrospinal tract is critical in the normal cat during skilled movements that require accurate paw placements and trajectories like those seen during peg walkway crossing. Rubrospinal connections were assessed following Fluoro-Gold injections, caudal to the hemisection. Significantly more retrogradely labeled right (axotomized) red nucleus (RN) neurons were seen in Ch'ase ABC-treated (23%) compared with control-treated cats (8%; p = 0.032) indicating that a larger number of RN neurons in Ch'ase ABC-treated cats had axons below the lesion level. Thus, following SCI, Ch'ase ABC may facilitate axonal growth at the spinal level, enhance adaptive features of locomotion, and affect plasticity of rubrospinal circuitry known to support adaptive behaviors in the normal cat.

Reflections of experience-expectant development in repair of the adult damaged brain.

Behavioral experience has long been known to influence functional outcome after brain injury, but only recently has its pervasive role in the reorganization of the adult brain after damage become appreciated. We briefly review findings from animal models on the role of experience in shaping neuronal events after stroke-like injury. Experience-dependent neural plasticity can be enhanced or impaired by brain damage, depending upon injury parameters and timing. The neuronal growth response to some experiences is heightened due to interactions with denervation-induced plasticity. This includes compensatory behavioral strategies developed in response to functional impairments. Early behavioral experiences can constrain later experience-dependent plasticity, leading to suboptimal functional outcome. Time dependencies and facets of neural growth patterns are reminiscent of experience-expectant processes that shape brain development. As with sensitive periods in brain development, this process may establish behavioral patterns early after brain injury which are relatively resistant to later change.

Cortical Stimulation Concurrent With Skilled Motor Training Improves Forelimb Function and Enhances Motor Cortical Reorganization Following Controlled Cortical Impact.

BACKGROUND: Electrical and magnetic brain stimulation can improve motor function following stroke in humans, rats, and nonhuman primates, especially when paired with rehabilitative training (RT). Previously, we found in rodent stroke models that epidural electrical cortical stimulation (CS) of the ipsilesional motor cortex (MC) combined with motor RT enhances motor function and motor cortical plasticity. It was unknown whether CS following experimental traumatic brain injury (TBI) would have similar effects. OBJECTIVE: To test the effects of CS combined with motor training after moderate/severe TBI on behavioral outcome and motor cortical organization. METHODS: Following unilateral controlled cortical impact (CCI) over the caudal forelimb area of the MC in adult male rats, forelimb reach training was administered daily for 9 weeks concurrently with subthreshold, 100-Hz monopolar CS or no-stimulation control procedures. The rate and magnitude of behavioral improvements and changes in forelimb movement representations in the injured MC as revealed by intracortical microstimulation were measured. RESULTS: CCI resulted in severe motor impairments persisting throughout the 9 weeks of training in both groups, but CS-treated animals had significantly greater behavioral improvements. CS also increased wrist motor cortical representation, one of the main movements used in the training task, when compared with RT alone. However, the overall recovery level was modest, leaving animals still extremely impaired. CONCLUSIONS: These data suggest that CS may be useful for improving rehabilitation efficacy after TBI but also raise the possibility that the CS parameters that are highly effective following stroke are suboptimal after moderate/severe TBI.

Retina-specific expression of 5A11/Basigin-2, a member of the immunoglobulin gene superfamily.

PURPOSE: 5A11/Basigin has recently been identified as a critical glycoprotein for full maturity and function of the mouse retina. However, the biological function of 5A11/Basigin has yet to be determined. Previous reports indicate the presence of multiple 5A11/Basigin polypeptides within the retina. Therefore, in an effort to determine the function of 5A11/Basigin, the molecular diversity of its expression was evaluated. METHODS: Northern blot and immunoblot techniques were used to evaluate the number of forms of 5A11/Basigin in the mouse retina. cDNA cloning, using a mouse retina library or RT-PCR from rat, chicken, zebrafish, and human retina, was performed to determine the sequence of 5A11/Basigin transcripts. A peptide was generated, based on the deduced amino acid sequence, for subsequent antibody production. Localization of 5A11/Basigin expression was evaluated by immunoblot, immunohistochemistry, and real-time RT-PCR. RESULTS: Two 5A11/Basigin transcripts of approximately 1.5 kb and approximately 1.8 kb, which correspond to glycosylated proteins of approximately 45 and approximately 55 kDa, respectively, were identified in mouse retina. The shorter form was previously cloned. However, the longer form, a splice variant of mouse 5A11/Basigin, is a member of the immunoglobulin gene superfamily and has been named 5A11/Basigin-2. Homologous transcripts were also cloned from rat, chicken, zebrafish, and human retina. 5A11/Basigin-2 expression was limited to the retina, specifically to photoreceptor cells, where it appeared to be most concentrated in the inner segments. CONCLUSIONS: The specific and limited expression of 5A11/Basigin-2 explicitly within photoreceptor cells implies that this glycoprotein plays a fundamental role within the retina. However, its role remains to be determined.

