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Voltage-driven stochastic magnetization switching in a nanomagnet has attracted more attention recently with its superiority in achieving energy-efficient artificial neuron. Here, a novel pure voltage-driven scheme with â¼27.66 aJ energy dissipation is proposed, which could rotate magnetization vector randomly using only a pair of electrodes covered on the multiferroic nanomagnet. Results show that the probability of 180° magnetization switching is examined as a sigmoid-like function of the voltage pulse width and magnitude, which can be utilized as the activation function of designed neuron. Considering the size errors of designed neuron in fabrication, it's found that reasonable thickness and width variations cause little effect on recognition accuracy for MNIST hand-written dataset. In other words, the designed pure voltage-driven spintronic neuron could tolerate size errors. These results open a new way toward the realization of artificial neural network with low power consumption and high reliability.
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Repetitive transcranial magnetic stimulation (rTMS) is a popular noninvasive technique for modulating motor cortical plasticity and has therapeutic potential for the treatment of Parkinson's disease (PD). However, the therapeutic benefits and related mechanisms of rTMS in PD are still uncertain. Accordingly, preclinical animal research is helpful for enabling translational research to explore an effective therapeutic strategy and for better understanding the underlying mechanisms. Therefore, the current study was designed to identify the therapeutic effects of rTMS on hemiparkinsonian rats. A hemiparkinsonian rat model, induced by unilateral injection of 6-hydroxydopamine (6-OHDA), was applied to evaluate the therapeutic potential of rTMS in motor functions and neuroprotective effect of dopaminergic neurons. Following early and long-term rTMS intervention with an intermittent theta burst stimulation (iTBS) paradigm (starting 24 h post-6-OHDA lesion, 1 session/day, 7 days/week, for a total of 4 weeks) in awake hemiparkinsonian rats, the effects of rTMS on the performance in detailed functional behavioral tests, including video-based gait analysis, the bar test for akinesia, apomorphine-induced rotational analysis, and tests of the degeneration level of dopaminergic neurons, were identified. We found that four weeks of rTMS intervention significantly reduced the aggravation of PD-related symptoms post-6-OHDA lesion. Immunohistochemically, the results showed that tyrosine hydroxylase- (TH-) positive neurons in the substantia nigra pars compacta (SNpc) and fibers in the striatum were significantly preserved in the rTMS treatment group. These findings suggest that early and long-term rTMS with the iTBS paradigm exerts neuroprotective effects and mitigates motor impairments in a hemiparkinsonian rat model. These results further highlight the potential therapeutic effects of rTMS and confirm that long-term rTMS treatment might have clinical relevance and usefulness as an additional treatment approach in individuals with PD.
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Marcha/fisiologia , Córtex Motor/fisiopatologia , Destreza Motora/fisiologia , Neuroproteção/fisiologia , Doença de Parkinson Secundária/terapia , Estimulação Magnética Transcraniana/métodos , Animais , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Masculino , Córtex Motor/metabolismo , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/fisiopatologia , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
KEY POINTS: Activation of axonal dopamine D2 receptors (D2Rs) increases action potential (AP) threshold, and thus decreases neuronal excitability in layer II stellate cells of medial entorhinal cortex. Endogenous dopamine release increases the AP threshold of stellate cells by activating D2Rs. Activation of D2Rs shifts the activation curve of T-type Ca2+ channels in a positive direction in a protein kinase A-dependent manner. Immunofluorescence staining reveals the presence of T-type Ca2+ channels and D2Rs in the axon initial segments (AISs). This research makes the pioneering discovery of D2R-induced AP threshold plasticity in AISs of stellate cells. The findings are likely to have significant implications for understanding the cellular processes by which dopamine influences neuronal intrinsic excitability. ABSTRACT: Stellate cells in the medial entorhinal cortex (MEC) are considered to constitute the largest population of grid cells, which provide spatial representation to support animal estimation of location. Although dopaminergic fibres from the ventral tegmental area and substantia nigra pars compacta innervate the majority of the cortex, including the MEC, little is known about how dopamine modulates the function of MEC stellate cells. Because dopamine D2 receptors (D2Rs) are involved in spatial cognition and MEC contains high levels of D2Rs, we investigated how D2R activation modulates the neuronal intrinsic excitability of stellate cells. Electrophysiological recordings, optogenetics and molecular biology experiments were performed to investigate the mechanism in mice. Activation of axonal D2Rs, not dendritic or somatic D2Rs, elevated the action potential (AP) threshold and decreased the intrinsic excitability of stellate cells, which was caused by shifting rightward the activation properties of T-type Ca2+ channels in a D2R-protein kinase A-dependent manner without affecting their steady-state inactivation curve. In support, immunofluorescence assays revealed colocalization of D2Rs and Cav 3.2 calcium channels within the axon initial segment. These findings are likely to have significant implications for understanding the cellular processes by which dopamine influences neuronal excitability and they may also be applicable to other hippocampal and cortical regions as dopaminergic fibres innervate wide brain regions. Taken together, these findings provide a novel cellular mechanism by which D2Rs modulate AP threshold of stellate cells through T-type Ca2+ channels in MEC, indicating that D2Rs of MEC play a vital role in modulating the information processing of stellate cells.
