Temporal expression profiles of microRNAs associated with acute phase of brain ischemia in gerbil hippocampus.

Neuroprotective therapeutic potential for restoring dysregulated microRNA (miRNA) expression has previously been demonstrated in a gerbil cerebral infarction model. However, since temporal changes in miRNA expression profiles following stroke onset are unknown, miRNAs proving to be useful therapeutic targets have yet to be identified. We evaluated cognitive function, hippocampal neuronal cell death, and microarray-based miRNA expression profiles at 5, 9, 18, 36, and 72 h after 5-min whole brain ischemia in gerbils. A decline in cognitive function occurred in parallel with increased neuronal cell death 36-72 h after ischemia. The Jonckheere-Terpstra test was used to analyze miRNA expression trends 5-72 h after ischemia. The expression levels of 63 miRNAs were significantly upregulated, whereas 32 miRNAs were significantly downregulated, monotonically. Of the 32 monotonically downregulated miRNAs, 18 showed the largest decrease in expression 5-9 h after ischemia. A subset of these dysregulated miRNAs (miR-378a-5p, miR-204-5p, miR-34c-5p, miR-211-5p, miR-34b-3p, and miR-199b-3p) could be associated with brain ischemia and neuropsychiatric disorders.

Impacts of Age and Gender on Brain Edema in a Mouse Water Intoxication Model.

Brain edema causes abnormal fluid retention and can be fatal in severe cases. Although it develops in various diseases, most treatments for brain edema are classical. We analyzed the impacts of age and gender on the characteristics of a water intoxication model that induces pure brain edema in mice and examined the model's usefulness for research regarding new treatments for brain edema. C57BL/6J mice received an intraperitoneal administration of 10% body weight distilled water, and we calculated the brain water content by measuring the brain-tissue weight immediately after dissection and after drying. We analyzed 8-OHdG and caspase-3 values to investigate the brain damage. We also applied this model in aquaporin 4 knockout (AQP4-) mice and compared these mice with wild-type mice. The changes in water content differed by age and gender, and the 8-OHdG and caspase-3 values differed by age. Suppression of brain edema by AQP4- was also confirmed. These results clarified the differences in the onset of brain edema by age and gender, highlighting the importance of considering the age and gender of model animals. Similar studies using genetically modified mice are also possible. Our findings indicate that this water intoxication model is effective for explorations of new brain edema treatments.

Age­related brainstem degeneration through microRNA modulation in mice.

Histopathological changes occur in the brainstem during the early stages of Alzheimer's disease (AD), with the pathological changes of the brain lesions ascending progressively in accordance with the Braak staging system. The senescence­accelerated mouse prone 8 (SAMP8) mouse model has been previously used as a model of age­dependent neurodegenerative diseases, including AD. In the present study, microRNAs (miRNAs) that were upregulated or downregulated in SAMP8 brainstems were identified using miRNA profiling of samples obtained from miRNA arrays. The preliminary stage of cognitive dysfunction was examined using male 5­month­old SAMP8 mice, with age­matched senescence­accelerated mouse resistant 1 mice as controls. A Y­maze alternation test was performed to assess short­term working memory and miRNA profiling was performed in each region of the dissected brain (brainstem, hippocampus and cerebral cortex). SAMP8 mice tended to be hyperactive, but short­term working memory was preserved. Two miRNAs were upregulated (miR­491­5p and miR­764­5p) and two were downregulated (miR­30e­3p and miR­323­3p) in SAMP8 brainstems. In SAMP8 mice, the expression level of upregulated miRNAs were the highest in the brainstem, wherein age­related brain degeneration occurs early. It was demonstrated that the order of specific miRNA expression levels corresponded to the progression order of age­related brain degeneration. Differentially expressed miRNAs regulate multiple processes, including neuronal cell death and neuron formation. Changes in miRNA expression may result in the induction of target proteins during the early stages of neurodegeneration in the brainstem. These findings suggest that studying altered miRNA expression may provide molecular evidence for early age­related neuropathological changes.

