Comparative Enhancement of Motor Function and BDNF Expression Following Different Brain Stimulation Approaches in an Animal Model of Ischemic Stroke.

BACKGROUND: Combinatory intervention such as high-frequency (50-100 Hz) excitatory cortical stimulation (ECS) given concurrently with motor rehabilitative training (RT) improves forelimb function, except in severely impaired animals after stroke. Clinical studies suggest that low-frequency (≤1 Hz) inhibitory cortical stimulation (ICS) may provide an alternative approach to enhance recovery. Currently, the molecular mediators of CS-induced behavioral effects are unknown. Brain-derived neurotrophic factor (BDNF) has been associated with improved recovery and neural remodeling after stroke and thus may be involved in CS-induced behavioral recovery. OBJECTIVE: To investigate whether inhibitory stimulation during RT improves functional recovery of severely impaired rats, following focal cortical ischemia and if this recovery alters BDNF expression (study 1) and depends on BDNF binding to TrkB receptors (study 2). METHODS: Rats underwent ECS + RT, ICS + RT, or noCS + RT treatment daily for 3 weeks following a unilateral ischemic lesion to the motor cortex. Electrode placement for stimulation was either placed ipsilateral (ECS) or contralateral (ICS) to the lesion. After treatment, BDNF expression was measured in cortical tissue samples (study 1). In study 2, the TrkB inhibitor, ANA-12, was injected prior to treatment daily for 21 days. RESULTS: ICS + RT treatment significantly improved impaired forelimb recovery compared with ECS + RT and noCS + RT treatment. CONCLUSION: ICS given concurrently with rehabilitation improves motor recovery in severely impaired animals, and alters cortical BDNF expression; nevertheless, ICS-mediated improvements are not dependent on BDNF binding to TrkB. Conversely, inhibition of TrkB receptors does disrupt motor recovery in ECS + RT treated animals.

Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection.

Because complement activation in the subacute or chronic phase after stroke was recently shown to stimulate neural plasticity, we investigated how complement activation and complement inhibition in the acute phase after murine stroke interacts with subsequent rehabilitation therapy to modulate neuroinflammation and neural remodeling. We additionally investigated how complement and complement inhibition interacts with tissue plasminogen activator (tPA), the other standard of care therapy for stroke, and a U.S. Food and Drug Administration preclinical requirement for translation of an experimental stroke therapy. CR2fH, an injury site-targeted inhibitor of the alternative complement pathway, significantly reduced infarct volume, hemorrhagic transformation, and mortality and significantly improved long-term motor and cognitive performance when administered 1.5 or 24 h after middle cerebral artery occlusion. CR2fH interrupted a poststroke inflammatory process and significantly reduced inflammatory cytokine release, microglial activation, and astrocytosis. Rehabilitation alone showed mild anti-inflammatory effects, including reduced complement activation, but only improved cognitive recovery. CR2fH combined with rehabilitation significantly potentiated cognitive and motor recovery compared with either intervention alone and was associated with higher growth factor release and enhanced rehabilitation-induced neuroblast migration and axonal remodeling. Similar outcomes were seen in adult, aged, and female mice. Using a microembolic model, CR2fH administered in combination with acute tPA therapy improved overall survival and enhanced the neuroprotective effects of tPA, extending the treatment window for tPA therapy. A human counterpart of CR2fH has been shown to be safe and nonimmunogenic in humans and we have demonstrated robust deposition of C3d, the CR2fH targeting epitope, in ischemic human brains after stroke.SIGNIFICANCE STATEMENT Complement inhibition is a potential therapeutic approach for stroke, but it is not known how complement inhibition would interact with current standards of care. We show that, after murine ischemic stroke, rehabilitation alone induced mild anti-inflammatory effects and improved cognitive, but not motor recovery. However, brain-targeted and specific inhibition of the alternative complement pathway, when combined with rehabilitation, significantly potentiated cognitive and motor recovery compared with either intervention alone via mechanisms involving neuroregeneration and enhanced brain remodeling. Further, inhibiting the alternative pathway of complement significantly enhanced the neuroprotective effects of thrombolytic therapy and markedly expanded the therapeutic window for thrombolytic therapy.

Characterizing the corticomotor connectivity of the bilateral ankle muscles during rest and isometric contraction in healthy adults.

