Forelimb Function Research Articles

Compensatory adaptation of parallel motor pathways promotes skilled forelimb recovery after spinal cord injury.

Skilled forelimb patterning is regulated by the corticospinal tract (CST), with support from brainstem regions. When the CST is lesioned, there is a loss of forelimb function; however, if indirect pathways remain intact, rehabilitative training can facilitate recovery. Following spinal cord injury, rehabilitation is thought to enhance the reorganization and plasticity of spared supraspinal-propriospinal circuits, aiding functional recovery. This study focused on the roles of cervical propriospinal interneurons (PNs) and rubrospinal neurons (RNs) in the recovery of reaching and grasping behaviors in rats with bilateral lesions of the CST and dorsal columns at C5. The lesions resulted in a 50% decrease in pellet retrieval, which normalized over four weeks of training. Silencing PNs or RNs after recovery resulted in reduced retrieval success. Notably, silencing both pathways corresponded to greater functional loss, underscoring their parallel contributions to recovery, alongside evidence of CST fiber sprouting in the spinal cord and red nucleus.

A Kinematic Deviation Index (KDI) for Evaluation of Forelimb Function in Rodents.

Rodent models are widely used to study neurological conditions and assess forelimb movement to measure function performance, deficit, recovery and treatment effectiveness. Traditional assessment methods based on endpoints such as whether the task is accomplished, while easy to implement, provide limited information on movement patterns important to assess different functional strategies. On the other side, detailed kinematic analysis provides granular information on the movement patterns but is difficult to compare across laboratories, and may not translate to clinical metrics of upper limb function. To address these limitations, we developed and validated a kinematic deviation index (KDI) for rodents that mimics current trends in clinical research. The KDI is a unitless summary score that quantifies the difference between an animal movement during a task and its optimal performance derived from spatiotemporal marker sequences without pre-specifying movements. We demonstrate the utility of KDI in assessing reaching and grasping in mice and validate its discrimination between trial endpoints in healthy animals. Furthermore, we show KDI sensitivity to interventions, including acute and chronic spinal cord injury and optogenetic disruption of sensorimotor circuits. The KDI provides a comprehensive measure of motor function that bridges the gap between detailed kinematic analysis and simple success/failure metrics, offering a valuable tool for assessing recovery and compensation in rodent models of neurological disorders.

Novel comprehensive analysis of skilled reaching and grasping behavior in adult rats

BackgroundReaching and grasping (R&G) in rats is commonly used as an outcome measure to investigate the effectiveness of rehabilitation or treatment strategies to recover forelimb function post spinal cord injury. Kinematic analysis has been limited to the wrist and digit movements. Kinematic profiles of the more proximal body segments that play an equally crucial role in successfully executing the task remain unexplored. Additionally, understanding of different forelimb muscle activity, their interactions, and their correlation with the kinematics of R&G movement is scarce. New methodIn this work, novel methodologies to comprehensively assess and quantify the 3D kinematics of the proximal and distal forelimb joints along with associated muscle activity during R&G movements in adult rats are developed and discussed. ResultsOur data show that different phases of R&G identified using the novel kinematic and EMG-based approach correlate with the well-established descriptors of R&G stages derived from the Whishaw scoring system. Additionally, the developed methodology allows describing the temporal activity of individual muscles and associated mechanical and physiological properties during different phases of the motor task. Comparison with existing method(s)R&G phases and their sub-components are identified and quantified using the developed kinematic and EMG-based approach. Importantly, the identified R&G phases closely match the well-established qualitative descriptors of the R&G task proposed by Whishaw and colleagues. ConclusionsThe present work provides an in-depth objective analysis of kinematics and EMG activity of R&G behavior, paving the way to a standardized approach to assessing this critical rodent motor function in future studies.

Implantation of Optoelectronic Devices in the Rodent Spinal Cord.