A cerebrospinal fluid microRNA analysis: Progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy described as a syndrome of postural instability, supranuclear vertical gaze palsy, dysarthria, dystonic rigidity of the neck and trunk, dementia, and pseudobulbar palsy. The clinical diagnosis of PSP is often difficult because there are no established biomarkers, and diagnosis is currently based on clinical and imaging findings. Furthermore, the etiology and pathogenesis of PSP remain unknown. Dysregulation of microRNAs (miRNAs/miRs) has been reported to serve an important role in neurodegenerative diseases. However, the miRNA profiles of patients with PSP are rarely reported. The present study aimed to examine cerebrospinal fluid miRNAs, which are considered to be more sensitive indicators of changes in the brain, to elucidate the pathophysiology of PSP and to establish specific biomarkers for diagnosis. The present study used a microarray chip containing 2,632 miRNAs to examine cerebrospinal fluid miRNA expression levels in 11 patients with PSP aged 68­82 years. A total of 8 age­ and sex­matched controls were also included. A total of 38 miRNAs were significantly upregulated and one miRNA was significantly downregulated in the cerebrospinal fluid of patients with PSP. The patients were divided into two groups based on disease stage (early onset and advanced), and changes in miRNA expression were examined. The miRNAs that were most significantly upregulated or downregulated in the early onset group were miR­204­3p, miR­873­3p and miR­6840­5p. The target genes of these miRNAs were associated with molecules related to the ubiquitin­proteasome system and autophagy pathway. Furthermore, these miRNAs were found to target genes that have been reported to have epigenetic changes following an epigenome­wide association study of brain tissues of patients with PSP. This suggested that these miRNAs and genes may have some involvement in the pathogenesis of PSP. However, the sample size of the present study was small; therefore, a greater number of patients with PSP should be examined in future studies.

Ryanodine receptors are involved in the improvement of depression-like behaviors through electroconvulsive shock in stressed mice.

BACKGROUND: Electroconvulsive therapy (ECT) is effective for treating depression. However, the mechanisms underlying the antidepressant effects of ECT remain unknown. Depressed patients exhibit abnormal Ca2+ kinetics. Early stages of the intracellular Ca2+ signaling pathway involve the release of Ca2+ from the endoplasmic reticulum (ER) via Ca2+ release channels. OBJECTIVE: We considered that depression may be improved via ECT-induced normalization of intracellular Ca2+ regulation through the Ca2+ release channels. The current study aimed to investigate the effects of ECT on two Ca2+ release channels, ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs). METHODS: A mouse depression-like model subjected to water immersion with restraint stress was administered electroconvulsive shock (ECS) therapy. Their depression-like status was behaviorally and histologically assessed using forced swimming tests, novelty-suppressed feeding tests, and by evaluating neurogenesis in the hippocampal dentate gyrus, respectively. A RyRs blocker, dantrolene, was administered prior to ECS, and the changes in depression-like conditions were examined. RESULTS: The protein expressions of RyR1 and RyR3 significantly increased in the hippocampus of the mouse model with depression-like symptoms. This increase was attenuated as depression-like symptoms were reduced due to ECS application. However, pre-injection with dantrolene reduced the antidepressant effects of ECS. CONCLUSIONS: A significant increase in RyRs expression in a depression-like state and exacerbation of depression-like symptoms by RyRs inhibitors may be caused by RyRs dysfunction, suggesting overexpression of RyRs is a compensatory effect. Normalization of RyRs expression levels by ECS suggests that ECT normalizes the Ca2+ release via RyRs. Thus, normalizing the function of RyRs may play an important role in the therapeutic effect of ECT.

The protective effect and mechanism of COA-Cl in acute phase after spinal cord injury.