The investigation of the corticomotor connectivity (CMC) to leg muscles is an emerging research area, and establishing reliability of measures is critical. This study examined the measurement reliability and the differences between bilateral soleus (SOL) and tibialis anterior (TA) CMC in 21 neurologically intact adults. Using single pulse transcranial magnetic stimulation (TMS), each muscle's CMC was assessed twice (7 ±â€¯2 days apart) during rest and active conditions. CMC was quantified using a standardized battery of eight measures (4/condition): motor threshold during resting (RMT), motor evoked potential amplitude and latency (raw and normalized to height) in both conditions, contralateral silent period (CSP) during active. Using two reliability metrics (intraclass correlation coefficient and coefficient of variation of method error; good reliability: ≥0.75 and ≤15, respectively) and repeated-measures ANOVA, we investigated the reliability and Muscle X Body Side interaction. For both muscles, RMT, resting raw and normalized latencies, and active raw latency demonstrated good reliability, while CSP had good reliability only for TA. Amplitude did not demonstrate good reliability for both muscles. SOL CMC was significantly different from TA CMC for all measures but CSP; body side had no significant effect. Therefore, only certain measures may reliably quantify SOL and TA CMC while different CMC (except CSP) between SOL and TA suggests dissimilar corticospinal drive to each muscle regardless of the side.

Sensitivity of diffusion MRI to perilesional reactive astrogliosis in focal ischemia.

Reactive astrogliosis is a response to injury in the central nervous system that plays an essential role in inflammation and tissue repair. It is characterized by hypertrophy of astrocytes, alterations in astrocyte gene expression and astrocyte proliferation. Reactive astrogliosis occurs in multiple neuropathologies, including stroke, traumatic brain injury and Alzheimer's disease, and it has been proposed as a possible source of the changes in diffusion magnetic resonance imaging (dMRI) metrics observed with these diseases. In this study, the sensitivity of dMRI to reactive astrogliosis was tested in an animal model of focal acute and subacute ischemia induced by the vasoconstricting peptide, endothelin-1. Reactive astrogliosis in perilesional cortex was quantified by calculating the astrocyte surface density as determined with a glial fibrillary acidic protein (GFAP) antibody, whereas perilesional diffusion changes were measured in vivo with diffusional kurtosis imaging. We found substantial changes in the surface density of GFAP-positive astrocyte processes and modest changes in dMRI metrics in the perilesional motor cortex following stroke. Although there are time point-specific correlations between dMRI and histological measures, there is no definitive evidence for a causal relationship.

Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits.

Regulation of the formation and rewiring of neural circuits by neuropeptides may require coordinated production of these signaling molecules and their receptors that may be established at the transcriptional level. Here, we address this hypothesis by comparing absolute expression levels of opioid peptides with their receptors, the largest neuropeptide family, and by characterizing coexpression (transcriptionally coordinated) patterns of these genes. We demonstrated that expression patterns of opioid genes highly correlate within and across functionally and anatomically different areas. Opioid peptide genes, compared with their receptor genes, are transcribed at much greater absolute levels, which suggests formation of a neuropeptide cloud that covers the receptor-expressed circuits. Surprisingly, we found that both expression levels and the proportion of opioid receptors are strongly lateralized in the spinal cord, interregional coexpression patterns are side specific, and intraregional coexpression profiles are affected differently by left- and right-side unilateral body injury. We propose that opioid genes are regulated as interconnected components of the same molecular system distributed between distinct anatomic regions. The striking feature of this system is its asymmetric coexpression patterns, which suggest side-specific regulation of selective neural circuits by opioid neurohormones.-Kononenko, O., Galatenko, V., Andersson, M., Bazov, I., Watanabe, H., Zhou, X. W., Iatsyshyna, A., Mityakina, I., Yakovleva, T., Sarkisyan, D., Ponomarev, I., Krishtal, O., Marklund, N., Tonevitsky, A., Adkins, D. L., Bakalkin, G. Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits.

