Forelimb Muscles Research Articles

Posture-dependent modulation of marmoset cortical motor maps detected via rapid multichannel epidural stimulation

Recent neuroimaging and electrophysiological studies have suggested substantial short-term plasticity in the topographic maps of the primary motor cortex (M1). However, previous methods lack the temporal resolution to detect rapid modulation of these maps, particularly in naturalistic conditions. To address this limitation, we previously developed a rapid stimulation mapping procedure with implanted cortical surface electrodes. In this study, employing our previously established procedure, we examined rapid topographical changes in forelimb M1 motor maps in three awake male marmoset monkeys. The results revealed that although the hotspot (the location in M1 that elicited a forelimb muscle twitch with the lowest stimulus intensity) remained constant across postures, the stimulus intensity required to elicit the forelimb muscle twitch in the perihotspot region and the size of motor representations were posture-dependent. Hindlimb posture was particularly effective in inducing these modulations. The angle of the body axis relative to the gravitational vertical line did not alter the motor maps. These results provide a proof of concept that a rapid stimulation mapping system with chronically implanted cortical electrodes can capture the dynamic regulation of forelimb motor maps in natural conditions. Moreover, they suggest that posture is a crucial variable to be controlled in future studies of motor control and cortical plasticity. Further exploration is warranted into the neural mechanisms regulating forelimb muscle representations in M1 by the hindlimb sensorimotor state.

Changes in intra- and interlimb reflexes from forelimb cutaneous afferents after staggered thoracic lateral hemisections during locomotion in cats.

In quadrupeds, such as cats, cutaneous afferents from the forepaw dorsum signal external perturbations and send inputs to spinal circuits to co-ordinate the activity in muscles of all four limbs. How these cutaneous reflex pathways from forelimb afferents are reorganized after an incomplete spinal cord injury is not clear. Using a staggered thoracic lateral hemisections paradigm, we investigated changes in intralimb and interlimb reflex pathways by electrically stimulating the left and right superficial radial nerves in seven adult cats and recording reflex responses in five forelimb and ten hindlimb muscles. After the first (right T5-T6) and second (left T10-T11) hemisections, forelimb-hindlimb co-ordination was altered and weakened. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-, mid- and long-latency homonymous and crossed reflex responses in forelimb muscles and their phase modulation remained largely unaffected after staggered hemisections. The occurrence of homolateral and diagonal mid- and long-latency responses in hindlimb muscles evoked with left and right superficial radial nerve stimulation was significantly reduced at the first time point after the first hemisection, but partially recovered at the second time point with left superficial radial nerve stimulation. These responses were lost or reduced after the second hemisection. When present, all reflex responses, including homolateral and diagonal, maintained their phase-dependent modulation. Therefore, our results show a considerable loss in cutaneous reflex transmission from cervical to lumbar levels after incomplete spinal cord injury, albeit with preservation of phase modulation, probably affecting functional responses to external perturbations. KEY POINTS: Cutaneous afferent inputs co-ordinate muscle activity in the four limbs during locomotion when the forepaw dorsum contacts an obstacle. Thoracic spinal cord injury disrupts communication between spinal locomotor centres located at cervical and lumbar levels, impairing balance and limb co-ordination. We investigated cutaneous reflexes from forelimb afferents during quadrupedal locomotion by electrically stimulating the superficial radial nerve bilaterally, before and after staggered lateral thoracic hemisections in cats. We showed a loss/reduction of mid- and long-latency homolateral and diagonal reflex responses in hindlimb muscles early after the first hemisection that partially recovered with left superficial radial nerve stimulation, before being reduced after the second hemisection. Targeting cutaneous reflex pathways from forelimb afferents projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways.

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.

Constraint-Induced Movement Therapy (CIMT) and Neural Precursor Cell (NPC) Transplantation Synergistically Promote Anatomical and Functional Recovery in a Hypoxic-Ischemic Mouse Model.