Spinal cord injury (SCI) induces severe motor and sensory dysfunction. We previously showed the neuroprotective effects of COA-Cl, a novel synthesized adenosine analog, in a rat stroke model. In this study, we evaluated the neuroprotective effects of COA-Cl in acute phase of SCI. SCI was induced in rats at the T9 vertebra by using a drop device. Rats were divided into acute and subacute groups. A 5-day dose of 6 mg/kg COA-Cl in saline was given to the acute group immediately after SCI and the subacute group 4 days after SCI. Motor function assessed by Basso-Beattie-Bresnahan scoring and inclined plane test improved significantly in the acute group while the subacute group did not. Histological evaluation and TUNEL staining revealed that both the cavity volume and apoptosis were significantly decreased in the acute group compared with the subacute group. In addition, pERK/ERK was increased in the acute group 7 days after SCI. These results suggest that COA-Cl exerts neuroprotective effects via the ERK pathway when administered in the acute phase after SCI, resulting in the recovery of motor function. COA-Cl could be a novel therapeutic agent for the acute phase of SCI.

Light exercise without lactate elevation induces ischemic tolerance through the modulation of microRNA in the gerbil hippocampus.

Previously we studied the possible neuroprotective effects of ischemia-resistant exercise in a gerbil model of transient whole-brain ischemia and evaluated the histology, expression of specific proteins, and brain function under different conditions. The present study investigated the neuroprotective effects of light exercise, without lactate elevation, in a gerbil model of ischemia/reperfusion injury. Transient whole-brain ischemia was induced by occlusion of the bilateral common carotid arteries for 5 min. A group of animals was subjected to treadmill exercise before ischemia induction. Hippocampal neuronal damage and miRNA expression, as well as behavioral deficits and plasma lactate levels, were evaluated. Light exercise suppressed hippocampal neuron loss and preserved short-term memory. Moreover, 14 miRNAs (mmu-miR-211-3p, -327, -451b, -711, -3070-3p, -3070-2-3p, -3097-5p, -3620-5p, -6240, -6916-5p, -6944-5p, 7083-5p, -7085-5p, and -7674-5p) were upregulated and 6 miRNAs (mmu-miR-148b-3p, -152-3p, -181c-5p, -299b-5p, -455-3p, and -664-3p) were downregulated due to ischemia. However, the expression of these miRNAs remained unchanged when animals performed light exercise before the ischemic event. Differentially expressed miRNAs regulate multiple biological processes such as inflammation, metabolism, and cell death. These findings suggest that light exercise reduces neuronal death and behavioral deficits after transient ischemia by regulating hippocampal miRNAs.

Very Early Initiation Reduces Benefits of Poststroke Rehabilitation Despite Increased Corticospinal Projections.

Background. Although the effect of rehabilitation is influenced by aspects of the training protocol, such as initiation time and intensity of training, it is unclear whether training protocol modifications affect the corticospinal projections. Objective. The present study was designed to investigate how modification of initiation time (time-dependency) and affected forelimb use (use-dependency) influence the effects of rehabilitation on functional recovery and corticospinal projections. Methods. The time-dependency of rehabilitation was investigated in rats forced to use their impaired forelimb immediately, at 1 day, and 4 days after photothrombotic stroke. The use-dependency of rehabilitation was investigated by comparing rats with affected forelimb immobilization (forced nonuse), unaffected forelimb immobilization (forced use), and a combination of forced use and skilled forelimb training beginning at 4 days after stroke. Results. Although forced use beginning 1 day or 4 days after stroke caused significant functional improvement, immediate forced limb use caused no functional improvement. On the other hand, a combination of forced use and skilled forelimb training boosted functional recovery in multiple tasks compared to simple forced use treatment. Histological examination showed that no treatment caused brain damage. However, a retrograde tracer study revealed that immediate forced use and combination training, including forced use and skilled forelimb training, increased corticospinal projections from the contralesional and ipsilesional motor cortex, respectively. Conclusions. These results indicate that although both very early initiation time and enhanced skilled forelimb use increased corticospinal projections, premature initiation time hampers the functional improvement induced by poststroke rehabilitation.