Striatal Mitochondrial Disruption following Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) results in oxidative stress and calcium dysregulation in mitochondria. However, little work has examined perturbations of mitochondrial homeostasis in peri-injury tissue. We examined mitochondrial homeostasis after a unilateral controlled cortical impact over the sensorimotor cortex in adult male rats. There was a significant reduction in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) messenger RNA (mRNA) at post-injury days 3 and 6 and a transient reduction in mitochondrial DNA copy number at 3 days post-injury that recovered by 6 days in the ipsi-injury striatum. In ipsilateral cortex, PGC-1α mRNA was reduced only at 6 days post-injury. Additionally, expression of mitochondrial-encoded mRNAs, cytochrome c oxidase subunit 1 and NADH dehydrogenase subunit 1, was decreased at 3 and 6 days post-injury in ipsilesional striatum and at 6 days post-injury in ipsilesional cortex. There was no observable decrease in nuclear-encoded mRNAs mitochondrial transcription factor A or NADH dehydrogenase (ubiquinone) Fe-S protein 1. We detected an acute increase in superoxide dismutase 2 mRNA expression, as well as an induction of microRNA (miR)-21 and miR-155, which have been previously demonstrated to disrupt mitochondrial homeostasis. Behaviorally, rats with TBI exhibited marked error rates in contrainjury forelimb performance on the ladder test. These findings reveal that there may be differential susceptibilities of various peri-injury brain structures to mitochondrial dysfunction and associated behavioral deficits, and that molecular pathways demonstrated to interfere with mitochondrial homeostasis and function are activated subacutely post-TBI.

Disrupted mitochondrial genes and inflammation following stroke.

AIMS: Determine the subacute time course of mitochondria disruption, cell death, and inflammation in a rat model of unilateral motor cortical ischemic stroke. MAIN METHODS: Rats received unilateral ischemia of the motor cortex and were tested on behavioral tasks to determine impairments. Animals were euthanized at 24h, 72h and 144h and mRNA expression of key mitochondria proteins and indicators of inflammation, apoptosis and potential regenerative processes in ipsilesion cortex and striatum, using RT-qPCR. Mitochondrial proteins were examined at 144h using immunoblot analysis. KEY FINDINGS: Rats with stroke induced-behavioral deficits had sustained, 144h post-lesion, decreases in mitochondrial-encoded electron transport chain proteins NADH dehydrogenase subunit-1 and cytochrome c oxidase subunit-1 (mRNA and protein) and mitochondrial DNA content in perilesion motor and sensory cortex. Uncoupling-protein-2 gene expression, but not superoxide dismutase-2, remained elevated in ipsilateral cortex and striatum at this time. Cortical inflammatory cytokine, interleukin-6, was increased early and was followed by increased macrophage marker F4/80 after stroke. Cleaved caspase-3 activation was elevated in cortex and growth associated protein-43 was elevated in the cortex and striatum six days post-lesion. SIGNIFICANCE: We identified a relationship between three disrupted pathways, (1) sustained loss of mitochondrial proteins and mitochondrial DNA copy number in the cortex linked to decreased mitochondrial gene transcription; (2) early inflammatory response mediated by interleukin- 6 followed by macrophages; (3) apoptosis in conjunction with the activation of regenerative pathways. The stroke-induced spatial and temporal profiles lay the foundation to target pharmacological therapeutics to these three pathways.

Enhanced Motor Recovery After Stroke With Combined Cortical Stimulation and Rehabilitative Training Is Dependent on Infarct Location.

BACKGROUND: Cortical electrical stimulation of the motor cortex in combination with rehabilitative training (CS/RT) has been shown to enhance motor recovery in animal models of focal cortical stroke, yet in clinical trials, the effects are much less robust. The variability of stroke location in human patient populations that include both cortical and subcortical brain regions may contribute to the failure to find consistent effects clinically. OBJECTIVE: This study sought to determine whether infarct location influences the enhanced motor recovery previously observed in response to CS/RT. The efficacy of CS/RT to promote improvements in motor function was examined in 2 different rat models of stroke that varied the amount and location of cortical and subcortical damage. METHODS: Ischemic infarctions were induced by injecting the vasoconstricting peptide endothelin-1 either (1) onto the middle cerebral artery (MCA) producing damage to the frontal cortex and lateral striatum or (2) into a subcortical region producing damage to the posterior thalamus and internal capsule (subcortical capsular ischemic injury [SCII]). Daily CS/RT or RT alone was then given for 20 days, during which time performance on a skilled reaching task was assessed. RESULTS: Animals with MCA occlusion infarctions exhibited enhanced improvements on a skilled reaching task in response to CS/RT relative to RT alone. No such enhancement was observed in animals with SCII infarctions across the 20 days of treatment. CONCLUSIONS: The efficacy of CS for enhancing motor recovery after stroke may depend in part on the extent and location of the ischemic infarct.

Enduring Poststroke Motor Functional Improvements by a Well-Timed Combination of Motor Rehabilitative Training and Cortical Stimulation in Rats.

