Acute intermittent hypoxia alters disease course and promotes CNS repair including resolution of inflammation and remyelination in the experimental autoimmune encephalomyelitis model of MS.

Remyelination and neurodegeneration prevention mitigate disability in Multiple Sclerosis (MS). We have shown acute intermittent hypoxia (AIH) is a novel, non-invasive and effective therapy for peripheral nerve repair, including remyelination. Thus, we posited AIH would improve repair following CNS demyelination and address the paucity of MS repair treatments. AIH's capacity to enhance intrinsic repair, functional recovery and alter disease course in the experimental autoimmune encephalomyelitis (EAE) model of MS was assessed. EAE was induced by MOG35-55 immunization in C57BL/6 female mice. EAE mice received either AIH (10 cycles-5 min 11% oxygen alternating with 5 min 21% oxygen) or Normoxia (control; 21% oxygen for same duration) once daily for 7d beginning at near peak EAE disease score of 2.5. Mice were followed post-treatment for an additional 7d before assessing histopathology or 14d to examine maintenance of AIH effects. Alterations in histopathological correlates of multiple repair indices were analyzed quantitatively in focally demyelinated ventral lumbar spinal cord areas to assess AIH impacts. AIH begun at near peak disease significantly improved daily clinical scores/functional recovery and associated histopathology relative to Normoxia controls and the former were maintained for at least 14d post-treatment. AIH enhanced correlates of myelination, axon protection and oligodendrocyte precursor cell recruitment to demyelinated areas. AIH also effected a dramatic reduction in inflammation, while polarizing remaining macrophages/microglia toward a pro-repair state. Collectively, this supports a role for AIH as a novel non-invasive therapy to enhance CNS repair and alter disease course following demyelination and holds promise as a neuroregenerative MS strategy.

A modified rehabilitation paradigm bilaterally increased rat extensor digitorum communis muscle size but did not improve forelimb function after stroke.

Malnutrition after stroke may lessen the beneficial effects of rehabilitation on motor recovery through influences on both brain and skeletal muscle. Enriched rehabilitation (ER), a combination of environmental enrichment and forelimb reaching practice, is used preclinically to study recovery of skilled reaching after stroke. However, the chronic food restriction typically used to motivate engagement in reaching practice is a barrier to using ER to investigate interactions between nutritional status and rehabilitation. Thus, our objectives were to determine if a modified ER program comprised of environmental enrichment and skilled reaching practice motivated by a short fast would enhance post-stroke forelimb motor recovery and preserve forelimb muscle size and metabolic fiber type, relative to a group exposed to stroke without ER. At one week after photothrombotic cortical stroke, male, Sprague-Dawley rats were assigned to modified ER or standard care for 2 weeks. Forelimb recovery was assessed in the Montoya staircase and cylinder task before stroke and on days 5-6, 22-23, and 33-34 after stroke. ER failed to improve forelimb function in either task (p > 0.05). Atrophy of extensor digitorum communis (EDC) and triceps brachii long head (TBL) muscles was not evident in the stroke-targeted forelimb on day 35, but the area occupied by hybrid fibers was increased in the EDC muscle (p = 0.038). ER bilaterally increased EDC (p = 0.046), but not TBL, muscle size; EDC muscle fiber type was unchanged by ER. While the modified ER did not promote forelimb motor recovery, it does appear to have utility for studying the role of skeletal muscle plasticity in post-stroke recovery.

Repetitive intermittent hypoxia induces respiratory and somatic motor recovery after chronic cervical spinal injury.

