Striatal Dopamine Contributions to Skilled Motor Learning.

Coordinated multijoint limb and digit movements-"manual dexterity"-underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinson's disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that corticostriatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release in both male and female mice as they learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In the dorsolateral striatum, dopamine dynamics are faster than in the dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of the striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.

Skilled reaching test for shoulder function assessment in a rat model of rotator cuff tear: a pilot study.

BACKGROUND: Functional assessments are crucial to evaluate treatment outcomes in clinical and animal studies on rotator cuff injuries. While gait analysis is commonly used to assess animal models of rotator cuff tears, it is less relevant for human patients as the human shoulder is typically assessed in a non-weight-bearing condition. The present study introduces the skilled reaching test as a shoulder functional assessment tool for rats, which allows for evaluation without weight bearing. METHODS: In the control group, 8 male Sprague-Dawley rats received rotator cuff tear surgery without repair. In the rotator cuff repair group, 20 rats received rotator cuff repair at 4 weeks post rotator cuff tear. For the skilled reaching test, rats were trained to extend their forelimbs to fetch food pellets, and the number of trials, number of attempts and the success rate were recorded. The gait analysis and skilled reaching test were performed at baseline, 4 weeks post-tear, 1, 2, 4, and 8 weeks post-repair. The repeated measures analysis of variance was used to evaluate the effects of time on the shoulder function. The significance level was set at 0.05. RESULTS: The skilled reaching test required 216 h to conduct, while the gait analysis took 44 h. In the rotator cuff repair group, gait performance significantly deteriorated at 1 week post-repair and restored to 4 weeks post-tear levels at 4 weeks post-repair. Regarding the skilled reaching test, the number of attempts, number of trials and the success rate decreased at 1 week post-repair. Subsequently, there was a brief rebound in performance observed at 2 weeks post-repair, followed by a continued decline in the number of attempts and trials. By 8 weeks post-repair, only the success rate had restored to levels similar to those observed at 4 weeks post-tear. CONCLUSION: The skilled reaching test can detect functional deficiencies following rotator cuff tear and repair, while it requires high time and labour costs.

EphA4 Is Required for Neural Circuits Controlling Skilled Reaching.

Skilled forelimb movements are initiated by feedforward motor commands conveyed by supraspinal motor pathways. The accuracy of reaching and grasping relies on internal feedback pathways that update ongoing motor commands. In mice lacking the axon guidance molecule EphA4, axonal misrouting of the corticospinal tract and spinal interneurons is manifested, leading to a hopping gait in hindlimbs. Moreover, mice with a conditional forebrain deletion of EphA4, display forelimb hopping in adaptive locomotion and exploratory reaching movements. However, it remains unclear how loss of EphA4 signaling disrupts function of forelimb motor circuit and skilled reaching and grasping movements. Here we investigated how neural circuits controlling skilled reaching were affected by the loss of EphA4. Both male and female C57BL/6 wild-type, heterozygous EphA4+/-, and homozygous EphA4-/- mice were used in behavioral and in vivo electrophysiological investigations. We found that EphA4 knock-out (-/-) mice displayed impaired goal-directed reaching movements. In vivo intracellular recordings from forelimb motor neurons demonstrated increased corticoreticulospinal excitation, decreased direct reticulospinal excitation, and reduced direct propriospinal excitation in EphA4 knock-out mice. Cerebellar surface recordings showed a functional perturbation of the lateral reticular nucleus-cerebellum internal feedback pathway in EphA4 knock-out mice. Together, our findings provide in vivo evidence at the circuit level that loss of EphA4 disrupts the function of both feedforward and feedback motor pathways, resulting in deficits in skilled reaching.SIGNIFICANCE STATEMENT The central advances of this study are the demonstration that null mutation in the axon guidance molecule EphA4 gene impairs the ability of mice to perform skilled reaching, and identification of how these behavioral deficits correlates with discrete neurophysiological changes in central motor pathways involved in the control of reaching. Our findings provide in vivo evidence at the circuit level that loss of EphA4 disrupts both feedforward and feedback motor pathways, resulting in deficits in skilled reaching. This analysis of motor circuit function may help to understand the pathophysiological mechanisms underlying movement disorders in humans.