BACKGROUND: In animal stroke models, peri-infarct cortical stimulation (CS) combined with rehabilitative reach training (RT) enhances motor functional outcome and cortical reorganization, compared with RT alone. It was unknown whether the effects of CS + RT (a) persist long after treatment, (b) can be enhanced by forcing greater use of the paretic limb, and (C) vary with treatment onset time. OBJECTIVE: To test the endurance, time sensitivity, and the potential for augmentation by forced forelimb use of CS + RT treatment effects following ischemic stroke. METHODS: Adult rats that were proficient in skilled reaching received unilateral ischemic motor cortical lesions. RT was delivered for 3 weeks alone or concurrently with 100-Hz cathodal epidural CS, delivered at 50% of movement thresholds. In study 1, this treatment was initiated at 14 days postinfarct, with some subgroups receiving an overlapping period of continuous constraint of the nonparetic forelimb to force use of the paretic limb. The function of the paretic limb was assessed weekly for 9 to 10 months posttreatment. In study 2, rats underwent CS, RT, and the combination during the chronic postinfarct period. RESULTS: Early onset CS + RT resulted in greater functional improvements than RT alone. The CS-related gains persisted for 9 to 10 months posttreatment and were not significantly influenced by forced use of the paretic limb. When treatment onset was delayed until 3 months post-infarct, RT alone improved function, but CS + RT was no more effective than RT alone. CONCLUSION: CS can enhance the persistence, as well as the magnitude of RT-driven functional improvements, but its effectiveness in doing so may vary with time postinfarct.

Motor Cortex and Motor Cortical Interhemispheric Communication in Walking After Stroke: The Roles of Transcranial Magnetic Stimulation and Animal Models in Our Current and Future Understanding.

Despite the plethora of human neurophysiological research, the bilateral involvement of the leg motor cortical areas and their interhemispheric interaction during both normal and impaired human walking is poorly understood. Using transcranial magnetic stimulation (TMS), we have expanded our understanding of the role upper-extremity motor cortical areas play in normal movements and how stroke alters this role, and probed the efficacy of interventions to improve post-stroke arm function. However, similar investigations of the legs have lagged behind, in part, due to the anatomical difficulty in using TMS to stimulate the leg motor cortical areas. Additionally, leg movements are predominately bilaterally controlled and require interlimb coordination that may involve both hemispheres. The sensitive, but invasive, tools used in animal models of locomotion hold great potential for increasing our understanding of the bihemispheric motor cortical control of walking. In this review, we discuss 3 themes associated with the bihemispheric motor cortical control of walking after stroke: (a) what is known about the role of the bihemispheric motor cortical control in healthy and poststroke leg movements, (b) how the neural remodeling of the contralesional hemisphere can affect walking recovery after a stroke, and (c) what is the effect of behavioral rehabilitation training of walking on the neural remodeling of the motor cortical areas bilaterally. For each theme, we discuss how rodent models can enhance the present knowledge on human walking by testing hypotheses that cannot be investigated in humans, and how these findings can then be back-translated into the neurorehabilitation of poststroke walking.

Combinatorial Motor Training Results in Functional Reorganization of Remaining Motor Cortex after Controlled Cortical Impact in Rats.

Cortical reorganization subsequent to post-stroke motor rehabilitative training (RT) has been extensively examined in animal models and humans. However, similar studies focused on the effects of motor training after traumatic brain injury (TBI) are lacking. We previously reported that after a moderate/severe TBI in adult male rats, functional improvements in forelimb use were accomplished only with a combination of skilled forelimb reach training and aerobic exercise, with or without nonimpaired forelimb constraint. Thus, the current study was designed to examine the relationship between functional motor cortical map reorganization after experimental TBI and the behavioral improvements resulting from this combinatorial rehabilitative regime. Adult male rats were trained to proficiency on a skilled reaching task, received a unilateral controlled cortical impact (CCI) over the forelimb area of the caudal motor cortex (CMC). Three days post-CCI, animals began RT (n = 13) or no rehabilitative training (NoRT) control procedures (n = 13). The RT group participated in daily skilled reach training, voluntary aerobic exercise, and nonimpaired forelimb constraint. This RT regimen significantly improved impaired forelimb reaching success and normalized reaching strategies, consistent with previous findings. RT also enlarged the area of motor cortical wrist representation, derived by intracortical microstimulation, compared to NoRT. These findings indicate that sufficient RT can greatly improve motor function and improve the functional integrity of remaining motor cortex after a moderate/severe CCI. When compared with findings from stroke models, these findings also suggest that more intense RT may be needed to improve motor function and remodel the injured cortex after TBI.