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Potenciais de Ação/fisiologia , Canais de Cálcio Tipo T/metabolismo , Córtex Entorrinal/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/fisiologia , Dopamina/metabolismo , Córtex Entorrinal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/fisiologiaRESUMO
Transcranial direct current stimulation (tDCS) is a noninvasive technique for modulating neural plasticity and is considered to have therapeutic potential in neurological disorders. For the purpose of translational neuroscience research, a suitable animal model can be ideal for providing a stable condition for identifying mechanisms that can help to explore therapeutic strategies. Here, we developed a tDCS protocol for modulating motor excitability in anesthetized rats. To examine the responses of tDCS-elicited plasticity, the motor evoked potential (MEP) and MEP input-output (IO) curve elicited by epidural motor cortical electrical stimulus were evaluated at baseline and after 30 min of anodal tDCS or cathodal tDCS. Furthermore, a paired-pulse cortical electrical stimulus was applied to assess changes in the inhibitory network by measuring long-interval intracortical inhibition (LICI) before and after tDCS. In the results, analogous to those observed in humans, the present study demonstrates long-term potentiation- (LTP-) and long-term depression- (LTD-) like plasticity can be induced by tDCS protocol in anesthetized rats. We found that the MEPs were significantly enhanced immediately after anodal tDCS at 0.1 mA and 0.8 mA and remained enhanced for 30 min. Similarly, MEPs were suppressed immediately after cathodal tDCS at 0.8 mA and lasted for 30 min. No effect was noted on the MEP magnitude under sham tDCS stimulation. Furthermore, the IO curve slope was elevated following anodal tDCS and presented a trend toward diminished slope after cathodal tDCS. No significant differences in the LICI ratio of pre- to post-tDCS were observed. These results indicated that developed tDCS schemes can produce consistent, rapid, and controllable electrophysiological changes in corticomotor excitability in rats. This newly developed tDCS animal model could be useful to further explore mechanical insights and may serve as a translational platform bridging human and animal studies, establishing new therapeutic strategies for neurological disorders.
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Potencial Evocado Motor/fisiologia , Córtex Motor/fisiologia , Plasticidade Neuronal/fisiologia , Estimulação Transcraniana por Corrente Contínua/métodos , Animais , Eletrodos Implantados , Masculino , Ratos , Ratos Sprague-Dawley , Estimulação Transcraniana por Corrente Contínua/instrumentaçãoRESUMO
KEY POINTS: ERG3 channels have a high expression level in the central nervous system. Knockdown of ERG3 channels enhances neuronal intrinsic excitability (caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials) in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. The expression of ERG3 protein is reduced in human and mouse hippocampal epileptogenic foci. Knockdown of ERG3 channels in hippocampus enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. The results provide strong evidence that ERG3 channels have a crucial role in the regulation of neuronal intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells and are critically involved in the onset and development of epilepsy. ABSTRACT: The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements. Profound changes in intrinsic properties have been observed in various physiological and pathological processes, such as learning, memory and epilepsy. However, the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood. Here, we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability, which is mainly caused by decreased fast afterhyperpolarization, shortened delay time to the generation of an action potential and enhanced summation of somatic excitatory postsynaptic potentials. Interestingly, the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy. Moreover, ERG3 channel knockdown in hippocampus significantly enhanced seizure susceptibility, while mice treated with the ERG channel activator NS-1643 were less prone to epileptogenesis. Taken together, our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy. ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.