Spinal injury disrupts connections between the brain and spinal cord, causing life-long paralysis. Most spinal injuries are incomplete, leaving spared neural pathways to motor neurons that initiate and coordinate movement. One therapeutic strategy to induce functional motor recovery is to harness plasticity in these spared neural pathways. Chronic intermittent hypoxia (CIH) (72 episodes per night, 7 nights) increases synaptic strength in crossed spinal synaptic pathways to phrenic motoneurons below a C2 spinal hemisection. However, CIH also causes morbidity (e.g., high blood pressure, hippocampal apoptosis), rendering it unsuitable as a therapeutic approach to chronic spinal injury. Less severe protocols of repetitive acute intermittent hypoxia may elicit plasticity without associated morbidity. Here we demonstrate that daily acute intermittent hypoxia (dAIH; 10 episodes per day, 7 d) induces motor plasticity in respiratory and nonrespiratory motor behaviors without evidence for associated morbidity. dAIH induces plasticity in spared, spinal pathways to respiratory and nonrespiratory motor neurons, improving respiratory and nonrespiratory (forelimb) motor function in rats with chronic cervical injuries. Functional improvements were persistent and were mirrored by neurochemical changes in proteins that contribute to respiratory motor plasticity after intermittent hypoxia (BDNF and TrkB) within both respiratory and nonrespiratory motor nuclei. Collectively, these studies demonstrate that repetitive acute intermittent hypoxia may be an effective and non-invasive means of improving function in multiple motor systems after chronic spinal injury.

Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease.

We review progress towards greater mechanistic understanding and clinical translation of a strategy to improve respiratory and non-respiratory motor function in people with neuromuscular disorders, therapeutic acute intermittent hypoxia (tAIH). In 2016 and 2020, workshops to create and update a "road map to clinical translation" were held to help guide future research and development of tAIH to restore movement in people living with chronic, incomplete spinal cord injuries. After briefly discussing the pioneering, non-targeted basic research inspiring this novel therapeutic approach, we then summarize workshop recommendations, emphasizing critical knowledge gaps, priorities for future research effort, and steps needed to accelerate progress as we evaluate the potential of tAIH for routine clinical use. Highlighted areas include: 1) greater mechanistic understanding, particularly in non-respiratory motor systems; 2) optimization of tAIH protocols to maximize benefits; 3) identification of combinatorial treatments that amplify plasticity or remove plasticity constraints, including task-specific training; 4) identification of biomarkers for individuals most/least likely to benefit from tAIH; 5) assessment of long-term tAIH safety; and 6) development of a simple, safe and effective device to administer tAIH in clinical and home settings. Finally, we update ongoing clinical trials and recent investigations of tAIH in SCI and other clinical disorders that compromise motor function, including ALS, multiple sclerosis, and stroke.

Prolonged acute intermittent hypoxia improves forelimb reach-to-grasp function in a rat model of chronic cervical spinal cord injury.

Repetitive acute intermittent hypoxia (AIH - brief, episodes of low inspired oxygen) elicits spinal motor plasticity, resulting in sustained improvements of respiratory and non-respiratory motor function in both animal models and humans with chronic spinal cord injury (SCI). We previously demonstrated that 7 days of AIH combined with task-specific training improves performance on a skilled locomotor task for at least 3 weeks post-treatment in rats with incomplete SCI. Here we investigated the effect of repetitive AIH administered for 12 wks on a forelimb reach-to-grasp task in a rat model of chronic, incomplete cervical SCI. In a replicated, sham-controlled, randomized and blinded study, male Spraque-Dawley rats were subject to partial hemisection at the 3rd cervical spinal segment, and exposed to daily AIH (10, 5 min episodes of 11% inspired O2; 5 min intervals of 21% O2) or sham normoxia (continuous 21% O2) for 7 days beginning 8 weeks post-injury. Treatments were then reduced to 4 daily treatments per week, and continued for 11 weeks. Performance on 2 pre-conditioned motor tasks, single pellet reaching and horizontal ladder walking, was recorded each week for up to 12 weeks after initiating treatment; performance on spontaneous adhesive removal was also tested. SCI significantly impaired reach-to-grasp task performance 8 weeks post-injury (pre-treatment). Daily AIH improved reaching success by the first week of treatment versus sham controls, and this difference was maintained at 12 weeks (p < 0.0001). Daily AIH did not affect step asymmetry or stride length during ladder walking or adhesive removal time. Thus, prolonged AIH combined with task-specific training improved forelimb reach-to-grasp function in rats with a chronic cervical hemisection, but not off-target motor tasks. This study further supports the idea that daily AIH improves limb function when combined with task-specific training.