Cerebral palsy (CP) is a common neurodevelopmental disorder characterized by pronounced motor dysfunction and resulting in physical disability. Neural precursor cells (NPCs) have shown therapeutic promise in mouse models of hypoxic-ischemic (HI) perinatal brain injury, which mirror hemiplegic CP. Constraint-induced movement therapy (CIMT) enhances the functional use of the impaired limb and has emerged as a beneficial intervention for hemiplegic CP. However, the precise mechanisms and optimal application of CIMT remain poorly understood. The potential synergy between a regenerative approach using NPCs and a rehabilitation strategy using CIMT has not been explored. We employed the Rice-Vannucci HI model on C57Bl/6 mice at postnatal day (PND) 7, effectively replicating the clinical and neuroanatomical characteristics of hemiplegic CP. NPCs were transplanted in the corpus callosum (CC) at PND21, which is the age corresponding to a 2-year-old child from a developmental perspective and until which CP is often not formally diagnosed, followed or not by Botulinum toxin injections in the unaffected forelimb muscles at PND23, 26, 29 and 32 to apply CIMT. Both interventions led to enhanced CC myelination and significant functional recovery (as shown by rearing and gait analysis testing), through the recruitment of endogenous oligodendrocytes. The combinatorial treatment indicated a synergistic effect, as shown by newly recruited oligodendrocytes and functional recovery. This work demonstrates the mechanistic effects of CIMT and NPC transplantation and advocates for their combined therapeutic potential in addressing hemiplegic CP.

ROLE OF FORELIMB MORPHOLOGY IN MUSCLE SENSORIMOTOR FUNCTIONS DURING LOCOMOTION IN THE CAT.

Previous studies established strong links between morphological characteristics of mammalian hindlimb muscles and their sensorimotor functions during locomotion. Less is known about the role of forelimb morphology in motor outputs and generation of sensory signals. Here, we measured morphological characteristics of 46 forelimb muscles from 6 cats. These characteristics included muscle attachments, physiological cross-sectional area (PCSA), fascicle length, etc. We also recorded full-body mechanics and EMG activity of forelimb muscles during level overground and treadmill locomotion in 7 and 16 adult cats of either sex, respectively. We computed forelimb muscle forces along with force- and length-dependent sensory signals mapped onto corresponding cervical spinal segments. We found that patterns of computed muscle forces and afferent activities were strongly affected by the muscle's moment arm, PCSA, and fascicle length. Morphology of the shoulder muscles suggests distinct roles of the forelimbs in lateral force production and movements. Patterns of length-dependent sensory activity of muscles with long fibers (brachioradialis, extensor carpi radialis) closely matched patterns of overall forelimb length, whereas the activity pattern of biceps brachii matched forelimb orientation. We conclude that cat forelimb muscle morphology contributes substantially to locomotor function, particularly to control lateral stability and turning, rather than propulsion.

Exercise training induces mild skeletal muscle adaptations without altering disease progression in a TDP-43 mouse model.

Exercise training is considered a nonpharmacological therapeutic approach for many diseases. Mild-to-moderate endurance exercise training is suggested to improve the mental and physical state of people with amyotrophic lateral sclerosis (ALS). The aim of the present study was to determine the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TAR DNA-binding protein 43 (TDP-43) pathology and motor dysfunction, to perform mild-to-moderate intensity treadmill exercise training and to evaluate the effects of this training on skeletal muscle health and disease progression. Symptomatic rNLS8 mice were able to complete 4 wk of mild-to-moderate treadmill running (30 min at 6-13 m/min, 3 days a week). Exercise training induced an increase in the percentage of type IIA fibers in the tibialis anterior muscle as well as minor adaptations in molecular markers of myogenic, mitochondrial, and neuromuscular junction health in some forelimb and hindlimb muscles. However, this exercise training protocol did not attenuate the loss in motor function or delay disease progression. Alternative exercise regimens need to be investigated to better understand the role exercise training may play in alleviating symptoms of ALS.NEW & NOTEWORTHY This is the first study to investigate the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TDP-43 pathology and motor dysfunction, to perform exercise training. We demonstrate that despite the ALS-reminiscent aggressive disease progression characterizing the rNLS8 mouse model, rNLS8 mice are capable of performing mild-to-moderate endurance treadmill training for at least 3-4 wk. We demonstrate that exercise training induces several minor skeletal muscle adaptations without delaying disease progression in rNLS8 mice.

The comparative and functional anatomy of the forelimb muscle architecture of Humboldt's woolly monkey (Lagothrix lagotricha)

The comparative and functional anatomy of the forelimb muscle architecture of <scp>Humboldt's</scp> woolly monkey (<i>Lagothrix lagotricha</i>)

Systemic Pharmacotherapeutic Treatment of the ACTA1-MCM/FLExDUX4 Preclinical Mouse Model of FSHD.