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Giro Denteado/fisiologia , Epilepsia do Lobo Temporal/prevenção & controle , Canais de Potássio Éter-A-Go-Go/metabolismo , Hipocampo/fisiologia , Canais de Potássio/metabolismo , Células Piramidais/fisiologia , Convulsões/prevenção & controle , Potenciais de Ação , Adulto , Animais , Estudos de Casos e Controles , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/patologia , Canais de Potássio Éter-A-Go-Go/genética , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Canais de Potássio/genética , Convulsões/metabolismo , Convulsões/patologiaRESUMO
OBJECTIVE: To investigate the effectiveness of traditional manual acupuncture combined with rehabilitation therapy versus rehabilitation therapy alone for shoulder hand syndrome after stroke. DATA SOURCES: PubMed, EMBASE, the Cochrane Library, Chinese Biomedicine Database, China National Knowledge Infrastructure, VIP Information Database, Wan Fang Database and reference lists of the eligible studies were searched up to July 2017 for relevant studies. METHODS: Randomized controlled trials that compared the combined effects of traditional manual acupuncture and rehabilitation therapy to rehabilitation therapy alone for shoulder hand syndrome after stroke were included. Two reviewers independently screened the searched records, extracted the data and assessed risk of bias of the included studies. The treatment effect sizes were pooled in a meta-analysis using RevMan 5.3 software. RESULTS: A total of 20 studies involving 1918 participants were included in this study. Compared to rehabilitation therapy alone, the combined therapy significantly reduced pain on the visual analogue scale and improved limb movement on the Fugl-Meyer Assessment scale and the performance of activities of daily living (ADL) on the Barthel Index scale or Modified Barthel Index scale. Of these, the visual analogue scale score changes were significantly higher (mean difference = 1.49, 95% confidence interval = 1.15-1.82, P < 0.00001) favoring the combined therapy after treatment, with severe heterogeneity ( I2 = 71%, P = 0.0005). CONCLUSION: Current evidence suggests that traditional manual acupuncture integrated with rehabilitation therapy is more effective in alleviating pain, improving limb movement and ADL. However, considering the relatively low quality of available evidence, further rigorously designed and large-scale randomized controlled trials are needed to confirm the results.
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Terapia por Acupuntura/métodos , Terapia por Exercício/métodos , Programas Nacionais de Saúde , Distrofia Simpática Reflexa/reabilitação , Acidente Vascular Cerebral/complicações , Atividades Cotidianas , Idoso , China , Terapia Combinada , Feminino , Humanos , Masculino , Medicina Tradicional , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Distrofia Simpática Reflexa/etiologia , Índice de Gravidade de Doença , Reabilitação do Acidente Vascular Cerebral/métodosRESUMO
In organism, energy homeostasis is a biological process that involves the coordinated homeostatic regulation of energy intake (food intake) and energy expenditure. The human brain, particularly the hypothalamic proopiomelanocortin (POMC)- and agouti-related protein/neuropeptide Y (AgRP/NPY)-expressing neurons in the arcuate nucleus, plays an essential role in regulating energy homeostasis. The regulation process is mainly dependent upon peripheral hormones such as leptin and insulin, as well as nutrients such as glucose, amino acids, and fatty acids. Although many studies have attempted to illustrate the exact mechanisms of glucose and hormones action on these neurons, we still cannot clearly see the full picture of this regulation action. Therefore, in this review we will mainly discuss those established theories and recent progresses in this area, demonstrating the possible physiological mechanism by which glucose, leptin, and insulin affect neuronal excitability of POMC and AgRP neurons. In addition, we will also focus on some important ion channels which are expressed by POMC and AgRP neurons, such as KATP channels and TRPC channels, and explain how these channels are regulated by peripheral hormones and nutrients and thus regulate energy homeostasis.