Changes in reach-to-grasp behaviour over the course of training in rats.

One complex task involving sequence of movements and movement refinement in the rat is the single-pellet reaching task, comprising orientation, transport and withdrawal in sequence. In turn, orientation comprises front wall detection, slot localization and nose poke until reach start. Video recordings of a rat in the reaching box highlighted three stages of temporal training: start of training (ST), forepaw dominance appearance (D) and fully trained (T). Regarding orientation, ST versus D and T presented a significant smaller frequency of approach to the front wall and a significant higher number of whisker cycles and nose touches during slot localization, involving a significant longer Orientation. At the ST stage, 44% of the trials were interrupted after nose poke, and poke took place at significant higher level from the shelf. The shelf was identified only when short whiskers contacted it, but the tongue and both forepaws were used without distinction to reach and grasp the pellet until a forepaw emerged as dominant at D stage. Regarding the temporal features of transport and withdrawal, comparing the D versus T stage revealed a significant longer duration. Finally, successes were significantly higher in T respect to D, meaning that after dominance emergence, more training was still necessary to improve reaching/grasping performance. This study provides evidence that, during training, the rats develop a strategy to obtain the pellets and then refine their movement pattern.

An assessment of the functional effects of amphetamine-induced dendritic changes in the nucleus accumbens, medial prefrontal cortex, and hippocampus on different types of learning and memory function.

The present experiments investigated the effects of repeated amphetamine exposure on neural networks mediating different forms of learning and memory. Different components of these networks were assessed using various functional assays. The hypothesis was that abnormal dendritic changes in nucleus accumbens, medial prefrontal cortex, and hippocampus mediated by repeated amphetamine exposure would produce impairments on forms of learning and memory dependent on neural circuits relying on these brain systems, and have little or no effect on other forms of learning not dependent on these networks. Surprisingly, the results showed that many of the dendritic changes normally found in the nucleus accumbens, prefrontal cortex, and hippocampus following repeated amphetamine exposure were reversed back to control levels following extensive multi-domain cognitive training. Learning and memory functions associated with different neural networks also appeared normal except in one case. A neural network that includes, but is not limited to, the basolateral amygdala and nucleus accumbens was dysfunctional in rats repeatedly exposed to amphetamine despite the reversal of the majority of dendritic changes in the nucleus accumbens following cognitive training. Importantly, an increase in spine density that normally occurs in these brain regions following repeated amphetamine exposure remained following extensive cognitive training, particularly in the nucleus accumbens.

Altered Recruitment of Motor Cortex Neuronal Activity During the Grasping Phase of Skilled Reaching in a Chronic Rat Model of Unilateral Parkinsonism.

Parkinson's disease causes prominent difficulties in the generation and execution of voluntary limb movements, including regulation of distal muscles and coordination of proximal and distal movement components to achieve accurate grasping. Difficulties with manual dexterity have a major impact on activities of daily living. We used extracellular single neuron recordings to investigate the neural underpinnings of parkinsonian movement deficits in the motor cortex of chronic unilateral 6-hydroxydopamine lesion male rats performing a skilled reach-to-grasp task the. Both normal movements and parkinsonian deficits in this task have striking homology to human performance. In lesioned animals there were several differences in the activity of cortical neurons during reaches by the affected limb compared with control rats. These included an increase in proportions of neurons showing rate decreases, along with increased amplitude of their average rate-decrease response at specific times during the reach, suggesting a shift in the balance of net excitation and inhibition of cortical neurons; a significant increase in the duration of rate-increase responses, which could result from reduced coupling of cortical activity to specific movement components; and changes in the timing and incidence of neurons with pure rate-increase or biphasic responses, particularly at the end of reach when grasping would normally be occurring. The changes in cortical activity may account for the deficits that occur in skilled distal motor control following dopamine depletion, and highlight the need for treatment strategies targeted toward modulating cortical mechanisms for fine distal motor control in patients.SIGNIFICANCE STATEMENT We show for the first time in a chronic lesion rat model of Parkinson's disease movement deficits that there are specific changes in motor cortex neuron activity associated with the grasping phase of a skilled motor task. Such changes provide a possible mechanism underpinning the problems with manual dexterity seen in Parkinson's patients and highlight the need for treatment strategies targeted toward distal motor control.