Preventing protein-energy malnutrition after cortical stroke enhances recovery of symmetry in forelimb use during spontaneous exploration.

Protein-energy malnutrition (PEM) commonly arises after stroke. We investigated the effects of preventing PEM on spontaneous recovery of forelimb use, infarct size, and the acute phase response in the chronic post-stroke period. Male, adult, Sprague-Dawley rats were acclimatized to control diet (12.5% protein), tested for pre-stroke forelimb use symmetry in the cylinder test, and exposed to photothrombotic cortical stroke or sham surgery. Food intake was monitored daily, and body weight weekly. Forelimb use was tested on day 4 after surgery, before assignment to control diet or PEM (0.5% protein), with subsequent testing on days 16 and 29. Blood, brain, and liver were collected on day 30. The low protein diet resulted in PEM, measured by decreased body weight (p < 0.001) and food intake (p = 0.016) and increased liver lipid (p < 0.001). Stroke (p = 0.016) and PEM (p = 0.001) independently elicited increases in serum α-2-macroglobulin concentration, whereas PEM alone decreased albumin (p < 0.001). PEM reduced recovery of forelimb use symmetry during exploration on days 16 (p = 0.024) and 29 (p = 0.013) but did not influence infarct size (p = 0.775). Stroke reduced reliance on the stroke-affected forelimb to initiate exploration up until day 29 (p < 0.001); PEM had no influence (p ≥ 0.463). Preventing post-stroke PEM appears to yield direct benefits for certain types of motor recovery. Novelty Preventing post-stroke malnutrition benefits certain types of motor recovery. An acute phase response may contribute to the poorer recovery with malnutrition.

The differential effects of cervical and thoracic dorsal funiculus lesions in rats.

The purpose of this research was to compare the locomotor abilities of rats with cervical dorsal spinal funicular (DF) lesions to those of rats with the same lesion at the mid-thoracic level. The dorsal funiculus, consisting of ascending sensory fibers and the main component of the corticospinal tract, was transected either at spinal level C2 or at T8. We examined limb force generation and limb timing and coordination during overground locomotion, as well as foot placement errors during locomotion over a horizontal ladder. At 6 weeks post-surgery, bilateral lesions of the cervical DF caused subtle but persistent changes in the generation of ground reaction forces and limb timing during overground locomotion, and caused persistent forelimb, but not hindlimb, errors during ladder crossing. In contrast, the same lesion at the mid-thoracic level did not affect overground locomotion and caused only minor forelimb and hindlimb errors during ladder walking at 2 weeks post-lesion which recovered to pre-surgical levels by 6 weeks post-lesion. DF lesions at cervical vs. thoracic levels thus have differential effects on locomotor abilities in rats. We compare these results with previous work and suggest that the differential response to DF transection might be related to both functional distinctions between the fore- and hindlimbs and to anatomical differences in the dorsal funiculi at different spinal levels. These findings have implications for the mechanisms of recovery as well as the types of behavioural tests which can be practically used to measure functional changes in different lesion models.

Acute intermittent hypoxia and rehabilitative training following cervical spinal injury alters neuronal hypoxia- and plasticity-associated protein expression.