Clinical outcome of conversion from external fixation to definitive internal fixation for open fracture of the lower limb.

INTRODUCTION: Few reports have examined the outcomes and complications of temporary bridging external fixation (EF) in open fracture of the lower limb followed by conversion to open reduction internal fixation (ORIF). The purpose of this study was to evaluate healing rates and complications in patients treated with conversion from external fixation to definitive internal fixation for open fracture of the lower limb. METHOD: Patients who underwent temporary bridging EF and subsequent conversion to internal fixation (IF) for open fracture of the lower limb, with follow-up period ≥12 months were included in this study. Demographic data, Gustilo-Anderson classification, fracture type, duration to definitive surgery, surgical procedure, perioperative complications, and additional procedures for cases with complications were obtained. RESULTS: In total, 58 patients (43 males, 15 females), 63 fractures were included in this study. Four fractures (6.3%) were Gustilo grade I, 11 fractures (17.5%) were grade II, 34 fractures (54.0%) were grade IIIa, 12 fractures (19.0%) were grade IIIb, and two fractures (3.2%) were grade IIIc. Mean duration of the application of EF was 12.4 days (range, 3-45 days) until conversion to definitive IF. Rates of deep infection and nonunion were both 9.5%, with two cases showing concomitant infection and nonunion. Rates of infection were 8.8% (3/34) in grade IIIa and 25% (3/12) in grade IIIb. Rates of nonunion were 9.1% (1/11) in grade II, 2.9% (1/34) in grade IIIa and 33% (4/12) in grade IIIb. CONCLUSION: Temporary EF for open fracture of the lower limb followed by conversion to IF, as early as soft tissue and general condition permit, may be a safe and effective procedure for patients with lower-limb open fracture of Gustilo grade IIIa or less. LEVEL OF EVIDENCE: Level IV, Case series.

Effects of intravesicular loading of a Ca2+ chelator and depolymerization of actin fibers on neurotransmitter release in frog motor nerve terminals.

Ca2+ -induced Ca2+ release (CICR) via type-3 ryanodine receptor enhances neurotransmitter release in frog motor nerve terminals. To test a possible role of synaptic vesicle in CICR, we examined the effects of loading of EGTA, a Ca2+ chelator, into synaptic vesicles and depolymerization of actin fibers. Intravesicular EGTA loading via endocytosis inhibited the ryanodine sensitive enhancement of transmitter release induced by tetanic stimulation and the associated rises in intracellular-free Ca2+ ([Ca2+ ]i : Ca2+ transients). Latrunculin A, a depolymerizer of actin fibers, enhanced both spontaneous and stimulation-induced transmitter release, but inhibited the enhancement of transmitter release elicited by successive tetanic stimulation. The results suggest a possibility that the activation of CICR from mobilized synaptic vesicles caused the enhancement of neurotransmitter release.

Improvement of motor function induced by skeletal muscle contraction in spinal cord-injured rats.