Neuromodulation can provide diagnostic, modulatory, and therapeutic applications. While extensive work has been conducted in the brain, modulation of the spinal cord remains relatively unexplored. The inherently delicate and mobile spinal cord tissue imposes constraints that make the precise implantation of neural probes challenging. Despite recent advances in neuromodulation devices, particularly flexible bioelectronics, opportunities to expand their use in the spinal cord have been limited by the surgical complexities of device implantation. Here, we provide a series of surgical protocols tailored specifically for the implantation of a custom-made optoelectronic device that interfaces with the spinal cord in rodents. The steps to place and anchor an optical shank on a specific segment of the spinal cord via two different surgical implantation methods are detailed here. These methods are optimized for a diverse range of devices and applications, which may or may not require direct contact with the spinal cord for optical stimulation. To elucidate the methodology, the vertebral anatomy is referenced first to identify prominent landmarks before making a skin incision. The surgical steps to secure an optical shank over the cervical spine in rodents are demonstrated. Procedures are then outlined for securing the optoelectronic device connected to the optical shank in a subcutaneous space away from the spinal cord, minimizing unnecessary direct contact. Behavioral studies comparing animals receiving the implants to those undergoing sham surgeries indicate that the optical shanks did not adversely affect hindlimb or forelimb function seven days post-implantation. The present work broadens the neuromodulation toolkit for use in future studies aimed at investigating various spinal cord interventions.

Overexpression of PRDM16 improves muscle function after rotator cuff tears

Muscle atrophy, fibrosis, and fatty infiltration are commonly seen in rotator cuff tears (RCTs), which are critical factors that directly determine the clinical outcomes for patients with this injury. Therefore, improving muscle quality after RCT is crucial in improving the clinical outcome of tendon repair. In recent years, it has been discovered that adults have functional beige/brown adipose tissue (BAT) that can secrete batokines to promote muscle growth. PRDM16, a PR-domain-containing protein, was discovered with the ability to determine the brown fat cell fate and stimulate its development. Thus, the goal of this study was to discover the role of PRDM16 in improving muscle function after massive tendon tears using a transgenic mouse model with an elevated level of PRDM16 expression. Transgenic aP2-driven PRDM16-overexpressing mice and C57BL/6J mice underwent unilateral supraspinatus (SS) tendon transection and suprascapular nerve transection (TTDN) as described previously (n=8 in each group). DigiGait was performed to evaluate forelimb function at 6 weeks post the TTDN injury. Bilateral SS muscles, interscapular brown fat, epididymal white fat, and inguinal beige fat were harvested for analysis. The expression of PRDM16 in adipose tissue was detected by Western blot. Masson Trichrome staining was conducted to evaluate the muscle fibrosis, and Oil Red O staining was used to determine the fat infiltration. Muscle fiber type was determined by major histocompatibility complex (MHC) expression via immunostaining. All data were presented in the form of mean±standard deviation. t test and 2-way analysis of variance was performed to determine a statistically significant difference between groups. Significance was considered when P<.05. Western blot data showed an increased expression of PRDM16 protein in both white and brown fat in PRDM16-overexpressing mice compared with wild-type (WT) mice. Even though PRDM16 overexpression had no effect on increasing muscle weight, it significantly improved the forelimbs function with longer brake, stance, and stride time and larger stride length and paw area in mice after RCT. Additionally, PRDM16-overexpressing mice showed no difference in the amount of fibrosis when compared to WT mice; however, they had a significantly reduced area of fatty infiltration. These mice also exhibited abundant MHC-IIx fiber percentage in the supraspinatus muscle after TTDN. Overexpression of PRDM16 significantly improved muscle function and reduced fatty infiltration after rotator cuff tears. Promoting BAT activity is beneficial in improving rotator cuff muscle quality and shoulder function after RCT.

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.

Transformation of the pectoral girdle in pennaraptorans: critical steps in the formation of the modern avian shoulder joint.