Motor System Reorganization After Stroke: Stimulating and Training Toward Perfection.

Stroke instigates regenerative responses that reorganize connectivity patterns among surviving neurons. The new connectivity patterns can be suboptimal for behavioral function. This review summarizes current knowledge on post-stroke motor system reorganization and emerging strategies for shaping it with manipulations of behavior and cortical activity to improve functional outcome.

Experience with the "good" limb induces aberrant synaptic plasticity in the perilesion cortex after stroke.

Following unilateral stroke, the contralateral (paretic) body side is often severely impaired, and individuals naturally learn to rely more on the nonparetic body side, which involves learning new skills with it. Such compensatory hyper-reliance on the "good" body side, however, can limit functional improvements of the paretic side. In rats, motor skill training with the nonparetic forelimb (NPT) following a unilateral infarct lessens the efficacy of rehabilitative training, and reduces neuronal activation in perilesion motor cortex. However, the underlying mechanisms remain unclear. In the present study, we investigated how forelimb movement representations and synaptic restructuring in perilesion motor cortex respond to NPT and their relationship with behavioral outcomes. Forelimb representations were diminished as a result of NPT, as revealed with intracortical microstimulation mapping. Using transmission electron microscopy and stereological analyses, we found that densities of axodendritic synapses, especially axo-spinous synapses, as well as multiple synaptic boutons were increased in the perilesion cortex by NPT. The synaptic density was negatively correlated with the functional outcome of the paretic limb, as revealed in reaching performance. Furthermore, in animals with NPT, there was dissociation between astrocytic morphological features and axo-spinous synaptic density in perilesion motor cortex, compared with controls. These findings demonstrate that skill learning with the nonparetic limb following unilateral brain damage results in aberrant synaptogenesis, potentially of transcallosal projections, and this seems to hamper the functionality of the perilesion motor cortex and the paretic forelimb.

Combining Multiple Types of Motor Rehabilitation Enhances Skilled Forelimb Use Following Experimental Traumatic Brain Injury in Rats.

BACKGROUND: Neuroplasticity and neurorehabilitation have been extensively studied in animal models of stroke to guide clinical rehabilitation of stroke patients. Similar studies focused on traumatic brain injury (TBI) are lacking. OBJECTIVE: The current study was designed to examine the effects of individual and combined rehabilitative approaches, previously shown to be beneficial following stroke, in an animal model of moderate/severe TBI, the controlled cortical impact (CCI). METHODS: Rats received a unilateral CCI, followed by reach training, voluntary exercise, or unimpaired forelimb constraint, alone or in combination. Forelimb function was assessed at different time points post-CCI by tests of skilled reaching, motor coordination, and asymmetrical limb use. RESULTS: Following CCI, skilled reaching and motor coordination were significantly enhanced by combinations of rehabilitation strategies, not by individual approaches. The return of symmetrical limb use benefited from forelimb constraint alone. None of the rehabilitation strategies affected the size of injury, suggesting that enhanced behavioral function was not a result of neuroprotection. CONCLUSIONS: The current study has provided evidence that individual rehabilitation strategies shown to be beneficial in animal models of stroke are not similarly sufficient to enhance behavioral outcome in a model of TBI. Motor rehabilitation strategies for TBI patients may need to be more intense and varied. Future basic science studies exploring the underlying mechanisms of combined rehabilitation approaches in TBI as well as clinical studies comparing rehabilitation approaches for stroke versus TBI would prove fruitful.

Diffusional kurtosis and diffusion tensor imaging reveal different time-sensitive stroke-induced microstructural changes.