BACKGROUND: The involvement of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) in functional recovery after spinal cord injury (SCI) by treadmill training has been suggested. The precise mechanism is poorly understood. However, muscle-derived bioactive molecules (myokines) are known to be produced by muscle contraction. Although BDNF is a myokine and is considered to be a potential mediator of neuroplasticity following exercise, its contribution to motor function recovery after SCI has not yet been described in detail. PURPOSE: To investigate the role of muscle contraction in motor function recovery after SCI, with a focus on BDNF. STUDY DESIGN: Male Sprague-Dawley rats (aged 8-9 weeks) were used to establish the SCI model. Percutaneous electrical muscle stimulation (10 mA, 2 Hz, 10 minutes) was applied to both hindlimbs of the rats immediately after SCI. The stimulation was performed once per day for 4 weeks. The sham, SCI only (SCI), and SCI with electrical muscle stimulation (SCI+ES) groups were compared. METHODS: Spinal cord injury was induced by dropping a 20 g rod with an apex diameter of 2 mm from a height of 25 mm onto the spine of an anesthetized rat at the T9 level. Motor function was assessed using the Basso-Beattie-Bresnahan Locomotor Scale, inclined plane test, and rotarod test. One week after injury, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were counted at the injury epicenter, and the level of BDNF was measured in both the spinal cord and the anterior tibial muscle. Four weeks after injury, the cavity volume of the epicenter and the level of phosphorylated growth-associated protein 43 in the spinal cord were measured. RESULTS: Significantly improved Basso-Beattie-Bresnahan scores and inclined plane test results were observed in the SCI+ES group compared with those in the SCI group at 4 weeks post-SCI. We also observed a decrease in the cavity volume and an increase in phosphorylated growth-associated protein 43 levels in the SCI+ES group. Electrical muscle stimulation decreased the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells in the epicenter and increased the levels of BDNF in the spinal cord and lower limb muscles at 1 week post-SCI. CONCLUSIONS: Electrical muscle stimulation improved motor function and increased BDNF levels in both the muscles and the spinal cords of rats subjected to SCI. Muscle contraction-induced BDNF expression might be involved in motor recovery during rehabilitation. CLINICAL RELEVANCE: Our study provides experimental evidence for a possible therapeutic role of peripheral electrical muscle stimulation to enhance motor recovery after SCI.

Constraint-induced movement therapy improves efficacy of task-specific training after severe cortical stroke depending on the ipsilesional corticospinal projections.

Descending spinal pathways (corticospinal, rubrospinal, and reticulospinal) are believed to contribute to functional recovery resulting from rehabilitative training after stroke. However, the contribution of each pathway remains unclear. In the current study, we investigated rehabilitation-induced functional recovery and remodelling of the descending spinal pathways after severe cortical stroke in rats followed by 3 weeks of various rehabilitation [constraint-induced movement therapy (CIMT), skilled forelimb reaching, rotarod, and treadmill exercise]. Following photothrombotic stroke, 96% of corticospinal neurons in the ipsilesional motor cortex were destroyed. Despite the preservation of 82% of total spinal projection neurons (e.g. rubrospinal and reticulospinal projection neurons), rats showed persistent and severe disability, especially in skilled motor function. In this severe stroke model, only CIMT promoted functional recovery, associated with increased corticospinal projections from the peri-infarct motor cortex. Rehabilitation-induced recovery was reversed when the restored corticospinal neurons were destroyed by a second stroke. These data indicate that training-induced functional recovery is dependent on ipsilesional corticospinal projections, which highlights the importance of using strategies to enhance survival, axonal remodelling, or regeneration of corticospinal neurons to effectively restore function in severely affected stroke patients.

Rehabilitative skilled forelimb training enhances axonal remodeling in the corticospinal pathway but not the brainstem-spinal pathways after photothrombotic stroke in the primary motor cortex.

Task-specific rehabilitative training is commonly used for chronic stroke patients. Axonal remodeling is believed to be one mechanism underlying rehabilitation-induced functional recovery, and significant roles of the corticospinal pathway have previously been demonstrated. Brainstem-spinal pathways, as well as the corticospinal tract, have been suggested to contribute to skilled motor function and functional recovery after brain injury. However, whether axonal remodeling in the brainstem-spinal pathways is a critical component for rehabilitation-induced functional recovery is not known. In this study, rats were subjected to photothrombotic stroke in the caudal forelimb area of the primary motor cortex and received rehabilitative training with a skilled forelimb reaching task for 4 weeks. After completion of the rehabilitative training, the retrograde tracer Fast blue was injected into the contralesional lower cervical spinal cord. Fast blue-positive cells were counted in 32 brain areas located in the cerebral cortex, hypothalamus, midbrain, pons, and medulla oblongata. Rehabilitative training improved motor performance in the skilled forelimb reaching task but not in the cylinder test, ladder walk test, or staircase test, indicating that rehabilitative skilled forelimb training induced task-specific recovery. In the histological analysis, rehabilitative training significantly increased the number of Fast blue-positive neurons in the ipsilesional rostral forelimb area and secondary sensory cortex. However, rehabilitative training did not alter the number of Fast blue-positive neurons in any areas of the brainstem. These results indicate that rehabilitative skilled forelimb training enhances axonal remodeling selectively in the corticospinal pathway, which suggests a critical role of cortical plasticity, rather than brainstem plasticity, in task-specific recovery after subtotal motor cortex destruction.