One of the most promising approaches to improve recovery after spinal cord injury (SCI) is the augmentation of spontaneously occurring plasticity in uninjured neural pathways. Acute intermittent hypoxia (AIH, brief exposures to reduced O2 levels alternating with normal O2 levels) initiates plasticity in respiratory systems and has been shown to improve recovery in respiratory and non-respiratory spinal systems after SCI in experimental animals and humans. Although the mechanism by which AIH elicits its effects after SCI are not well understood, AIH is known to alter protein expression in spinal neurons in uninjured animals. Here, we examine hypoxia- and plasticity-related protein expression using immunofluorescence in spinal neurons in SCI rats that were treated with AIH combined with motor training, a protocol which has been demonstrated to improve recovery of forelimb function in this lesion model. Specifically, we assessed protein expression in spinal neurons from animals with incomplete cervical SCI which were exposed to AIH treatment + motor training either for 1 or 7 days. AIH treatment consisted of 10 episodes of AIH: (5 min 11% O2: 5 min 21% O2) for 7 days beginning at 4 weeks post-SCI. Both 1 or 7 days of AIH treatment + motor training resulted in significantly increased expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) relative to normoxia-treated controls, in neurons both proximal (cervical) and remote (lumbar) to the SCI. All other markers examined were significantly elevated in the 7 day AIH + motor training group only, at both cervical and lumbar levels. These markers included vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and phosphorylated and nonphosphorylated forms of the BDNF receptor tropomyosin-related kinase B (TrkB). In summary, AIH induces plasticity at the cellular level after SCI by altering the expression of major plasticity- and hypoxia-related proteins at spinal regions proximal and remote to the SCI. These changes occur under the same AIH protocol which resulted in recovery of limb function in this animal model. Thus AIH, which induces plasticity in spinal circuitry, could also be an effective therapy to restore motor function after nervous system injury.

Sensorimotor behaviour following incomplete cervical spinal cord injury in the rat.

Rats are one of the most commonly used species for spinal cord injury research. Since the advent of the Basso, Beattie, Bresnahan (BBB) locomotor rating scale, the majority of spinal cord injury research relies upon evaluating locomotor behaviour in thoracic spinal cord injury rat models. Slightly more than 50% of all traumatic spinal cord injuries in humans, however, occur at the level of the cervical spinal cord. Further, therapies aimed at thoracic spinal cord injuries may not be directly transferable to cervical spinal cord injuries. This could be due to (1) differences in distance between the cell bodies of injured axons and the injury site and (2) because some behaviours (e.g. stepping movements) used to evaluate the therapeutic potential of a given treatment are governed primarily by intraspinal neuronal circuitry while other behaviours (e.g. skilled reaching) require more sophisticated conscious integration of the sensorimotor system. Consequently, there is a need to develop and use experimental cervical spinal cord injury models and understand the behavioural characteristics of such models. The present review highlights the sensorimotor abilities of cervical spinal cord-injured rats, including both forelimb, hind limb, and whole body behaviours. We also provide insight into the neuroanatomic substrates important for performing a given behaviour, information which may prove essential in the development of site-directed therapeutic strategies.

Delayed Intervention with Intermittent Hypoxia and Task Training Improves Forelimb Function in a Rat Model of Cervical Spinal Injury.

The reduction of motor, sensory and autonomic function below the level of an incomplete spinal cord injury (SCI) has devastating consequences. One approach to restore function is to induce neural plasticity as a means of augmenting spontaneous functional recovery. Acute intermittent hypoxia (AIH-brief exposures to reduced O2 levels alternating with normal O2 levels) elicits plasticity in respiratory and nonrespiratory somatic spinal systems, including improvements in ladder walking performance in rats with incomplete SCI. Here, we determined whether delayed treatment with AIH, with or without concomitant motor training, could improve motor recovery in a rat model of incomplete cervical SCI. In a randomized, blinded, sham-controlled study, rats were exposed to AIH for 7 days beginning at 4 weeks post-SCI, after much spontaneous recovery on a horizontal ladder-crossing task had already occurred. For up to 2 months post-treatment, AIH-treated rats made fewer footslips on the ladder task compared with sham-treated rats. Importantly, concomitant ladder-specific motor training was needed to elicit AIH-induced improvements, such that AIH-treated SCI rats receiving no motor training or nontask-specific treadmill training during the treatment week did not show improvements over sham-treated rats with SCI. AIH treatment combined with task-specific training did not improve recovery on two different reach-to-grasp tasks, however, nor on tasks involving unskilled forepaw use. In brief, our results indicate that task-specific training is needed for AIH to improve ladder performance in a rat model of incomplete cervical SCI.