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Fenômenos Eletrofisiológicos , Metabolismo Energético , Neurônios/fisiologia , Nutrientes , Proteína Relacionada com Agouti/fisiologia , Núcleo Arqueado do Hipotálamo/citologia , Glucose/fisiologia , Homeostase , Humanos , Insulina/fisiologia , Leptina/fisiologia , Neuropeptídeo Y/fisiologia , Pró-Opiomelanocortina/fisiologiaRESUMO
Behavioral timescale synaptic plasticity (BTSP) is a type of non-Hebbian synaptic plasticity reported to underlie place field formation. Despite this important function, the molecular mechanisms underlying BTSP are poorly understood. The α-calcium-calmodulin-dependent protein kinase II (αCaMKII) is activated by synaptic transmission-mediated calcium influx, and its subsequent phosphorylation is central to synaptic plasticity. Because the activity of αCaMKII is known to outlast the event triggering phosphorylation, we hypothesized that it could mediate the extended timescale of BTSP. To examine the role of αCaMKII in BTSP, we performed whole-cell in vivo and in vitro recordings in CA1 pyramidal neurons from mice engineered with a point mutation at the autophosphorylation site (T286A) causing accelerated signaling kinetics. Here, we demonstrate a profound deficit in synaptic plasticity, strongly suggesting that αCaMKII signaling is required for BTSP. This study elucidates part of the molecular mechanism of BTSP and provides insight into the function of αCaMKII in place cell formation and ultimately learning and memory.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Células Piramidais , Animais , Camundongos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Hipocampo , Cinética , Plasticidade NeuronalRESUMO
OBJECTIVE: Cortical electrical stimulation (CES) can modulate cortical excitability through a plasticity-like mechanism and is considered to have therapeutic potentials in Parkinson's disease (PD). However, the precise therapeutic value of such approach for PD remains unclear. Accordingly, we adopted a PD rat model to determine the therapeutic effects of CES. The current study was thus designed to identify the therapeutic potential of CES in PD rats. METHODS: A hemiparkinsonian rat model, in which lesions were induced using unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, was applied to identify the therapeutic effects of long-term (4-week) CES with intermittent theta-burst stimulation (iTBS) protocol (starting 24 h after PD lesion observation, 1 session/day, 5 days/week) on motor function and neuroprotection. After the CES intervention, detailed functional behavioral tests including gait analysis, akinesia, open-field locomotor activity, apomorphine-induced rotation as well as degeneration level of dopaminergic neurons were performed weekly up to postlesion week 4. RESULTS: After the CES treatment, we found that the 4-week CES intervention ameliorated the motor deficits in gait pattern, akinesia, locomotor activity, and apomorphine-induced rotation. Immunohistochemistry and tyrosine hydroxylase staining analysis demonstrated that the number of dopamine neurons was significantly greater in the CES intervention group than in the sham treatment group. CONCLUSION: This study suggests that early and long-term CES intervention could reduce the aggravation of motor dysfunction and exert neuroprotective effects in a rat model of PD. Further, this preclinical model of CES may increase the scope for the potential use of CES and serve as a link between animal and PD human studies to further identify the therapeutic mechanism of CES for PD or other neurological disorders.
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Objective: Individuals with different severities of traumatic brain injury (TBI) often suffer long-lasting motor, sensory, neurological, or cognitive disturbances. To date, no neuromodulation-based therapies have been used to manage the functional deficits associated with TBI. Cortical electrical stimulation (CES) has been increasingly developed for modulating brain plasticity and is considered to have therapeutic potential in TBI. However, the therapeutic value of such a technique for TBI is still unclear. Accordingly, an animal model of this disease would be helpful for mechanistic insight into using CES as a novel treatment approach in TBI. The current study aims to apply a novel CES scheme with a theta-burst stimulation (TBS) protocol to identify the therapeutic potential of CES in a weight drop-induced rat model of TBI. Methods: TBI rats were divided into the sham CES treatment group and CES treatment group. Following early and long-term CES intervention (starting 24 h after TBI, 1 session/day, 5 days/week) in awake TBI animals for a total of 4 weeks, the effects of CES on the modified neurological severity score (mNSS), sensorimotor and cognitive behaviors and neuroinflammatory changes were identified. Results: We found that the 4-week CES intervention significantly alleviated the TBI-induced neurological, sensorimotor, and cognitive deficits in locomotor activity, sensory and recognition memory. Immunohistochemically, we found that CES mitigated the glial fibrillary acidic protein (GFAP) activation in the hippocampus. Conclusion: These findings suggest that CES has significant benefits in alleviating TBI-related symptoms and represents a promising treatment for TBI.