Important transformations of the pectoral girdle are related to the appearance of flight capabilities in the Dinosauria. Previous studies on this topic focused mainly on paravians yet recent data suggests flight evolved in dinosaurs several times, including at least once among non-avialan paravians. Thus, to fully explore the evolution of flight-related avian shoulder girdle characteristics, it is necessary to compare morphology more broadly. Here, we present information from pennaraptoran specimens preserving pectoral girdle elements, including all purportedly volant taxa, and extensively compare aspects of the shoulder joint. The results show that many pectoral girdle modifications appear during the evolution from basal pennaraptorans to paravians, including changes in the orientation of the coracoid body and the location of the articulation between the furcula and scapula. These modifications suggest a change in forelimb range of motion preceded the origin of flight in paravians. During the evolution of early avialans, additional flight adaptive transformations occur, such as the separation of the scapula and coracoid and reduction of the articular surface between these two bones, reduction in the angle between these two elements, and elongation of the coracoid. The diversity of coracoid morphologies and types of articulations joining the scapula-coracoid suggest that each early avialan lineage evolved these features in parallel as they independently evolved more refined flight capabilities. In early ornithothoracines, the orientation of the glenoid fossa and location of the acrocoracoid approaches the condition in extant birds, suggesting a greater range of motion in the flight stroke, which may represent the acquisition of improved powered flight capabilities, such as ground take-off. The formation of a new articulation between the coracoid and furcula in the Ornithuromorpha is the last step in the formation of an osseous triosseal canal, which may indicate the complete acquisition of the modern flight apparatus. These morphological transitions equipped birds with a greater range of motion, increased and more efficient muscular output and while at the same time transmitting the increased pressure being generated by ever more powerful flapping movements in such a way as to protect the organs. The driving factors and functional adaptations of many of these transitional morphologies are as yet unclear although ontogenetic transitions in forelimb function observed in extant birds provide an excellent framework through which we can explore the behavior of Mesozoic pennaraptorans.

STAT3 protects dopaminergic neurons against degeneration in animal model of Parkinson's disease

IntroductionParkinson's disease (PD) is the most prevalent disorder of the basal ganglia, propagated by the degeneration of axon terminals within the striatum and subsequent loss of dopaminergic neurons in the substantia nigra (SN). Exposure of environmental neurotoxins and mutations of several mitochondrial and proteasomal genes are primarily responsible. MethodsTo determine whether signal transducer and activator of transcription 3 (STAT3) could protect dopaminergic neurons against degeneration, we first screened it in the in vitro capacity using immortalized rat dopaminergic N27 cells under 6-OHDA neurotoxicity. We then evaluated the effectiveness of constitutively active (ca) STAT3 as a neuroprotective agent on N27 cells in a 6-hydroxydopamine (6-OHDA) induced rat model of PD and compared it to control animals or animals where AAV/caRheb was expressed in SN. Behavioral outcomes were assessed using rotational and cylinder assays and mitochondrial function using reactive oxygen species (ROS) levels. ResultsUsing flow cytometry, the in vitro analysis determined caSTAT3 significantly decreased dopaminergic neuronal death under 6-OHDA treatment conditions. Importantly, in vivo overexpression of caSTAT3 in SN dopaminergic neurons using AAV-mediated expression demonstrated significant neuroprotection of dopaminergic neurons following 6-OHDA. Both caSTAT3 and caRheb + caSTAT3 co-injection into substantia nigra reduced D-amphetamine-induced rotational behavior and increased ipsilateral forelimb function when compared to control animals. In addition, caSTAT3 decreased mitochondrial ROS production following 6-OHDA induced neurotoxicity. ConclusioncaSTAT3 confers resistance against ROS production in mitochondria of susceptible SN dopaminergic neurons potentially offering a new avenue for treatment against PD.

Motor Rehabilitation Provides Modest Functional Benefits After Intracerebral Hemorrhage: a Systematic Review and Meta-Analysis of Translational Rehabilitation Studies.