Compensatory locomotor adjustments of rats with cervical or thoracic spinal cord hemisections.

The accurate measurement of behavioral compensation after CNS trauma, such as spinal cord injury, is important when assessing the functional effects of injury and treatment in animal models. We investigated the locomotor abilities of rats with unilateral thoracic or cervical spinal cord injuries using a locomotor rating (BBB) scale, reflex tests, and quantitative kinetic measurements. The BBB rating scale indicated that thoracic spinal hemisected (TH) rats had more severely affected hindlimbs compared to cervical spinal hemisected (CH) and sham-operated animals. Kinetic measurements revealed that CH and TH animals moved with different ground reaction force patterns, which nevertheless shared some similarities with each other and with the gait patterns of rats with different unilateral CNS lesions. Uninjured rats typically had an equal distribution of their body weight over the forelimbs and hind limbs, and used their forelimbs predominantly for braking while using their hind limbs mostly for propulsion. CH rats bore more weight on their hind limbs than their forelimbs, while TH animals bore more weight on their forelimbs than their hind limbs. Neither CH nor TH rats used the forelimb ipsilateral to the spinal hemisection for net braking or propulsion. The hindlimb contralateral to the hemisection was placed on the ground prematurely during the stride cycle for both CH and TH animals. The altered kinetics of the locomotor pattern in hemisected animals resulted in changes in the oscillations of total body potential and kinetic energies. These two forms of energy oscillate synchronously in intact locomoting rats, but were asynchronous during parts of the stride cycle in spinal hemisected animals. We conclude that rats develop a general compensatory response for unilateral CNS lesions, which may help stabilize the animal during locomotion.

Course of motor recovery following ventrolateral spinal cord injury in the rat.

The purpose of this study was to determine the importance of the pathways running in the ventrolateral spinal funiculus for overground locomotion in adult, freely behaving rats. Left-sided ventrolateral cervical spinal cord injury was performed in adult female Long-Evans rats. The behavioural abilities of these animals were analyzed at 2 days, and weekly for up to 5.5 weeks following spinal cord injury. Behavioural testing consisted of Von Frey filament testing, ladder walking, a paw usage task, and the assessment of ground reaction forces during unrestrained trotting. Animals with injury to the left ventrolateral cervical spinal cord did not develop enhanced sensitivity to pedal mechanical stimulation. At 2 days following injury, animals had impaired skilled locomotion as indicated by increased number of footslips during ladder walking. At 2 days, these animals also used both limbs together more often for support while rearing, while using the forelimb ipsilateral to the injury less than did uninjured animals. Ground reaction force determination revealed that animals tend to bear less weight on the forelimb and hindlimb ipsilateral to the spinal cord injury 2 days after injury. All animals recovered normal or near normal sensorimotor abilities although subtle asymmetries in ground reaction forces were detectable at 5.5 weeks following spinal cord injury. These results suggest that axons in the ventrolateral spinal funiculi contribute to limb movements during exploration and locomotion but their roles can be served by other pathways after ventrolateral spinal injury.

Fischer (F-344) rats have different morphology, sensorimotor and locomotor abilities compared to Lewis, Long-Evans, Sprague-Dawley and Wistar rats.