Aberrant expression of the double homeobox 4 (DUX4) gene in skeletal muscle predominantly drives the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). We recently demonstrated that berberine, an herbal extract known for its ability to stabilize guanine-quadruplex structures, effectively downregulates DUX4 expression in FSHD patient-derived myoblasts and in mice overexpressing exogenous DUX4 after viral vector-based treatment. Here, we sought to confirm berberine's inhibitory efficacy on DUX4 in the widely used FSHD-like transgenic mouse model, ACTA1-MCM/FLExDUX4, where DUX4 is induced at pathogenic levels using tamoxifen. Animals repeatedly treated with berberine via intraperitoneal injections for 4 weeks exhibited significant reductions in both mRNA and protein levels of DUX4, and in mRNA expression of murine DUX4-related genes. This inhibition translated into improved forelimb muscle strength and positive alterations in important FSHD-relevant cellular pathways, although its impact on muscle mass and histopathology was less pronounced. Collectively, our data confirm the efficacy of berberine in downregulating DUX4 expression in the most relevant FSHD mouse model. However, further optimization of dosing regimens and new studies to enhance the bioavailability of berberine in skeletal muscle are warranted to fully leverage its therapeutic potential for FSHD treatment.

Functional and morphological divergence in the forelimb musculoskeletal system of scratch-digging subterranean mammals (Rodentia: Bathyergidae).

Whether the forelimb-digging apparatus of tooth-digging subterranean mammals has similar levels of specialization as compared to scratch-diggers is still unknown. We assessed the scapular morphology and forelimb musculature of all four solitary African mole rats (Bathyergidae): two scratch-diggers, Bathyergus suillus and Bathyergus janetta, and two chisel-tooth diggers, Heliophobius argenteocinereus and Georychus capensis. Remarkable differences were detected: Bathyergus have more robust neck, shoulder, and forearm muscles as compared to the other genera. Some muscles in Bathyergus were also fused and often showing wider attachment areas to bones, which correlate well with its more robust and larger scapula, and its wider and medially oriented olecranon. This suggests that shoulder, elbow, and wrist work in synergy in Bathyergus for generating greater out-forces and that the scapula and proximal ulna play fundamental roles as pivots to maximize and accommodate specialized muscles for better (i) glenohumeral and scapular stabilization, (ii) powerful shoulder flexion, (iii) extension of the elbow and (iv) flexion of the manus and digits. Moreover, although all bathyergids showed a similar set of muscles, Heliophobius lacked the m. tensor fasciae antebrachii (aiding with elbow extension and humeral retraction), and Heliophobius and Georychus lacked the m. articularis humeri (aiding with humeral adduction), indicating deeper morphogenetic differences among digging groups and suggesting a relatively less specialized scratch-digging ability. Nevertheless, Heliophobius and Bathyergus shared some similar adaptations allowing scratch-digging. Our results provide new information about the morphological divergence within this family associated with the specialization to distinct functions and digging behaviors, thus contributing to understand the mosaic of adaptations emerging in phylogenetically and ecologically closer subterranean taxa. This and previous anatomical studies on the Bathyergidae will provide researchers with a substantial basis on the form and function of the musculoskeletal system for future kinematic investigations of digging behavior, as well as to define potential indicators of scratch-digging ability.

Short-term treatment of Tat-Beclin1 and endurance exercise enhances autophagy and increases grip strength in old male mice but not in female