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Lesões Encefálicas Traumáticas , Transtornos Cognitivos , Disfunção Cognitiva , Animais , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/terapia , Cognição , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/terapia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/terapia , Modelos Animais de Doenças , Estimulação Elétrica , RatosRESUMO
Objective: This study explored whether acupuncture affects the maintenance of long-term potentiation (LTP)-like plasticity induced by transcranial magnetic stimulation (TMS) and the acquisition of motor skills following repetitive sequential visual isometric pinch task (SVIPT) training. Methods: Thirty-six participants were recruited. The changes in the aftereffects induced by intermittent theta-burst stimulation (iTBS) and followed acupuncture were tested by the amplitude motor evoked potential (MEP) at pre-and-post-iTBS for 30 min and at acupuncture-in and -off for 30 min. Secondly, the effects of acupuncture on SVIPT movement in inducing error rate and learning skill index were tested. Results: Following one session of iTBS, the MEP amplitude was increased and maintained at a high level for 30 min. The facilitation of MEP was gradually decreased to the baseline level during acupuncture-in and did not return to a high level after needle extraction. The SVIPT-acupuncture group had a lower learning skill index than those in the SVIPT group, indicating that acupuncture intervention after SVIPT training may restrain the acquisition ability of one's learning skills. Conclusion: Acupuncture could reverse the LTP-like plasticity of the contralateral motor cortex induced by iTBS. Subsequent acupuncture may negatively affect the efficacy of the acquisition of learned skills in repetitive exercise training.
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Terapia por Acupuntura , Córtex Motor , Potencial Evocado Motor , Humanos , Plasticidade Neuronal , Ritmo Teta , Estimulação Magnética TranscranianaRESUMO
BACKGROUND: Major depressive disorder is a prevalent and life-threatening illness in modern society. The susceptibility to major depressive disorder is profoundly influenced by environmental factors, such as stressful lifestyle or traumatic events, which could impose maladaptive transcriptional program through epigenetic regulation. However, the underlying molecular mechanisms remain elusive. Here, we examined the role of histone crotonylation, a novel type of histone modification, and chromodomain Y-like protein (CDYL), a crotonyl-coenzyme A hydratase and histone methyllysine reader, in this process. METHODS: We used chronic social defeat stress and microdefeat stress to examine the depressive behaviors. In addition, we combined procedures that diagnose behavioral strategy in male mice with histone extraction, viral-mediated CDYL manipulations, RNA sequencing, chromatin immunoprecipitation, Western blot, and messenger RNA quantification. RESULTS: The results indicate that stress-susceptible rodents exhibit lower levels of histone crotonylation in the medial prefrontal cortex concurrent with selective upregulation of CDYL. Overexpression of CDYL in the prelimbic cortex, a subregion of the medial prefrontal cortex, increases microdefeat-induced social avoidance behaviors and anhedonia in mice. Conversely, knockdown of CDYL in the prelimbic cortex prevents chronic social defeat stress-induced depression-like behaviors. Mechanistically, we show that CDYL inhibits structural synaptic plasticity mainly by transcriptional repression of neuropeptide VGF nerve growth factor inducible, and this activity is dependent on its dual effect on histone crotonylation and H3K27 trimethylation on the VGF promoter. CONCLUSIONS: Our results demonstrate that CDYL-mediated histone crotonylation plays a critical role in regulating stress-induced depression, providing a potential therapeutic target for major depressive disorder.