Locomotor and/or sensory behaviour is commonly evaluated in laboratory rats in the field of neuroscience. Many strains of rats, however, have been propagated through intensive breeding programs. With any breeding program, traits are selected purposefully or inadvertently. We set out to investigate whether differences in morphology, sensory or motor behaviours exist using five age-matched strains of laboratory rats. Personal observations of morphological differences between different strains of rats led us to hypothesize that Fischer rats were dissimilar to the other strains in each of the parameters investigated. Evaluation of morphology involved measuring long-bone lengths and body weights of each strain. Motor skills were evaluated by measuring paw preferences while rearing, abduction of the distal portion of hindlimbs during locomotion, footfalls through a horizontal ladder during locomotion, and ground reaction forces generated during trotting. Sensory ability was assessed by von Frey testing. Fischer rats had shorter long-bone lengths, weighed less, and had significantly abducted distal portion of their hindlimbs during locomotion compared to the other strains. Lewis and Sprague-Dawley rats were less sensitive to mechanical pedal stimulation compared to Fischer rats. While rearing, all strains of rats tended to use individual forelimbs 25% of the time for each right and left limbs, and both forelimbs together 50% of the time. There were no significant differences in the number of footfalls during the ladder task. Ground reaction force determination revealed that Fischer and Sprague-Dawley rats bore more weight on their hindlimbs compared to forelimbs during locomotion, Long-Evans and Lewis rats bore more weight on their forelimbs compared to their hindlimbs, while Wistar rats distributed weight evenly between forelimbs and hindlimbs during trotting. We conclude that morphologic, sensory and motor differences exist between the five strains of laboratory rats examined and several of these differences are most pronounced in the Fischer strain.

Steroid-responsive meningitis-arteritis in dogs with noninfectious, nonerosive, idiopathic, immune-mediated polyarthritis.

Signs related to spinal pain are commonly reported in dogs with noninfectious, nonerosive, idiopathic immune-mediated polyarthritis (IMPA). This study examined the prevalence and etiology of spinal pain in these dogs through a retrospective review of 62 case records of dogs with IMPA. All dogs with IMPA and signs suggestive of spinal pain were described with regard to age, gender, breed, physical stature, location of vertebral pain, rectal temperature, and clinical laboratory findings. The prevalence of spinal pain in these dogs was 29% (18 of 62). Fourteen of the 18 dogs with spinal pain and IMPA were male. Cerebrospinal fluid (CSF) from 11 dogs with signs of spinal pain was analyzed. Five of these (46%) had concurrent steroid-responsive meningitis-arteritis (SRMA). We concluded that SRMA does occur concurrently in some dogs having IMPA. Meningeal involvement may explain the origin of spinal pain observed in some of these dogs.

The biomechanics of locomotor compensation after peripheral nerve lesion in the rat.

Functional recovery in animal models of nervous system disorders commonly involves behavioural compensation, in which animals alter the use of their limbs after injury, making it difficult to distinguish 'true' recovery from substitution of novel movements. The purpose of this study is to investigate how abnormal movements are produced by using biomechanical assessment of limb joint motion, an approach commonly used to diagnose human pathological gait. Rats were trained to cross a runway whilst kinetic (ground reaction forces) and kinematic (limb segment positions) data were synchronously recorded. Inverse dynamic analysis was used to calculate limb joint moments, or torques, and joint mechanical power throughout the stride for major joints of the forelimbs and hindlimbs, both before and after denervation of a major ankle extensor muscle. Before surgery, rats moved with joint moment and power profiles comparable to other quadrupeds, with differences attributable to species variation in limb posture. After surgery, rats trotted asymmetrically, with a near plantigrade stance of the left hindlimb. Surprisingly, ankle joint moments and power were largely preserved, with dramatic reductions in range of motion and joint moments at the proximal joints of the affected limb. Stiffening of the proximal limb compensated for increased compliance at the ankle but decreased the total mechanical work done by the injured limb. In turn, more work was done by the opposite, i.e. uninjured, hindlimb. This is the first study to quantify the biomechanical adjustments made within and between limbs in laboratory rodents after nervous system injury.

Task-dependent compensation after pyramidal tract and dorsolateral spinal lesions in rats.