Sarcopenia is a geriatric disease causing loss of muscle mass and function, ultimately declining quality of life and causing death. Despite substantial efforts to prevent sarcopenia, there are no approved drugs for treating this muscle disease. Autophagy, a critical process for maintaining muscle health, offers potential avenues for intervention. However, an integrative therapy comprised of an autophagic-specific compound and endurance exercise in old animals has yet to be tested. We hypothesize that combining Tat-Beclin1 (a potent autophagy-specific inducer) and endurance exercise improves muscle force and autophagy in both male and female old mice. Female and male mice at 23 months of age were divided into four groups: Control, Tat-Beclin1 (TB), endurance exercise (Exe), and TB+Exe. Short-term combined treatment underwent for one month. Exercise training at moderate intensity (70% of running peak test) was performed on Mondays, Wednesdays, and Fridays. Tat-Beclin1 administration (15 mg/kg/day) was conducted on Tuesdays and Thursdays. We assessed muscle function through forelimb grip strength and muscle autophagic markers by western blotting. There was no difference in grip strength in female groups. In contrast, there was an increase in grip strength in treated male mice (p&lt;0.05; TB, Exe, and TB+Exe vs. Control group). Notably, the combination treatment in the TB+Exe group outperformed the individual treatments (TB and Exe groups) in enhancing grip strength (p=0.05). Beclin1 and GLIPR2 (a novel autophagic suppressor) were unchanged in both male and female mice. Sequestosome/p62 was decreased in males only, indicating autophagy cargo degradation. Our findings demonstrate that a short-term treatment of Tat-Beclin1 combined with endurance exercise improves grip strength (muscle force) and autophagy in old male mice. Notably, female mice did not exhibit a similar response to the short-term treatment, suggesting that a more extended therapy duration may be necessary to explore potential benefits for female mice. This synergy of an autophagic-specific agonist with endurance exercise may represent a novel strategy to tackle sarcopenia. Camden Health Research Initiative - Startup fundings. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Chronic Cervical Midline Contusion in Rats Disrupts Multiple Facets of Cardiovascular Function

Cardiovascular dysfunction is the leading cause of morbidity and mortality following spinal cord injury (SCI). There are a limited number of studies assessing cardiovascular deficits after cervical SCI. This study aimed to assess disrupted cardiovascular function following a chronic severe incomplete C8 SCI in rats, via damaging descending sympathetic projections to the spinal sympathetic preganglionic neurons. Rats were first trained on the isometric pull task before receiving a C8 midline contusion (Infinite Horizon Impact Device; 250 kilodynes; 0 s dwell time) or laminectomy and were tested one day per week from weeks 7-13 following surgery. Isometric forelimb strength and correlates of muscle endurance were monitored during pull task sessions. Cardiovascular function was evaluated 16 weeks post-surgery. Tilt table testing was used to induce an orthostatic challenge by tilting rats 90 degrees head-up from a supine position and 90 degrees head-down from supine position as a control. Following tilt table testing, dobutamine (DOB; 2 μg/kg/min and 10 μg/kg/min) and norepinephrine (NE; 1 μg/kg/min and 4 μg/kg/min) were infused into the femoral vein separately to assess cardiovascular responses to a pharmacological challenge. We monitored cardiovascular physiology during all terminal testing. A blood pressure catheter was inserted into the left common carotid artery and advanced to the aortic arch to monitor interatrial blood pressure, 2 pairs of impedance cardiography (ICG) electrodes were placed on the left side of the thorax to evaluate inotropic correlates of cardiac function, and 2 photoplethysmography (PPG) sensors were affxed over the forelimbs flexor muscles to examine peripheral hemodynamics. To verify the accuracy of ICG-derived cardiac function, rats were examined by echocardiography at week 15. Spinal cords were collected for lesion analysis and were also stained for tyrosine hydroxylase. Our preliminary results demonstrate that chronic severe incomplete C8 SCI resulted in a significant and sustained hypotension during the 3-minute period of 90 degrees head-up tilting (systolic blood pressure = ~ -22 mmHg; diastolic blood pressure = ~ -19 mmHg) compared to laminectomy. There were also significant differences in left ventricular ejection time, heart rate, and stroke volume across groups, whereas forelimb hemodynamics did not differ across groups. Additionally, correlates of forelimb muscle endurance significantly decreased in SCI rats, despite similar isometric forelimb strength across groups. Intravenous infusion of DOB and NE demonstrated significant and dose-dependent effects on cardiovascular parameters. Overall, our data demonstrate that chronic severe C8 SCI in rats leads to orthostatic hypotension and also impairs multiple additional aspects of function. This study was supported by: NIH (R01 NS131493) and Florida Department of Health (COPBC). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Changes in intra- and interlimb reflexes from hindlimb cutaneous afferents after staggered thoracic lateral hemisections during locomotion in cats.