Coordinated Plasticity of Synapses and Astrocytes Underlies Practice-Driven Functional Vicariation in Peri-Infarct Motor Cortex.

Motor rehabilitative training after stroke can improve motor function and promote topographical reorganization of remaining motor cortical movement representations, but this reorganization follows behavioral improvements. A more detailed understanding of the neural bases of rehabilitation efficacy is needed to inform therapeutic efforts to improve it. Using a rat model of upper extremity impairments after ischemic stroke, we examined effects of motor rehabilitative training at the ultrastructural level in peri-infarct motor cortex. Extensive training in a skilled reaching task promoted improved performance and recovery of more normal movements. This was linked with greater axodendritic synapse density and ultrastructural characteristics of enhanced synaptic efficacy that were coordinated with changes in perisynaptic astrocytic processes in the border region between head and forelimb areas of peri-infarct motor cortex. Disrupting synapses and motor maps by infusions of anisomycin (ANI) into anatomically reorganized motor, but not posterior parietal, cortex eliminated behavioral gains from rehabilitative training. In contrast, ANI infusion in the equivalent cortical region of intact animals had no effect on reaching skills. These results suggest that rehabilitative training efficacy for improving manual skills is mediated by synaptic plasticity in a region of motor cortex that, before lesions, is not essential for manual skills, but becomes so as a result of the training. These findings support that experience-driven synaptic structural reorganization underlies functional vicariation in residual motor cortex after motor cortical infarcts.SIGNIFICANCE STATEMENT Stroke is a leading cause of long-term disability. Motor rehabilitation, the main treatment for physical disability, is of variable efficacy. A better understanding of neural mechanisms underlying effective motor rehabilitation would inform strategies for improving it. Here, we reveal synaptic underpinnings of effective motor rehabilitation. Rehabilitative training improved manual skill in the paretic forelimb and induced the formation of special synapse subtypes in coordination with structural changes in astrocytes, a glial cell that influences neural communication. These changes were found in a region that is nonessential for manual skill in intact animals, but came to mediate this skill due to training after stroke. Therefore, motor rehabilitation efficacy depends on synaptic changes that enable remaining brain regions to assume new functions.

Axotomized Corticospinal Neurons Increase Supra-Lesional Innervation and Remain Crucial for Skilled Reaching after Bilateral Pyramidotomy.

Skilled upper limb function heavily depends on the corticospinal tract. After bilateral lesions to this tract, motor control is disrupted but can be partially substituted by other motor systems to allow functional recovery. However, the remaining roles of motor cortex and especially of axotomized corticospinal neurons (CSNs) are not well understood. Using the single pellet retrieval task in adult rats, we induced significant recovery of skilled reaching after bilateral pyramidotomy by rehabilitative reaching training, and show that reach-related motor cortex activity, recorded in layer V, topographically reappeared shortly after axotomy. Using a chemogenetic neuronal silencing technique, we found that axotomized CSNs retained a crucial role for the recovered pellet retrieval success. The axotomized CSNs sprouted extensively in the red nucleus supplying new innervation to its magnocellular and parvocellular parts. Specific silencing of the rubrospinal tract (RST) also strongly abolished the recovered pellet retrieval success, suggesting a role of this cervically projecting nucleus in relaying cortical motor control. In summary, our results show that after bilateral corticospinal axotomy, motor cortex still actively engages in forelimb motor control and axotomized CSNs are crucially involved in the recovered reaching movement, potentially by relaying motor control via the RST.