The purpose of this research was to investigate whether pathways in the dorsal part of the lateral spinal funiculus (DLF) can compensate for loss of corticospinal input (CST) to the spinal cord. The CST is known to control skilled limb movements in rats. The DLF contains several different pathways, including the rubrospinal tract (RST) which is also thought to influence limb movements. After lesions of either the corticospinal or the rubrospinal system, it is unclear how much of the remaining forelimb function is due to the presence of the alternate pathway. To begin to address this issue, the present study investigates the compensatory role of pathways in the DLF, including the rubrospinal tract, after bilateral lesions of the pyramidal tract (PT). We initially performed bilateral PT lesions in rats, which effectively removed the CST input to the spinal cord. We tested these rats during overground locomotion, skilled locomotion and skilled forelimb usage. After a 6 week recovery period, we then performed bilateral DLF lesions and compared the behavioural abilities of these rats to those of animals which underwent simultaneous PT and DLF lesions. If DLF pathways do compensate for PT lesions, then animals with PT lesions would rely more on DLF pathways than animals without PT lesions. Thus we hypothesized that animals with DLF lesions which were performed 6 weeks after PT lesions would exhibit more deficits on several behavioural tasks compared to animals which received PT and DLF lesions simultaneously. Our hypothesis was supported only for skilled pellet retrieval. Hence some DLF pathways, including the RST, were able to compensate for loss of CST input during skilled reaching but not during overground or skilled locomotion in PT-lesioned rats. These differential responses suggest that behavioural tasks vary in their reliance on specific pathways after injury, and, furthermore, that compensation for loss of specific connections can arise from numerous sources.

Effects of combined dorsolateral and dorsal funicular lesions on sensorimotor behaviour in rats.

The purpose of this research was to investigate the compensatory role of undamaged spinal pathways after partial spinal injury in rats. We have previously shown that bilateral lesions of the dorsal funiculus (DF) at the cervical level caused changes in overground and skilled locomotion that affected the forelimbs more than the hindlimbs. The same lesions also caused fore-paw deficits during a skilled pellet retrieval task (Kanagal and Muir, 2007). In contrast, bilateral cervical lesions of the dorsolateral funiculus (DLF) caused alterations in overground and skilled locomotion that were most marked in the hindlimbs rather than the forelimbs, but also caused fore-paw deficits during skilled pellet retrieval (Muir et al., 2007). We hypothesized that the relative lack of forelimb deficits during locomotion after DLF lesions was due to compensatory input arising from intact pathways in the DF. We tested this hypothesis in the present study by performing bilateral DF lesions in animals in which both DLFs had been transected 6 weeks previously. These secondary DF lesions involved either only ascending sensory pathways (DLF+ASP group) in the DF, i.e. sparing the corticospinal tract (CST), or involved both the ASP and the CST (DLF+DF group). All animals were assessed during overground locomotion, while crossing a horizontal ladder and during a pellet retrieval task. During overground locomotion, both groups moved with slightly altered forces and timing in both forelimbs and hindlimbs. During both ladder crossing and reaching, secondary lesions to DF (with or without CST) exacerbated the deficits seen after initial DLF lesions and additionally caused changes in the manner in which the rats used their forelimbs during reaching. Nevertheless, the relative magnitude of the deficits indicates that DF pathways in rats likely do not compensate for loss of DLF pathways during the execution of locomotor tasks, though there is indirect evidence that DLF-lesioned rats might rely more on ascending sensory pathways in the DF during skilled forelimb movements. The plastic changes mediating recovery are therefore necessarily occurring in other regions of the CNS, and, importantly, need time to develop, because animals with DLF+DF lesions performed simultaneously displayed marked functional deficits and were unable to use their forelimbs for skilled locomotion or reaching.

Bilateral dorsal funicular lesions alter sensorimotor behaviour in rats.