Pathologic Fractures Extended to the Metacarpal Head Related with Enchondromas at the Metacarpal Neck.

We present two cases of pathologic fractures extended to the metacarpal head related with enchondromas at the metacarpal neck treated by surgery. The timing of surgery varied between the two cases. The first was operated without delay, using tumor curettage and ß-TCP (tricalcium phosphate) packing in the cavity, followed by internal fixation of the fracture using a screw and Kirshner wires. In the second case, tumor curettage and ß-TCP packing was performed after fracture union. Favorable clinical outcomes were obtained for both cases.

Axonal remodeling in the corticospinal tract after stroke: how does rehabilitative training modulate it?

Stroke causes long-term disability, and rehabilitative training is commonly used to improve the consecutive functional recovery. Following brain damage, surviving neurons undergo morphological alterations to reconstruct the remaining neural network. In the motor system, such neural network remodeling is observed as a motor map reorganization. Because of its significant correlation with functional recovery, motor map reorganization has been regarded as a key phenomenon for functional recovery after stroke. Although the mechanism underlying motor map reorganization remains unclear, increasing evidence has shown a critical role for axonal remodeling in the corticospinal tract. In this study, we review previous studies investigating axonal remodeling in the corticospinal tract after stroke and discuss which mechanisms may underlie the stimulatory effect of rehabilitative training. Axonal remodeling in the corticospinal tract can be classified into three types based on the location and the original targets of corticospinal neurons, and it seems that all the surviving corticospinal neurons in both ipsilesional and contralesional hemisphere can participate in axonal remodeling and motor map reorganization. Through axonal remodeling, corticospinal neurons alter their output selectivity from a single to multiple areas to compensate for the lost function. The remodeling of the corticospinal axon is influenced by the extent of tissue destruction and promoted by various therapeutic interventions, including rehabilitative training. Although the precise molecular mechanism underlying rehabilitation-promoted axonal remodeling remains elusive, previous data suggest that rehabilitative training promotes axonal remodeling by upregulating growth-promoting and downregulating growth-inhibiting signals.

Synovial Osteochondromatosis at the Carpometacarpal Joint of the Thumb.

Synovial osteochondromatosis (SOC) is a benign tumor characterized by synovial connective tissue metaplasia. SOC commonly affects major joints including the knee followed by the hip, elbow, and wrist. SOC cases in the hand are not reported as often as SOC of major joints. Particularly SOC of the carpometacarpal joint of the thumb is rare. We report on a 57-year-old female with primary SOC of the carpometacarpal joint of her left thumb. Surgical excision was performed and the patient had no symptoms with full range of motion of her left thumb. At 3 years of follow-up, there was no recurrence.

The Role of Endogenous Neurogenesis in Functional Recovery and Motor Map Reorganization Induced by Rehabilitative Therapy after Stroke in Rats.