BACKGROUND AND PURPOSE: Diffusion MRI is a promising, clinically feasible imaging technique commonly used to describe white matter changes after stroke. We investigated the sensitivity of diffusion MRI to detect microstructural alterations in gray matter after sensorimotor cortex stroke in adult male rats. METHODS: The mean diffusivity (MD) and mean kurtosis of perilesional motor cortex were compared with measures in the contralesional forelimb area of sensorimotor cortex at 2 hours, 24 hours, 72 hours, or 25 days after surgery. MD and mean kurtosis were correlated to the surface densities of glia, dendrites, and axons. RESULTS: Perilesional mean kurtosis was increased at 72 hours and 25 days after stroke, whereas MD was no longer different from contralesional sensorimotor cortex at 24 hours after stroke. There was a significant increase in the density of glial processes at 72 hours after stroke in perilesional motor cortex, which correlated with perilesional MD. CONCLUSIONS: These data support that mean kurtosis and MD provide different but complimentary information on acute and chronic changes in perilesional cortex. Glia infiltration is associated with pseudonormalization of MD in the perilesional motor cortex at 72 hours after lesion; however, this association is absent 25 days after lesion. These data suggest that there are likely several different, time-specific microstructural changes underlying these 2 complimentary diffusion measures.

Age-dependent reorganization of peri-infarct "premotor" cortex with task-specific rehabilitative training in mice.

BACKGROUND: The incidence of stroke in adulthood increases with advancing age, but there is little understanding of how poststroke treatment should be tailored by age. OBJECTIVE: The goal of this study was to determine if age and task specificity of rehabilitative training affect behavioral improvement and motor cortical organization after stroke. METHODS: Young and aged mice were trained to proficiency on the Pasta Matrix Reaching Task prior to lesion induction in primary motor cortex with endothelin-1. After a short recovery period, mice received 9 weeks of rehabilitative training on either the previously learned task (Pasta Matrix Reaching), a different reaching task (Tray Reaching), or no training. To determine the extent of relearning, mice were tested once weekly on the Pasta Matrix Reaching Task. Mice then underwent intracortical microstimulation mapping to resolve the remaining forelimb movement representations in perilesion motor cortex. RESULTS: Although aged mice had significantly larger lesions compared with young mice, Pasta Matrix Reaching served as effective rehabilitative training for both age-groups. Young animals also showed improvement after Tray Reaching. Behavioral improvement in young mice was associated with an expansion of the rostral forelimb area ("premotor" cortex), but we failed to see reorganization in the aged brain, despite similar behavioral improvements. CONCLUSIONS: Our results indicate that reorganization of motor cortex may be limited by either aging or greater tissue damage, but the capacity to improve motor function via task-specific rehabilitative training continues to be well maintained in aged animals.

Impaired limb reaction to displacement of center of gravity in rats with unilateral striatal ischemic injury.

Clinical stroke often results in impaired balance and increased vulnerability to severe injuries due to falling. To evaluate potential preclinical treatments that might target these deficits, it will be important to include tests capable of assessing these impairments chronically in animal models. Previously, we developed a postural instability test (PIT) that revealed chronic, unilateral impairments in postural stability in rat models of hemi-Parkinson's disease (PD) and of unilateral cervical spinal cord injury. Here, we investigated whether this test was also capable of revealing long-term stroke-induced impairments in postural support in rats. Additionally, we examined the ability of more common tests of sensorimotor function to detect chronic impairments. We found that the PIT detected chronic deficits in postural stability/balance enduring for up to 6 weeks post-stroke, outlasting impairments detected in other tests of forelimb sensorimotor function, including asymmetries in upright postural support (cylinder test) and vibrissae-evoked forelimb placing.

Skill learning induced plasticity of motor cortical representations is time and age-dependent.

Movement representations in the motor cortex can reorganize to support motor skill learning during young adulthood. However, little is known about how motor representations change during aging or whether their change is influenced by continued practice of a skill after it is learned. We used intracortical microstimulation to characterize the organization of the forelimb motor cortex in young and aged C57/BL6 mice after short (2-4 weeks) or long (8 weeks) durations of training on a skilled reaching task or control procedures. In young mice, a short duration of reach training increased the area of proximal forelimb movement representations at the expense of distal representations. Following a longer training duration, ratios of proximal to distal movements returned to baseline, even with ongoing practice and skill maintenance. However, lingering changes were evident in thresholds for eliciting distal forelimb movements, which declined over the longer training period. In aged mice, movement representations and movement thresholds failed to change after either duration of training. Furthermore, there was an age-related loss of digit representations and performance decrements on other sensorimotor tests. Nevertheless, in quantitative measures of reaching success, aged mice learned and performed the skilled reaching task at least as well as younger mice. These results indicate that experience-driven topographical reorganization of motor cortex varies with age, as well as time, and is partially dissociable from behavioral performance. They also support an enduring capacity to learn new manual skills during aging, even as more youthful forms of cortical plasticity and sensorimotor function are lost.