Enhancing Spinal Plasticity Amplifies the Benefits of Rehabilitative Training and Improves Recovery from Stroke.

The limited recovery that occurs following stroke happens almost entirely in the first weeks postinjury. Moreover, the efficacy of rehabilitative training is limited beyond this narrow time frame. Sprouting of spared corticospinal tract axons in the contralesional spinal cord makes a significant contribution to sensorimotor recovery, but this structural plasticity is also limited to the first few weeks after stroke. Here, we tested the hypothesis that inducing plasticity in the spinal cord during chronic stroke could improve recovery from persistent sensorimotor impairment. We potentiated spinal plasticity during chronic stroke, weeks after the initial ischemic injury, in male Sprague-Dawley rats via intraspinal injections of chondroitinase ABC. Our data show that chondroitinase injections into the contralesional gray matter of the cervical spinal cord administered 28 d after stroke induced significant sprouting of corticospinal axons originating in the peri-infarct cortex. Chondroitinase ABC injection during chronic stroke without additional training resulted in moderate improvements of sensorimotor deficits. Importantly, this therapy dramatically potentiated the efficacy of rehabilitative training delivered during chronic stroke in a skilled forelimb reaching task. These novel data suggest that spinal therapy during chronic stroke can amplify the benefits of delayed rehabilitative training with the potential to reduce permanent disability in stroke survivors.SIGNIFICANCE STATEMENT The brain and spinal cord undergo adaptive rewiring ("plasticity") following stroke. This plasticity allows for partial functional recovery from stroke induced sensorimotor impairments. However, the plasticity that underlies recovery occurs predominantly in the first weeks following stroke, and most stroke survivors are left with permanent disability even after rehabilitation. Using animal models, our data show that removal of plasticity-inhibiting signals in the spinal cord (via intraspinal injections of the enzyme chondroitinase ABC) augments rewiring of circuits connecting the brain to the spinal cord, even weeks after stroke. Moreover, this plasticity can be harnessed by rehabilitative training to significantly promote sensorimotor recovery. Thus, intraspinal therapy may augment rehabilitative training and improve recovery even in individuals living with chronic disability due to stroke.

Reduction of the foreign body response and neuroprotection by apyrase and minocycline in chronic cannula implantation in the rat brain.

Implantation of electrodes or cannulae into the brain is accompanied by a tissue response referred to as foreign body response. Adenosine triphosphate (ATP) is one of the signalling molecules released by injured cells which mediate the chemoattraction of microglial cells. The constitutive release of pro-inflammatory and cytotoxic substances by microglial cells in chronic implants exacerbates neuronal cell death and the immune response. This study aimed to interfere with the initial events of the foreign body response in order to mitigate neurotoxicity and inflammation. For this purpose, the ATP-hydrolysing enzyme apyrase and the antibiotic minocycline with a broad range of anti-inflammatory, anti-apoptotic and glutamate-antagonist properties were locally infused during cannula implantation in the caudal forelimb area of the motor cortex in Lister Hooded rats. The rats' motor performance was assessed in a skilled reaching task and the distribution of neurons and glial cells in the vicinity of the implant was examined 2 and 6 weeks post-implantation. Apyrase as well as minocycline increased the number of surviving neurons and reduced microglial activation. Moreover, minocycline improved the motor performance and, additionally, caused a temporary reduction in astrogliosis, suggesting it as a possible therapeutic candidate to improve the biocompatibility of chronic brain implants.

Perilesional treatment with chondroitinase ABC and motor training promote functional recovery after stroke in rats.