Altered obstacle negotiation after low thoracic hemisection in the cat.

Following a lateralized spinal cord injury (SCI) in humans, substantial walking recovery occurs; however, deficits persist in adaptive features of locomotion critical for community ambulation, including obstacle negotiation. Normal obstacle negotiation is accomplished by an increase in flexion during swing. If an object is unanticipated or supraspinal input is absent, obstacle negotiation may involve the spinally organized stumbling corrective response. How these voluntary and reflex components are affected following partial SCI is not well studied. This study is the first to characterize recovery of obstacle negotiation following low-thoracic spinal hemisection in the cat. Cats were trained pre- and post-injury to cross a runway with an obstacle. Assessments focused on the hindlimb ipsilateral to the lesion. Pre-injury, cats efficiently cleared an obstacle by increasing knee flexion during swing. Post-injury, obstacle clearance permanently changed. At 2 weeks, when basic overground walking ability been recovered, the hindlimb was dragged over the obstacle (∼90%). Surprisingly, the stumbling corrective response was not elicited until after 2 weeks. Despite a notable increase, between 4 and 8 weeks, in the ability to modify limb trajectory when approaching an obstacle, limb lift during obstacle approach was insufficient during ∼50% of encounters and continued to evoke the stumbling corrective response even at 16 weeks. A post-injury lead limb bias identified during negotiations with complete clearance, suggests a potential training strategy to increase the number of successful clearances. Therefore, following complete severing of half of the spinal cord, the ability to modify ipsilateral hindlimb trajectory shows significant recovery and by 16 weeks permits effective clearing of an obstacle, without contact, ∼50% of the time. Although this suggests plasticity of supporting circuitry, it is insufficient to support consistent clearance. This inconsistency, even at the most chronic time point assessed (16 weeks), is probably a contributing factor to falls reported for people with SCI.

Cough following low thoracic hemisection in the cat.

A function of the abdominal expiratory muscles is the generation of cough, a critical respiratory defense mechanism that is often disrupted following spinal cord injury. We assessed the effects of a lateral T9/10 hemisection on cough production at 4, 13 and 21 weeks post-injury in cats receiving extensive locomotor training. The magnitudes of esophageal pressure as well as of bilateral rectus abdominis electromyogram activity during cough were not significantly different from pre-injury values at all time points evaluated. The results show that despite considerable interruption of the descending pre-motor drive from the brainstem to the expiratory motoneuron pools, the cough motor system shows a significant function by 4 weeks following incomplete thoracic injury.

Recovery of airway protective behaviors after spinal cord injury.

Pulmonary morbidity is high following spinal cord injury and is due, in part, to impairment of airway protective behaviors. These airway protective behaviors include augmented breaths, the cough reflex, and expiration reflexes. Functional recovery of these behaviors has been reported after spinal cord injury. In humans, evidence for functional recovery is restricted to alterations in motor strategy and changes in the frequency of occurrence of these behaviors. In animal models, compensatory alterations in motor strategy have been identified. Crossed descending respiratory motor pathways at the thoracic spinal cord levels exist that are composed of crossed premotor axons, local circuit interneurons, and propriospinal neurons. These pathways can collectively form a substrate that supports maintenance and/or recovery of function, especially after asymmetric spinal cord injury. Local sprouting of premotor axons in the thoracic spinal cord also can occur following chronic spinal cord injury. These mechanisms may contribute to functional resiliency of the cough reflex that has been observed following chronic spinal cord injury in the cat.