When the foot dorsum contacts an obstacle during locomotion, cutaneous afferents signal central circuits to coordinate muscle activity in the four limbs. Spinal cord injury disrupts these interactions, impairing balance and interlimb coordination. We evoked cutaneous reflexes by electrically stimulating left and right superficial peroneal nerves before and after two thoracic lateral hemisections placed on opposite sides of the cord at 9- to 13-week interval in seven adult cats (4males and 3 females). We recorded reflex responses in ten hindlimb and five forelimb muscles bilaterally. After the first (right T5-T6) and second (left T10-T11) hemisections, coordination of the fore- and hindlimbs was altered and/or became less consistent. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-latency reflex responses in homonymous and crossed hindlimb muscles largely remained unaffected after staggered hemisections. However, mid- and long-latency homonymous and crossed responses in both hindlimbs occurred less frequently after staggered hemisections. In forelimb muscles, homolateral and diagonal mid- and long-latency response occurrence significantly decreased after the first and second hemisections. In all four limbs, however, when present, short-, mid- and long-latency responses maintained their phase-dependent modulation. We also observed reduced durations of short-latency inhibitory homonymous responses in left hindlimb extensors early after the first hemisection and delayed short-latency responses in the right ipsilesional hindlimb after the first hemisection. Therefore, changes in cutaneous reflex responses correlated with impaired balance/stability and interlimb coordination during locomotion after spinal cord injury. Restoring reflex transmission could be used as a biomarker to facilitate locomotor recovery. KEY POINTS: Cutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the foot dorsum contacts an obstacle. Thoracic spinal cord injury disrupts communication between spinal locomotor centres located at cervical and lumbar levels, impairing balance and limb coordination. We investigated cutaneous reflexes during quadrupedal locomotion by electrically stimulating the superficial peroneal nerve bilaterally, before and after staggered lateral thoracic hemisections of the spinal cord in cats. We showed a loss/reduction of mid- and long-latency responses in all four limbs after staggered hemisections, which correlated with altered coordination of the fore- and hindlimbs and impaired balance. Targeting cutaneous reflex pathways projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways.

Recording Forelimb Muscle Activity in Head-Fixed Mice with Chronically Implanted EMG Electrodes.

Powerful genetic and molecular tools available in mouse systems neuroscience research have enabled researchers to interrogate motor system function with unprecedented precision in head-fixed mice performing a variety of tasks. The small size of the mouse makes the measurement of motor output difficult, as the traditional method of electromyographic (EMG) recording of muscle activity was designed for larger animals like cats and primates. Pending commercially available EMG electrodes for mice, the current gold-standard method for recording muscle activity in mice is to make electrode sets in-house. This article describes a refinement of established procedures for hand fabrication of an electrode set, implantation of electrodes in the same surgery as headplate implantation, fixation of a connector on the headplate, and post-operative recovery care. Following recovery, millisecond-resolution EMG recordings can be obtained during head-fixed behavior for several weeks without noticeable changes in signal quality. These recordings enable precise measurement of forelimb muscle activity alongside in vivo neural recording and/or perturbation to probe mechanisms of motor control in mice.

Multichannel bridges and NSC synergize to enhance axon regeneration, myelination, synaptic reconnection, and recovery after SCI

Regeneration in the injured spinal cord is limited by physical and chemical barriers. Acute implantation of a multichannel poly(lactide-co-glycolide) (PLG) bridge mechanically stabilizes the injury, modulates inflammation, and provides a permissive environment for rapid cellularization and robust axonal regrowth through this otherwise inhibitory milieu. However, without additional intervention, regenerated axons remain largely unmyelinated (<10%), limiting functional repair. While transplanted human neural stem cells (hNSC) myelinate axons after spinal cord injury (SCI), hNSC fate is highly influenced by the SCI inflammatory microenvironment, also limiting functional repair. Accordingly, we investigated the combination of PLG scaffold bridges with hNSC to improve histological and functional outcome after SCI. In vitro, hNSC culture on a PLG scaffold increased oligodendroglial lineage selection after inflammatory challenge. In vivo, acute PLG bridge implantation followed by chronic hNSC transplantation demonstrated a robust capacity of donor human cells to migrate into PLG bridge channels along regenerating axons and integrate into the host spinal cord as myelinating oligodendrocytes and synaptically integrated neurons. Axons that regenerated through the PLG bridge formed synaptic circuits that connected the ipsilateral forelimb muscle to contralateral motor cortex. hNSC transplantation significantly enhanced the total number of regenerating and myelinated axons identified within the PLG bridge. Finally, the combination of acute bridge implantation and hNSC transplantation exhibited robust improvement in locomotor recovery. These data identify a successful strategy to enhance neurorepair through a temporally layered approach using acute bridge implantation and chronic cell transplantation to spare tissue, promote regeneration, and maximize the function of new axonal connections.