Few certainties exist regarding the optimal type, timing, or dosage of rehabilitation after stroke. Despite differing injury mechanisms and recovery patterns following ischemic and hemorrhagic stroke, most translational stroke research is conducted after ischemia. As we enter the era of personalized medicine, exploring subtype-specific treatment efficacy is essential to optimizing recovery. Our objective was to characterize common rehabilitation interventions used after in vivo preclinical intracerebral hemorrhage (ICH) and assess the impact of post-ICH rehabilitation (vs. no-rehabilitation) on recovery of motor function. Following PRISMA guidelines, a systematic review (Academic Search Complete, CINAHL, EMBASE, Medline, PubMed Central) identified eligible articles published up to December 2022. Risk of bias (SYRCLE) and study quality (CAMARADES) were evaluated, and random-effects meta-analysis was used to assess treatment efficacy in recovery of forelimb and locomotor functions. Thirty articles met inclusion criteria, and 48 rehabilitation intervention groups were identified. Most used collagenase to model striatal ICH in young, male rodents. Aerobic exercise, enriched rehabilitation, and constraint-induced movement therapy represented ~ 70% of interventions. Study quality was low (median 4/10, range 2-8), and risk of bias was unclear. Rehabilitation provided modest benefits in skilled reaching, spontaneous impaired forelimb use, and locomotor function; however, effects varied substantially by endpoint, treatment type, and study quality. Rehabilitation statistically improves motor function after preclinical ICH, but whether these effects are functionally meaningful is unclear. Incomplete reporting and variable research quality hinder our capacity to analyze and interpret how treatment factors influence rehabilitation efficacy and recovery after ICH.

A comparative approach for characterizing the relationship among morphology, range-of-motion and locomotor behaviour in the primate shoulder.

Shoulder shape directly impacts forelimb function by contributing to glenohumeral (GH) range-of-motion (ROM). However, identifying traits that contribute most to ROM and visualizing how they do so remains challenging, ultimately limiting our ability to reconstruct function and behaviour in fossil species. To address these limitations, we developed an in silico proximity-driven model to simulate and visualize three-dimensional (3D) GH rotations in living primate species with diverse locomotor profiles, identify those shapes that are most predictive of ROM using geometric morphometrics, and apply subsequent insights to interpret function and behaviour in the fossil hominin Australopithecus sediba. We found that ROM metrics that incorporated 3D rotations best discriminated locomotor groups, and the magnitude of ROM (mobility) was decoupled from the anatomical location of ROM (e.g. high abduction versus low abduction). Morphological traits that enhanced mobility were decoupled from those that enabled overhead positions, and all non-human apes possessed the latter but not necessarily the former. Model simulation in A. sediba predicted high mobility and a ROM centred at lower abduction levels than in living apes but higher than in modern humans. Together these results identify novel form-to-function relationships in the shoulder and enhance visualization tools to reconstruct past function and behaviour.

The fossil record of appendicular muscle evolution in Synapsida on the line to mammals: Part I-Forelimb.

This paper is the first in a two-part series that charts the evolution of appendicular musculature along the mammalian stem lineage, drawing upon the exceptional fossil record of extinct synapsids. Here, attention is focused on muscles of the forelimb. Understanding forelimb muscular anatomy in extinct synapsids, and how this changed on the line to mammals, can provide important perspective for interpreting skeletal and functional evolution in this lineage, and how the diversity of forelimb functions in extant mammals arose. This study surveyed the osteological evidence for muscular attachments in extinct mammalian and nonmammalian synapsids, two extinct amniote outgroups, and a large selection of extant mammals, saurians, and salamanders. Observations were integrated into an explicit phylogenetic framework, comprising 73 character-state complexes covering all muscles crossing the shoulder, elbow, and wrist joints. These were coded for 33 operational taxonomic units spanning >330 Ma of tetrapod evolution, and ancestral state reconstruction was used to evaluate the sequence of muscular evolution along the stem lineage from Amniota to Theria. In addition to producing a comprehensive documentation of osteological evidence for muscle attachments in extinct synapsids, this work has clarified homology hypotheses across disparate taxa and helped resolve competing hypotheses of muscular anatomy in extinct species. The evolutionary history of mammalian forelimb musculature was a complex and nonlinear narrative, punctuated by multiple instances of convergence and concentrated phases of anatomical transformation. More broadly, this study highlights the great insight that a fossil-based perspective can provide for understanding the assembly of novel body plans.