Ischemic stroke insults may lead to chronic functional limitations that adversely affect patient movements. Partial motor recovery is thought to be sustained by neuronal plasticity, particularly in areas close to the lesion site. It is still unknown if treatments acting exclusively on cortical plasticity of perilesional areas could result in behavioral amelioration. We tested whether enhancing plasticity in the ipsilesional cortex using local injections of chondroitinase ABC (ChABC) could promote recovery of skilled motor function in a focal cortical ischemia of forelimb motor cortex in rats. Using the skilled reaching test, we found that acute and delayed ChABC treatment induced recovery of impaired motor skills in treated rats. vGLUT1, vGLUT2, and vGAT staining indicated that functional recovery after acute ChABC treatment was associated with local plastic modification of the excitatory cortical circuitry positive for VGLUT2. ChABC effects on vGLUT2 staining were present only in rats undergoing behavioral training. Thus, the combination of treatments targeting the CSPG component of the extracellular matrix in perilesional areas and rehabilitation could be sufficient to enhance functional recovery from a focal stroke.

Biphasic plasticity of dendritic fields in layer V motor neurons in response to motor learning.

Motor learning is associated with plastic reorganization of neural networks in primary motor cortex (M1) that advances through stages. An initial increment in spine formation is followed by pruning and maturation one week after training ended. A similar biphasic course was described for the size of the forelimb representation in M1. This study investigates the evolution of the dendritic architecture in response to motor skill training using Golgy-Cox silver impregnation in rat M1. After learning of a unilateral forelimb-reaching task to plateau performance, an increase in dendritic length of layer V pyramidal neurons (i.e. motor neurons) was observed that peaked one month after training ended. This increment in dendritic length reflected an expansion of the distal dendritic compartment. After one month dendritic arborization shrinks even though animals retain task performance. This pattern of evolution was observed for apical and basal dendrites alike - although the increase in dendritic length occurs faster in basal than in apical dendrites. Dendritic plasticity in response to motor training follows a biphasic course with initial expansion and subsequent shrinkage. This evolution takes fourth as long as the biphasic reorganization of spines or motor representations.

The effect of a skilled reaching task on hippocampal plasticity after intracerebral hemorrhage in adult rats.

[Purpose] The primary objective of this study was to assess the effects of a skilled reaching task on cognition, as indexed by the pattern of GAP-43 expression in the hippocampus, following intracerebral hemorrhage (ICH) in rats (when the hippocampus plays a critical role in spatial memory and learning). [Subjects and Methods] The model of ICH used in the present study involved intrastriatal injection of collagenase. Sixty male Sprague-Dawley rats (aged 12 weeks) were randomly assigned to either a control (n = 30; CON) or skilled reaching training group (n = 30; SRT). The SRT group were trained 5 days per week for 4 weeks following ICH. Animals were sacrificed 1, 2, or 4 weeks after ICH. Western blot analysis was used to evaluate GAP-43 expression. [Results] GAP-43 expression was increased in the SRT group, in accordance with greater elapsed time, but decreased in the CON group. At 1 week post injury, there were no significant differences between the CON and SRT groups. However, there were significant differences at both 2 and 4 weeks. [Conclusion] The present findings suggest that increased GAP-43 expression in the hippocampus following skilled reaching training may result in enhanced cognition and neural plasticity following ICH.

Dopamine receptors of the rodent fastigial nucleus support skilled reaching for goal-directed action.

The dopaminergic (DA) system regulates both motor function, and learning and memory. The cerebellum supports motor control and the acquisition of procedural memories, including goal-directed behavior, and is subjected to DA control. Its fastigial nucleus (FN) controls and interprets body motion through space. The expression of dopamine receptors has been reported in the deep cerebellar nuclei of mice. However, the presence of dopamine D1-like (D1R) and D2-like (D2R) receptors in the rat FN has not yet been verified. In this study, we first confirmed that DA receptors are expressed in the FN of adult rats and then targeted these receptors to explore to what extent the FN modulates goal-directed behavior. Immunohistochemical assessment revealed expression of both D1R and D2R receptors in the FN, whereby the medial lateral FN exhibited higher receptor expression compared to the other FN subfields. Bilateral treatment of the FN with a D1R antagonist, prior to a goal-directed pellet-reaching task, significantly impaired task acquisition and decreased task engagement. D2R antagonism only reduced late performance post-acquisition. Once task acquisition had occurred, D1R antagonism had no effect on successful reaching, although it significantly decreased reaching speed, task engagement, and promoted errors. Motor coordination and ambulation were, however, unaffected as neither D1R nor D2R antagonism altered rotarod latencies or distance and velocity in an open field. Taken together, these results not only reveal a novel role for the FN in goal-directed skilled reaching, but also show that D1R expressed in FN regulate this process by modulating motivation for action.