BACKGROUND AND OBJECTIVE: Endogenous neurogenesis is associated with functional recovery after stroke, but the roles it plays in such recovery processes are unknown. This study aims to clarify the roles of endogenous neurogenesis in functional recovery and motor map reorganization induced by rehabilitative therapy after stroke by using a rat model of cerebral ischemia (CI). METHODS: Ischemia was induced via photothrombosis in the caudal forelimb area of the rat cortex. First, we examined the effect of rehabilitative therapy on functional recovery and motor map reorganization, using the skilled forelimb reaching test and intracortical microstimulation. Next, using the same approaches, we examined how motor map reorganization changed when endogenous neurogenesis after stroke was inhibited by cytosine-ß-d-arabinofuranoside (Ara-C). RESULTS: Rehabilitative therapy for 4 weeks after the induction of stroke significantly improved functional recovery and expanded the rostral forelimb area (RFA). Intraventricular Ara-C administration for 4-10 days after stroke significantly suppressed endogenous neurogenesis compared to vehicle, but did not appear to influence non-neural cells (e.g., microglia, astrocytes, and vascular endothelial cells). Suppressing endogenous neurogenesis via Ara-C administration significantly inhibited (~50% less than vehicle) functional recovery and RFA expansion (~33% of vehicle) induced by rehabilitative therapy after CI. CONCLUSIONS: After CI, inhibition of endogenous neurogenesis suppressed both the functional and anatomical markers of rehabilitative therapy. These results suggest that endogenous neurogenesis contributes to functional recovery after CI related to rehabilitative therapy, possibly through its promotion of motor map reorganization, although other additional roles cannot be ruled out.

Neural network remodeling underlying motor map reorganization induced by rehabilitative training after ischemic stroke.

Motor map reorganization is believed to be one mechanism underlying rehabilitation-induced functional recovery. Although the ipsilesional secondary motor area has been known to reorganize motor maps and contribute to rehabilitation-induced functional recovery, it is unknown how the secondary motor area is reorganized by rehabilitative training. In the present study, using skilled forelimb reaching tasks, we investigated neural network remodeling in the rat rostral forelimb area (RFA) of the secondary motor area during 4weeks of rehabilitative training. Following photothrombotic stroke in the caudal forelimb area (CFA), rehabilitative training led to task-specific recovery and motor map reorganization in the RFA. A second injury to the RFA resulted in reappearance of motor deficits. Further, when both the CFA and RFA were destroyed simultaneously, rehabilitative training no longer improved task-specific recovery. In neural tracer studies, although rehabilitative training did not alter neural projection to the RFA from other brain areas, rehabilitative training increased neural projection from the RFA to the lower spinal cord, which innervates the muscles in the forelimb. Double retrograde tracer studies revealed that rehabilitative training increased the neurons projecting from the RFA to both the upper cervical cord, which innervates the muscles in the neck, trunk, and part of the proximal forelimb, and the lower cervical cord. These results suggest that neurons projecting to the upper cervical cord provide new connections to the denervated forelimb area of the spinal cord, and these new connections may contribute to rehabilitation-induced task-specific recovery and motor map reorganization in the secondary motor area.

Exercise in the Early Stage after Stroke Enhances Hippocampal Brain-Derived Neurotrophic Factor Expression and Memory Function Recovery.

BACKGROUND: Exercise in the early stage after stroke onset has been shown to facilitate the recovery from physical dysfunction. However, the mechanism of recovery has not been clarified. In this study, the effect of exercise on spatial memory function recovery in the early stage was shown, and the mechanism of recovery was discussed using a rat model of brain embolism. METHODS: Intra-arterial microsphere (MS) injection induced small emboli in the rat brain. Treadmill exercise was started at 24 hours (early group) or 8 days (late group) after MS injection. The non-exercise (NE) and sham-operated groups were included as controls. Memory function was evaluated by the Morris water maze test, and hippocampal levels of brain-derived neurotrophic factor (BDNF) were measured by enzyme-linked immunosorbent assays. To further investigate the effect of BDNF on memory function, BDNF was continuously infused into the hippocampus via implantable osmotic pumps in the early or late stage after stroke. RESULTS: Memory function significantly improved only in the early group compared with the late and the NE groups, although hippocampal BDNF concentrations were temporarily elevated after exercise in both the early and the late groups. Rats infused with BDNF in the early stage exhibited significant memory function recovery; however, rats that received BDNF infusion in the late stage showed no improvement. CONCLUSION: Exercise elevates hippocampal BDNF levels in the early stage after cerebral embolism, and this event facilitates memory function recovery.