Assessment of Sensorimotor Behaviour in Konzo-Induced Rats Using the Irvine, Beattie Bresnahan Forelimb Scale

Konzo is a neurological disorder of selective upper motor neurons. It is an irreversible paralytic disease associated with prolonged consumption of Cassava. It contains cyanogenic glycosides metabolized to hydrogen cyanide, which has been shown by studies to affect the motor neurons of the central nervous system. The Irvine, Beattie Bresnahan (IBB) scale is a recently developed forelimb scale for the assessment of fine control of the forelimb and digits after cervical spinal cord injury such as Konzo. 20 Adult male Wistar rats were assigned to 4 experimental groups (i) control n=5, (ii) konzo-induced group n=5, (iii) induced + Complan n=5 (iv) Induced + Bambara Nut (Okpa). The bitter cassava foods were taken by oral ingestion for a period of 4 weeks. The assessment of the forelimb and digits were done using the Irvine, Beattie Bresnahan (IBB) with specific parameters such as Predominant Elbow Joint movement, Contact Volar Support, and Grasping method. The body weight of the animals was also recorded every week. The data obtained were analyzed using ANOVA. The result obtained showed that there was a significant difference (p&lt;0.05) between the body weight of the animals induced with Konzo and rehabilitated with Complan milk and Bambara nut when compared to the unrehabilitated Konzo-induced group. There were differences in the results of the parameters being tested for the Irvine, Beattie Bresnahan (IBB) scaling. The IBB scale confirmed that there was a high level of cyanide content in the cassava which affected the behavioral attributes of the induced group and it also confirmed that the induced group can be ameliorated with the use of Complan and Bambara Nut (Okpa) which was shown in the parameters being tested such as Predominant Elbow Joint movement, Contact Volar Support, and Grasping method. It was concluded that insufficiently processed bitter cassava is toxic and has neurotoxicity effects on the Spinal Cord especially on the upper motor neurons and IBB scale is capable of measuring gradual improvements in motor forelimb functions in this model and may be a new and effective assessment tool for peripheral nerve injury.

Enriched Rehabilitation Reduces Abnormal Motor Synergies and Enhances Motor Plasticity Following Severe Stroke in Rats.

Stroke results in loss of upper motor neuron control over voluntary movements and emergence of abnormal synergies. Presently, it is unclear to what extent poststroke recovery reflects true recovery (restitution), compensation, or some combination of these processes. Here, we investigated this question using behavioral and kinematic analyses of skilled reaching in rats subjected to severe stroke that affected both the forelimb motor cortex and dorsolateral striatum. After stroke, male rats either spontaneously recovered or received enriched rehabilitation. We assessed forelimb motor recovery using behavioral and kinematic outcome measures. To provide insights into the mechanisms underlying the effects of rehabilitation on behavior, we used intracortical microstimulation and FosB (protein fosB) immunostaining techniques. Enriched rehabilitation significantly improved food pellet retrieval in the staircase-reaching task. Rehabilitation resulted in several poststroke flexion synergies returning to prestroke patterns, and across subjects, these changes correlated with the intensity of rehabilitation. Enriched rehabilitation increased the proportion of distal movement representation in the perilesional cortex and increased use-dependent activation in the ipsilesional red nucleus. These results provide evidence that enriched rehabilitation enhances recovery, at least in part, by restitution of forelimb function following severe stroke. Furthermore, the restitution of function is associated with changes in multiple motor-related structures at different levels of the central nervous system. A better understanding of the processes that underlie improved motor performance, along with the identification of midbrain circuits activated by rehabilitation, represent new insights and potential targets for optimizing poststroke recovery.

A novel therapeutic approach of ultrasound stimulation to restore forelimb functions following cervical cord injury in rats

Low-intensity pulsed ultrasound (LIPUS) stimulation has shown promising results in neurorehabilitation following a traumatic injury in brain and peripheral nerves. However, the effects of LIPUS stimulation in the injured neural circuit after spinal cord injury (SCI) are still unknown. We investigated the effects of LIPUS on forelimb functions in chronic cervical cord injured rats with and without a serotonergic agonist drug, Buspirone treatment. Twenty-six rats were trained for forelimb reaching and grasping followed by C4 dorsal funiculi crush injury. To deliver LIPUS, a silicon-coated ultrasound disc was implanted above the cervical cord and electromyography electrodes were implanted into forelimb muscles. In two cohorts (LIPUS and LIPUS + Buspirone combined) rats were tested pre-, with- and post-ultrasound stimulation. In LIPUS group rats, fore-limb reaching and grasping success rates first increased and then dropped after 3 weeks while for combination of drug and LIPUS stimulation the score continued to increase. Furthermore, LIPUS stimulation alone did not result in any significant improvement of grip strength compared to the control and combined groups. The findings of this study indicated the potential of LIPUS in SCI recovery and offer a future research direction of a new neuromodulation method.