Low-Dose LPS Modulates Microglia/Macrophages Phenotypic Transformation to Amplify Rehabilitation Effects in Chronic Spinal Cord Injured (CSCI) Mice.

Spinal cord injury (SCI) results in stalled motor function recovery under the chronic phase. One of the reasons due to the presence of ongoing inflammation. Therefore, regulating the status of immune cells may help reopen the window for neural repair, which represents a potential therapeutic target. In this study, we aimed to investigate whether this could be achieved in mice with cervical 5 crush CSCI (4W) by utilizing a concentration of 0.5mg/kg of lipopolysaccharide (LPS) to stimulate microglia/macrophages. Additionally, the mice underwent rehabilitation training for another 6 weeks. Our results showed that systemic injection of LPS enhanced the effects of forelimb rehabilitation training, as evaluated through single pellet grasping (SPG). Electrophysiological studies revealed the restoration of cortical drive to the injured side's forelimb muscles in the training combined with LPS group. Tract tracing studies demonstrated the reconstruction of cortical innervation to the cervical spinal cord. Furthermore, the levels of pro-inflammatory phenotype markers, such as inducible nitric oxide synthase (INOS) and CD68, decreased, while the expression of anti-inflammatory phenotype markers, including arginase 1 (ARG-1) and CD206, increased. Importantly, this phenotypic switch in microglia/macrophages was accompanied by an increase in phagocytic activity markers as indicated by BODIPY + IBA1 + staining. Collectively, our data suggests that low-dose LPS improves the effects of rehabilitation training by regulating the phenotypic transformation of microglia/macrophages in CSCI.This study provides a fresh perspective and intervention direction for the clinical treatment of chronic spinal cord injuries.

Trans-spinal magnetic stimulation induces co-activation of the diaphragm and biceps in healthy subjects.

The present study was designed to examine the effect of trans-spinal magnetic stimulation on bilateral respiratory and forelimb muscles in healthy subjects. Two wings of a figure-of-eight magnetic coil were placed on the dorsal vertebrae, from the fifth cervical to the second thoracic dorsal vertebra with a center at the seventh cervical vertebra. The surface electromyograms of bilateral diaphragm and biceps were recorded in response to trans-spinal magnetic stimulation with 20%-100% maximum output of the stimulatory device in male (n = 12) and female participants (n = 8). Trans-spinal magnetic stimulation can induce a co-activation of bilateral diaphragm and biceps when the stimulation intensity is above 60%. The onset latency was comparable between the left and right sides of the muscles, suggesting bilateral muscles could be simultaneously activated by trans-spinal magnetic stimulation. In addition, the intensity-response curve of the biceps was shifted upward compared with that of the diaphragm in males, indicating that the responsiveness of the biceps was greater than that of the diaphragm. This study demonstrated the feasibility of utilizing trans-spinal magnetic stimulation to co-activate the bilateral diaphragm and biceps. We proposed that this stimulatory configuration can be an efficient approach to activate both respiratory and forelimb muscles.

Forelimb muscle activation patterns in American alligators: Insights into the evolution of limb posture and powered flight in archosaurs.

The evolution of archosaurs provides an important context for understanding the mechanisms behind major functional transformations in vertebrates, such as shifts from sprawling to erect limb posture and the acquisition of powered flight. While comparative anatomy and ichnology of extinct archosaurs have offered insights into musculoskeletal and gait changes associated with locomotor transitions, reconstructing the evolution of motor control requires data from extant species. However, the scarcity of electromyography (EMG) data from the forelimb, especially of crocodylians, has hindered understanding of neuromuscular evolution in archosaurs. Here, we present EMG data for nine forelimb muscles from American alligators during terrestrial locomotion. Our aim was to investigate the modulation of motor control across different limb postures and examine variations in motor control across phylogeny and locomotor modes. Among the nine muscles examined, m. pectoralis, the largest forelimb muscle and primary shoulder adductor, exhibited significantly smaller mean EMG amplitudes for steps in which the shoulder was more adducted (i.e., upright). This suggests that using a more adducted limb posture helps to reduce forelimb muscle force and work during stance. As larger alligators use a more adducted shoulder and hip posture, the sprawling to erect postural transition that occurred in the Triassic could be either the cause or consequence of the evolution of larger body size in archosaurs. Comparisons of EMG burst phases among tetrapods revealed that a bird and turtle, which have experienced major musculoskeletal transformations, displayed distinctive burst phases in comparison to those from an alligator and lizard. These results support the notion that major shifts in body plan and locomotor modes among sauropsid lineages were associated with significant changes in muscle activation patterns.