Developmental coordination disorder: What can we learn from RI mice using motor learning tasks and QTL analysis.

Developmental Coordination Disorder (DCD) is a neurodevelopmental disorder of unknown etiology that affects one in 20 children. There is an indication that DCD has an underlying genetic component due to its high heritability. Therefore, we explored the use of a recombinant inbred family of mice known as the BXD panel to understand the genetic basis of complex traits (i.e., motor learning) through identification of quantitative trait loci (QTLs). The overall aim of this study was to utilize the QTL approach to evaluate the genome-to-phenome correlation in BXD strains of mice in order to better understand the human presentation of DCD. Results of this current study confirm differences in motor learning in selected BXD strains and strains with altered cerebellar volume. Five strains - BXD15, BXD27, BXD28, BXD75, and BXD86 - exhibited the most DCD-like phenotype when compared with other BXD strains of interest. Results indicate that BXD15 and BXD75 struggled primarily with gross motor skills, BXD28 primarily had difficulties with fine motor skills, and BXD27 and BXD86 strains struggled with both fine and gross motor skills. The functional roles of genes within significant QTLs were assessed in relation to DCD-like behavior. Only Rab3a (Ras-related protein Rab-3A) emerged as a high likelihood candidate gene for the horizontal ladder rung task. This gene is associated with brain and skeletal muscle development, but lacked nonsynonymous polymorphisms. This study along with Gill et al. (same issue) is the first studies to specifically examine the genetic linkage of DCD using BXD strains of mice.

Intersectional genetic tools to study skilled reaching in mice.

Reaching to grasp is an evolutionarily conserved behavior and a crucial part of the motor repertoire in mammals. As it is studied in the laboratory, reaching has become the prototypical example of dexterous forelimb movements, illuminating key principles of motor control throughout the spinal cord, brain, and peripheral nervous system. Here, we (1) review the motor elements or phases that comprise the reach, grasp, and retract movements of reaching behavior, (2) highlight the role of intersectional genetic tools in linking these movements to their neuronal substrates, (3) describe spinal cord cell types and their roles in skilled reaching, and (4) how descending pathways from the brain and the sensory systems contribute to skilled reaching. We emphasize that genetic perturbation experiments can pin-point the neuronal substrates of specific phases of reaching behavior.

Evolution of Gross Forelimb and Fine Digit Kinematics during Skilled Reaching Acquisition in Rats.

The ability to learn dexterous motor skills is a fundamental aspect of human behavior. However, the underlying neural circuit mechanisms for dexterous skill learning are unclear. Advancing our understanding of motor skill learning requires the integration of modern neuroscientific techniques with a rigorously characterized dexterous task. The development of automated rodent skilled reaching with paw tracking allows detailed analysis of how reach-to-grasp kinematics evolve during learning. We assessed how both "gross" forelimb and "fine" digit kinematics changed as rats learned skilled reaching. Rats whose success rates increased (learners) consistently reduced the variability in their reach trajectories. Refinement of fine digit control generally continued after consistency in gross hand transport to the pellet plateaued. Interestingly, most rats whose success rates did not increase (non-learners) also converged on consistent reach kinematics. Some non-learners, however, maintained substantial variability in hand and digit trajectories throughout training. These results suggest that gross and fine motor components of dexterous skill are, on average, learned over different timescales. Nonetheless, there is significant intersubject variability in learning rates as assessed by both reaching success and consistency of reach kinematics.