ID: 222489 Softening Multi-Electrode Arrays to Engage Cervical Spinal Cord Circuits

We have developed softening spinal cord stimulating leads for modulation of the cervical spinal cord in the rat. These devices use a softening polymer that allows them to be relatively stiff at room temperature, to aid with insertion into the epidural space, and become supple in the body, preventing injury to underlying cervical spinal cord. The devices are fabricated with photolithography, enabling them to be very thin (∼50 microns). Our previous work demonstrated that these devices can safely modulate the cervical spinal cord over months and help restore forelimb function in rats with spinal cord injury. Here we sought to optimize the pattern of electrodes to optimally engage afferents at the dorsal root entry zone. We printed arrays with electrodes of different sizes, positions, and orientations and tested their efficiency in provoking forelimb muscle responses in rats.

Effect of Tiaoshen Changzhi acupuncture on behavior and striatum ΔFosB in rats with levodopa-induced dyskinesias

ABSTRACT This study aims to study the effffects of Tiaoshen Changzhi acupuncture on behavior and striatum ΔFosB in rats with Levodopa-induced Dyskinesias (LIDs). In this experimental study, Levodopa-induced Dyskinesia (LID) rat models were established by 6-OHDA double-target injection and randomly assigned to six groups, with ten rats in each group. The rats were subjected to difffferent interventions for 28 days, and their behavior was observed. Additionally, the content of ΔFosB, a marker of neuronal activation, in the rat striatum was detected by immunohistochemistry and qRT-PCR. In contrallateral rotation behavior experiment and AIM experiment, the score of the model group was significantly increased, compared with the model group, the score of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi group was significantly decreased (P < 0.01), the score of the Western medicine group and the Tiaoshen Changzhi group was significantly lower than the ordinary acupuncture group (P < 0.01), there was no statistical significance between the Western medicine group and the Tiaoshen Changzhi group (P>0.05). In the left forelimb function test, the score of the model group was significantly decreased, and compared with the model group, the left forelimb function score of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi group were significantly increased (P < 0.01). The left forelimb function score of the Western medicine group and the Tiaoshen Changzhi group was higher than the ordinary acupuncture group (P < 0.05, P < 0.01). There was no statistical significance between Western medicine group and Tiaoshen Changzhi group (P > 0.05). After treatment, the content of ΔFosB in the striatum of the Western medicine group, the ordinary acupuncture group and the Tiaoshen Changzhi acupuncture group all decreased, the Western medicine group was better than the ordinary acupuncture group (P < 0.01), and the Tiaoshen Changzhi acupuncture group was better than the ordinary acupuncture group (P < 0.05). Tiaoshen Changzhi acupuncture can improve the behavioral performance of LID rats, reduce abnormal involuntary movement and contralateral rotation behavior and enhance the motor function of the left forelimb of rats. One of its therapeutic mechanisms for LID may be to reduce the expression level of ΔFosB in the striatum of LID rats, thereby reducing the symptoms of LID rats.

Using Operant Reach Chambers to Assess Mouse Skilled Forelimb Use After Stroke.

Skilled forelimb reaching and grasping are important components of rodent motor performance. The isometric pull task can serve as a tool for quantifying forelimb function following stroke or other CNS injury as well as in forelimb rehabilitation. This task has been extensively developed for use in rats. Here, we describe methods of setup and training of an operant reach chamber for mice. Using a reward of peanut oil, mice are adaptively trained to pull a handle positioned slightly outside of an operant chamber, with automated recording of the number of attempts, force generated, success rate, and latency to maximal force.