Spinal cord injury models often involve damage to the corticospinal tract (CST) because of the functional importance of this pathway in humans. In rats, the main component of the CST travels in the dorsal funiculus and cannot be damaged without concurrent damage to overlying sensory fibers. To distinguish deficits due to the loss of CST from those due to sensory fiber damage, we bilaterally axotomized ascending sensory fibers in dorsal columns without CST damage in one group of rats (ascending sensory pathways, ASP) and compared the results to a group with damage to ascending sensory fibers with CST damage (ASP+CST). We assessed the ability of rats to perform a skilled reaching task and to walk over a horizontal ladder. We also measured the forces exerted on the ground (ground reaction forces, GRF) and limb contact patterns produced during overground locomotion. After ASP lesions alone, endpoint measurements of reaching success and footslip errors on the ladder showed transitory impairments, although detailed analysis revealed persistent deficits in skilled forelimb movements. ASP+CST lesions caused persistent deficits in reaching success and ladder footslips throughout the 8-week post-surgical period. Measurement of GRFs and limb timing during overground locomotion revealed differences in both groups at 8 weeks post-surgery compared to pre-surgical values, but no differences between ASP and ASP+CST groups. These results emphasize the normal contribution of both ascending sensory axons and CST axons during skilled limb movements and support a role for ascending sensory information, but not descending CST input, during overground locomotion. These results also illustrate the value of using sensitive methods to reveal detailed behavioural changes after spinal injury.

Dorsolateral cervical spinal injury differentially affects forelimb and hindlimb action in rats.

In experimental spinal injury studies, damage to the dorsal half of the spinal cord is common but the behavioural effects of damage to specific pathways in the dorsal cord have been less well investigated. We performed bilateral transection of the dorsolateral spinal funiculus (DLF) on 12 Long-Evans rats at the third cervical spinal segment. We quantified overground locomotion by measuring ground reaction forces, step timing and step distances as animals moved unrestrained. We also assessed skilled locomotion by measuring footslip errors made while the animals crossed horizontal ladders, and examined paw usage in a cylinder exploration task and during a skilled reaching task. Ground reaction forces revealed that rats with bilateral DLF lesions moved with a symmetrical gait, characterized mainly by altered forces exerted by the hindlimbs, delayed onset of hindlimb stance, and understepping of the hindlimbs relative to the forelimbs. These alterations in overground locomotion were subtle but were nevertheless consistent between animals and persisted throughout the 6-week recovery period. During ladder crossing, rats with DLF lesions made more footslip errors with the hindlimbs after surgery than before. Spontaneous forelimb usage during exploration was not affected by DLF axotomy but lesioned animals were less successful during skilled reaching. This is the first study which describes preferentially altered hindlimb use during overground locomotion after cervical DLF transections. We discuss these findings in relation to previous work and to the possible contributions of different ascending and descending pathways in the DLF to locomotion and skilled movements in rats.

Treadmill training ameliorates dopamine loss but not behavioral deficits in hemi-parkinsonian rats.

The purpose of this study was to investigate whether locomotor training could ameliorate neurochemical changes and behavioral deficits in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. It has been recently demonstrated that forelimb motor training, or brief treadmill training, can attenuate dopamine loss and some deficits in forelimb usage in this animal model. Nevertheless, it is not known whether locomotor training could result in an amelioration of locomotor deficits. Rats were lesioned with 6-OHDA injected intracerebrally and randomly assigned to one of 3 groups: early treadmill trained, late treadmill trained and untrained. Animals in the early trained group underwent 2 x 20 min treadmill sessions daily for 30 days, beginning 24 h after 6-OHDA injection. Late trained animals underwent the same training regime beginning 7 days post-injection. All animals were assessed on their abilities to perform several behavioral tasks designed to test locomotor and forelimb movement abilities prior to 6-OHDA injection and at 3 and 6 weeks post-injection. Treadmill training resulted in the attenuation of dopamine depletion in the striatum compared to non-treadmill trained animals, as measured by in vivo apomorphine-induced rotations and post-mortem dopamine analysis. Nevertheless, treadmill training produced essentially no difference in behavioral deficits on most tests compared to untrained animals. We discuss the possible reasons for the discrepancies with previous studies, including differences in lesioning, training regimes and methods of behavioral assessment. We conclude that treadmill training does not ameliorate locomotor deficits in the 6-OHDA model of Parkinson's disease, even though this same training results in attenuation of dopamine loss in the striatum.