Translational Value of Skilled Reaching Assessment in Clinical and Preclinical Studies on Motor Recovery After Stroke.

BACKGROUND: Assessment of skilled reaching enables extensive analysis of upper limb function in clinical and preclinical studies on poststroke outcome. However, translational research if often limited by lack of correspondence between tests of human and rodent motor function. OBJECTIVES: To determine (1) the translational value of skilled reaching performance for preclinical research by comparing the behavioral recovery profiles of skilled reaching characteristics between humans and rats recovering from stroke and (2) the relationship between skilled reaching performance and commonly used clinical outcome measures after stroke. METHODS: Twelve patients with ischemic or hemorrhagic stroke and 17 rats with photothrombotic stroke underwent an equivalent skilled reaching test at different time points, representing early to late subacute stages poststroke. Success scores and a movement element rating scale were used to measure the skilled reaching performance. The Fugl-Meyer Upper Extremity (FM-UE) assessment and the Action Research Arm Test (ARAT) were used as clinical outcome measures. RESULTS: Both species had muscle flaccidity at the early subacute stage after stroke and showed motor recovery following a proximal-distal principle toward the early subacute stage, albeit for rats within a shorter time course. Human skilled reaching scores and FM-UE and ARAT scores in the first 3 months poststroke were significantly correlated (P < .05). CONCLUSIONS: Our study demonstrates that poststroke changes in skilled reaching performance are highly similar between rats and humans and correspond with standard clinical outcome measures. Skilled reaching testing therefore offers an effective and highly translational means for assessment of motor recovery in experimental and clinical stroke settings.

Cholinergic upregulation by optogenetic stimulation of nucleus basalis after photothrombotic stroke in forelimb somatosensory cortex improves endpoint and motor but not sensory control of skilled reaching in mice.

A network of cholinergic neurons in the basal forebrain innerve the forebrain and are proposed to contribute to a variety of functions including cortical plasticity, attention, and sensorimotor behavior. This study examined the contribution of the nucleus basalis cholinergic projection to the sensorimotor cortex on recovery on a skilled reach-to-eat task following photothrombotic stroke in the forelimb region of the somatosensory cortex. Mice were trained to perform a single pellet skilled reaching task and their pre and poststroke performance, from Day 4 to Day 28 poststroke, was assessed frame-by-frame by video analysis with endpoint, movement and sensorimotor integration measures. Somatosensory forelimb lesions produced impairments in endpoint and movement component measures of reaching and increased the incidence of fictive eating, a sensory impairment in mistaking a missed reach for a successful reach. Upregulated acetylcholine (ACh) release, as measured by local field potential recording, elicited via optogenetic stimulation of the nucleus basalis improved recovery of reaching and improved movement scores but did not affect sensorimotor integration impairment poststroke. The results show that the mouse cortical forelimb somatosensory region contributes to forelimb motor behavior and suggest that ACh upregulation could serve as an adjunct to behavioral therapy for acute treatment of stroke.

Precisely timed dopamine signals establish distinct kinematic representations of skilled movements.

Brain dopamine is critical for normal motor control, as evidenced by its importance in Parkinson Disease and related disorders. Current hypotheses are that dopamine influences motor control by 'invigorating' movements and regulating motor learning. Most evidence for these aspects of dopamine function comes from simple tasks (e.g. lever pressing). Therefore, the influence of dopamine on motor skills requiring multi-joint coordination is unknown. To determine the effects of precisely timed dopamine manipulations on the performance of a complex, finely coordinated dexterous skill, we optogenetically stimulated or inhibited midbrain dopamine neurons as rats performed a skilled reaching task. We found that reach kinematics and coordination between gross and fine movements progressively changed with repeated manipulations. However, once established, rats transitioned abruptly between aberrant and baseline reach kinematics in a dopamine-dependent manner. These results suggest that precisely timed dopamine signals have immediate and long-term influences on motor skill performance, distinct from simply 'invigorating' movement.