Establishment of longitudinal transcranial stimulation motor evoked potentials monitoring of the forelimbs and hindlimbs in an ischemic stroke rat model

Evaluation of motor function ischemic stroke rat models includes qualitative assessments such as the modified neurological severity score (mNSS). However, mNSS cannot evaluate the function of forelimbs and hindlimbs separately. We quantitatively assessed motor function in a middle cerebral artery occlusion (MCAO) rat model of ischemic stroke. We recorded transcranial stimulation motor evoked potentials (tcMEPs) from MCAO rats and measured the changes in onset latency and amplitude at the forelimbs and hindlimbs up to 28 days after stroke. All MCAO subjects showed hemiparesis. The amplitudes of tcMEPs in both fore- and hindlimbs were inversely correlated with mNSS scores, but the amplitudes in the forelimbs improved later than those in the hindlimbs. The onset latency of tcMEPs in the forelimbs and hindlimbs remained almost unchanged during the follow-up period. Our results showed the differences in tcMEPs amplitude recovery times between the forelimbs and hindlimbs after MCAO, which emphasizes the importance of separately evaluating forelimbs and hindlimbs in post-ischemic stroke models. This minimally invasive and longitudinal quantitative method could be useful for further research on diseases and neurogenesis.

Adaptation of a cervical bilateral contusive spinal cord injury for study of skilled forelimb function

We present an updated, clinically relevant model of moderately severe bilateral cervical level 6 contusive spinal cord injury (SCI) in the rat. This model is more clinically relevant than previous models due it its severity, yet animals readily survive the lesion. The C6 bilateral lesion is administered to Fischer 344 rats using the Infinite Horizons impactor adjusted to a 200 kdyne force with a 3.5 mm impactor head. The lesion results in loss of 60 ± 10% of the spinal cord area, including virtually the entire dorsal half of the spinal cord and complete interruption of the main corticospinal tract. Skilled forelimb performance declines by 60 ± 10% compared to the pre-operative baseline and deficits are sustained over time. This model is a substantial step closer to mimicking the most common level (cervical) and more severe form of SCI in humans and should provide a superior tool for assessing the likelihood that experimental interventions may promote motor recovery after SCI in humans.

Comparison of motor recovery after neonatal and adult hemidecortication

Hemidecortication produces a wide range of cognitive and motor symptoms in both children and lab animals that are generally far greater than smaller bilateral focal lesions of cerebral cortex. Although there have been many studies of motor functions after hemidecortication, the analyses largely have been of general motor functions rather than of more skilled motor functions such as forelimb reaching. The objective of the present experiment was to analyze the sensorimotor forelimb function of rats after infant or adult hemidecortication by utilizing multiple motor analyses. Rats were given hemidecortications either on postnatal day 10 (P10) or day 90 (P90). Both groups were then tested on a number of behavioural tasks (two tests of skilled reaching, forelimb placing during spontaneous vertical exploration, and a sunflower seed opening task) beginning at P 120. In a portion of the P10 female animals, topographic movement representations were derived in the hemisphere contralateral to lesion using Intracortical Microstimulation (ICMS). The brains of the male animals were prepared for Golgi-Cox staining and subsequent analysis of dendritic arborisation and spine density. There were three main findings. 1) Both groups of hemidecorticate animals were impaired when tested on the motor tasks, but the impairments were qualitatively different in the neonatal and adult operates. For example, the P 10 hemidecorticate animals displayed simultaneous bilateral forelimb movement, or “mirror movements.” 2) Hemidecortication at P90 but not P10, led to increased dendritic arborisation of Layer III pyramidal cells in the intact parietal cortex but whereas P90 animals showed a decrease in cortical thickness in the intact hemisphere, the P10 animals do not, even though there are no callosal connections. 3) P10 hemidecortication altered the details of the ICMS-delineated motor maps in a small group of female hemidecorticates that were studied. In conclusion, there was postinjury compensation for motor impairments in both P10 and P90 rats but the mechanisms were different. Furthermore, comparisons of postinjury behavioral and anatomical compensation in rats with focal cortical injuries at those ages in our previous studies showed marked differences. These results suggest that there is a fundamental difference in the way that the brain compensates from hemidecortication and focal injury in development.