Frequency Specific Optogenetic Stimulation of the Locus Coeruleus Induces Task-Relevant Plasticity in the Motor Cortex.

The locus ceruleus (LC) is the primary source of neocortical noradrenaline, which is known to be involved in diverse brain functions including sensory perception, attention, and learning. Previous studies have shown that LC stimulation paired with sensory experience can induce task-dependent plasticity in the sensory neocortex and in the hippocampus. However, it remains unknown whether LC activation similarly impacts neural representations in the agranular motor cortical regions that are responsible for movement planning and production. In this study, we test whether optogenetic stimulation of the LC paired with motor performance is sufficient to induce task-relevant plasticity in the somatotopic cortical motor map. Male and female TH-Cre + rats were trained on a skilled reaching lever-pressing task emphasizing the use of the proximal forelimb musculature, and a viral approach was used to selectively express ChR2 in noradrenergic LC neurons. Once animals reached criterial behavioral performance, they received five training sessions in which correct task performance was paired with optogenetic stimulation of the LC delivered at 3, 10, or 30 Hz. After the last stimulation session, motor cortical mapping was performed using intracortical microstimulation. Our results show that lever pressing paired with LC stimulation at 10 Hz, but not at 3 or 30 Hz, drove the expansion of the motor map representation of the task-relevant proximal FL musculature. These findings demonstrate that phasic, training-paired activation of the LC is sufficient to induce experience-dependent plasticity in the agranular motor cortex and that this LC-driven plasticity is highly dependent on the temporal dynamics of LC activation.

Comorbidity of cardiorespiratory and locomotor dysfunction following cervical spinal cord injury in the rat.

Cervical spinal cord injury interrupts supraspinal pathways innervating thoracic sympathetic preganglionic neurons and results in cardiovascular dysfunction. Both respiratory and locomotor functions were also impaired due to damages of motoneuron pools controlling respiratory and forelimb muscles, respectively. However, no study has investigated autonomic and somatic motor functions in the same animal model. The present study aimed to establish a cervical spinal cord injury model to evaluate cardiorespiratory response and locomotor activity in unanesthetized rats. Cardiovascular response and respiratory behavior following laminectomy or cervical spinal contusion were measured using noninvasive blood pressure analyzer and plethysmography systems, respectively. Locomotor activity was evaluated by an open-field test and a locomotor rating scale. The results demonstrated that mean arterial blood pressure and heart rate were significantly reduced in contused rats compared with uninjured rats at the acute injured stage. Tidal volume was also significantly reduced during the acute and subchronic stages. Moreover, locomotor function was severely impaired, evidenced by decreasing moving ability and locomotor rating scores from the acute to chronic injured stages. Retrograde neurotracer results revealed that cervical spinal cord injury caused a reduction in number of phrenic and triceps motoneurons. Immunofluorescence staining revealed a significant attenuation of serotonergic, noradrenergic, glutamatergic, and GABAergic fibers innervating the thoracic sympathetic preganglionic neurons in chronically contused rats. These results revealed the pathological mechanism underlying the comorbidity of cardiorespiratory and locomotor dysfunction following cervical spinal cord injury. We proposed that this animal model can be used to evaluate the therapeutic efficacy of potential strategies to improve different physiological functions.NEW & NOTEWORTHY The present study establishes a preclinical rodent model to comprehensively investigate physiological functions under unanesthetized condition following cervical spinal cord contusion. The results demonstrated that cervical spinal cord contusion is associated with impairments in cardiovascular, respiratory, and locomotor function. Respiratory and forelimb motoneurons and neurochemical innervations of sympathetic preganglionic neurons were damaged following injury. This animal model can be used to evaluate the therapeutic efficacy of potential strategies to improve different physiological functions.