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Proteínas Correpressoras/metabolismo , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/psicologia , Histonas/metabolismo , Hidroliases/metabolismo , Estresse Psicológico/psicologia , Acil-CoA Desidrogenases/metabolismo , Acilação , Adenoviridae/genética , Animais , Proteínas Correpressoras/biossíntese , Proteínas Correpressoras/genética , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/prevenção & controle , Epigênese Genética , Técnicas de Silenciamento de Genes , Vetores Genéticos , Hidroliases/biossíntese , Hidroliases/genética , Masculino , Metilação , Camundongos , Fatores de Crescimento Neural/biossíntese , Plasticidade Neuronal , Córtex Pré-Frontal/metabolismo , Ratos , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Regulação para CimaRESUMO
The aim of this study was to investigate the time-dependent effects of acupuncture on the excitability and long-term potentiation- (LTP-) like plasticity induced by paired-associative stimulation (PAS) over the primary motor cortex (M1). The present examination is the first to report the influence of acupuncture on the motor-evoked potential (MEP) throughout the treatment process, including baseline (before acupuncture), the needle in situ, and the needle removal. Subsequently, the LTP-like plasticity induced by paired-associative stimulation (PAS) was explored, which consisted of 200 pairs of electrical stimulation of the ulnar nerve at the first dorsal interosseous (FDI), followed by transcranial magnetic stimulation (TMS) over the bilateral M1. TMS-MEP amplitudes over the bilateral M1 in resting conditions were measured throughout the whole treatment process. Finally, we confirmed the behavioral measurements. Significant changes were found in both the contralateral and ipsilateral acupuncture sizes as compared to the baseline values. Our results indicated that acupuncture modulated the excitability of M1, and the synaptic plasticity was time-dependent. We concluded that acupuncture should be combined with rehabilitation techniques to improve the motor function in stroke patients. Therefore, we put forward the combined application of the acupuncture timing and rehabilitation for higher therapeutic effectiveness. This trial was registered in the Chinese Clinical Trial Registry (registration no. ChiCTR-IPR-1900020515).
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Terapia por Acupuntura/métodos , Potenciação de Longa Duração/fisiologia , Fatores de Tempo , Adolescente , Adulto , Povo Asiático/genética , China , Estimulação Elétrica/métodos , Eletromiografia/métodos , Potencial Evocado Motor/fisiologia , Feminino , Lateralidade Funcional , Mãos , Humanos , Masculino , Córtex Motor/fisiologia , Plasticidade Neuronal/fisiologia , Estimulação Magnética Transcraniana/métodosRESUMO
BACKGROUND: Functional electrical stimulation (FES) is known to promote the recovery of motor function in rats with ischemia and to upregulate the expression of growth factors which support brain neurogenesis. In this study, we investigated whether postischemic FES could improve functional outcomes and modulate neurogenesis in the subventricular zone (SVZ) after focal cerebral ischemia. METHODS: Adult male Sprague-Dawley rats with permanent middle cerebral artery occlusion (MCAO) were randomly assigned to the control group, the placebo stimulation group, and the FES group. The rats in each group were further assigned to one of four therapeutic periods (1, 3, 7, or 14 days). FES was delivered 48 hours after the MCAO procedure and divided into two 10-minute sessions on each day of treatment with a 10-minute rest between them. Two intraperitoneal injections of bromodeoxyuridine (BrdU) were given 4 hours apart every day beginning 48 hours after the MCAO. Neurogenesis was evaluated by immunofuorescence staining. Wnt-3 which is strongly implicated in the proliferation and differentiation of neural stem cells (NSCs) was investigated by Western blotting analysis. The data were subjected to one- way analysis of variance (ANOVA), followed by a Tukey/Kramer or Dunnett post hoc test. RESULTS: FES significantly increased the number of BrdU-positive cells and BrdU/glial fibrillary acidic protein double- positive neural progenitor cells in the SVZ on days 7 and 14 of the treatment (P < 0.05). The number of BrdU/doublecortin (DCX) double-positive migrating neuroblast cells in the ipsilateral SVZ on day 14 of the FES treatment group ((522.77 ± 33.32) cells/mm(2)) was significantly increased compared with the control group ((262.58 ± 35.11) cells/mm(2), P < 0.05) and the placebo group ((266.17 ± 47.98) cells/mm(2), P < 0.05). However, only a few BrdU/neuron-specific nuclear protein-positive cells were observed by day 14 of the treatment. At day 7, Wnt-3 was upregulated in the ipsilateral SVZs of the rats receiving FES ((0.44 ± 0.05)%) compared with those of the control group rats ((0.31 ± 0.02)%, P < 0.05) or the placebo group rats ((0.31 ± 0.04)%, P < 0.05). At day 14, the corresponding values were (0.56 ± 0.05)% in the FES group compared with those of the control group rats ((0.50 ± 0.06)%, P < 0.05) or the placebo group rats ((0.48 ± 0.06)%, P < 0.05). CONCLUSION: FES augments the proliferation, differentiation, and migration of NSCs and thus promotes neurogenesis, which may be related to the improvement of neurological outcomes.