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1.
Gene ; 766: 145022, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758579

RESUMO

BACKGROUND: A better understanding of the mechanism(s) underlying cardioembolic stroke can promote recovery and reduce the risk of recurrent embolisms. METHODS: Peripheral blood mononuclear cell (PBMC) gene expression datasets from cardioembolic patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database (GSE58294). The Limma software package was utilized to identify differentially-expressed genes (DEGs). Protein-protein interaction (PPI) analysis of the DEGs was performed using STRING. A weighted gene co-expression network analysis (WGCNA) was used to build a gene co-expression network. In vitro experiments assessed the effects on neutrophils exposed to oxygen and glucose-deprived (OGD) cortical neurons. An in vivo murine model of thromboembolic stroke was constructed through thrombin injection to examine effects on circulating neutrophils. Mechanistic in vitro studies were conducted using the proteasome inhibitor MG132, the p53-Mdm2 binding inhibitor Nutlin-3a, Mdm2 small-interfering RNA (siRNA), and Ctnnb1 siRNA. RESULTS: DEG analysis identified 44 upregulated and 66 downregulated genes in cardioembolic stroke PBMCs. PPI analysis of these DEGs yielded one eight-node protein module with ß-catenin (CTNNB1) as the central hub protein. Integration of the DEGs with WGCNA-derived hub genes revealed the key hub DEGs CTNNB1 and mouse double minute 2 (MDM2). Follow-up experiments revealed Mdm2, p53, and phospho-ß-catenin upregulation in neutrophils exposed to OGD neurons in vitro and following thromboembolic stroke in vivo. Mechanistic studies revealed that neutrophils transcriptionally upregulate Ctnnb1 expression to compensate for Mdm2/p53-mediated ß-catenin degradation induced by exposure to OGD neurons, thereby promoting neutrophil survival. CONCLUSION: Compensatory Ctnnb1 transcriptional upregulation in neutrophils induced by ischemic neuron exposure may be involved in promoting neutrophil survival following cardioembolic stroke.


Assuntos
Neutrófilos/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Proteína Supressora de Tumor p53/genética , Regulação para Cima/genética , beta Catenina/genética , Animais , Células Cultivadas , Regulação para Baixo/genética , Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Coração/fisiopatologia , Humanos , Leucócitos Mononucleares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Transcrição Genética/genética , Ativação Transcricional/genética
2.
Chemosphere ; 262: 127878, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33182097

RESUMO

Reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and mitochondrial dysfunction are known to affect the structural and functional damage in the neural system. Cadmium (Cd) is an environmental contaminant that is widely found in numerous environmental matrices and exhibits potential neurotoxic risk. However, it remains unclear how mitochondrial redox status induces, and whether Cd destabilizes, the ER-mitochondria crosstalk to have a toxic effect on the nervous system. Herein, in our present study, bioinformatics analysis revealed an important role of protein interaction and mitochondrial machinery in brain samples from Alzheimer's disease (AD) patients. Furthermore, we established a neurotoxicity model in vivo and in vitro induced by cadmium chloride (CdCl2). We demonstrated that CdCl2 exposure disrupts the balance in mitochondrial redox represented by enhanced mitochondrial ROS (mitoROS) levels, which enhance mitofusin 2 (Mfn2) S-glutathionylation and interrupt the mitochondria-associated ER membranes (MAMs) for crosstalk between the ER and mitochondria to induce neuronal necroptosis. Mechanistically, it was shown that CdCl2 exposure significantly enhances the mitochondria-associated degradation (MAD) of Mfn2 via S-glutathionylation, which inhibits Mfn2 localization to the MAMs and subsequently leads to the formation of the RIPK1-RIPK3-p-MLKL complex (a key component of the necrosome) at MAMs, to promote neuronal necroptosis. Furthermore, the glutaredoxin 1 (Grx1) catalyzed and Mfn2 overexpression restored S-glu-Mfn2, MAMs perturbation, necrosome formation, and necroptosis in neurons induced by CdCl2 exposure in vitro. Moreover, the intervention with antioxidants to reduce mitochondrial redox, such as N-acetyl-l-cysteine (NAC) and mitochondria-targeted antioxidant Mito-TEMPO, reduced the S-glutathionylation of Mfn2 involved in the antagonism of CdCl2-induced necroptosis and neurotoxicity in vivo and in vitro. Taken together, our results are the first time to demonstrate that S-glutathionylation of Mfn2 promotes neuronal necroptosis via disruption of ER-mitochondria crosstalk in CdCl2-induced neurotoxicity, providing the novel mechanistic insight into how hazardous chemical-induced adverse effects in various organs and tissues could be interpreted by intraorganellar pathways under the control of MAMs components in neurons.


Assuntos
Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Necroptose , Animais , Cádmio/metabolismo , Cloreto de Cádmio/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Neurônios/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores
3.
Nihon Yakurigaku Zasshi ; 155(6): 381-385, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132254

RESUMO

Conventional monoaminergic antidepressants have significant limitations, including delayed onset of therapeutic response and relatively low efficacy. Recent studies reveal that the NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant depressed patients. Despite the unique antidepressant efficacy, clinical use of ketamine as an antidepressant is limited due to its serious drawbacks, such as abuse potential and psychotomimetic/dissociative effects. The molecular and neuronal mechanisms underlying the antidepressant actions of ketamine have been intensively studied to pave the way for the development of novel, rapid and more efficacious antidepressants with fewer side effects than ketamine. Preclinical studies demonstrate that ketamine produces antidepressant effects through rapid release and/or expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and stimulation of mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex and hippocampus. We have recently found that resolvins (RvD1, RvD2, RvE1, RvE2 and RvE3), bioactive metabolites derived from docosahexaenoic acid and eicosapentaenoic acid, produce antidepressant effects, and that the antidepressant effects of RvD1, RvD2 and RvE1 require mTORC1 activation. These findings suggest that resolvins could be promising targets for the development of novel rapid antidepressants with fewer side effects than ketamine because they are endogenous lipid mediators that play an important role in homeostasis.


Assuntos
Ketamina , Fator A de Crescimento do Endotélio Vascular , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Ketamina/farmacologia , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato
4.
Brain Nerve ; 72(11): 1127-1134, 2020 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-33191291

RESUMO

Gamma-aminobutyric acid (GABA) generally induces hyperpolarization and inhibition in the adult brain, but causes depolarization (and can be excitatory) in the immature brain. Because GABAA receptors are Cl- channels, alternating GABA actions between hyperpolarization (Cl- influx) and depolarization (Cl- efflux) are induced by changes in the Cl- gradient, which is regulated by Cl- transporters. Thus, the dynamics of neural functions are modulated by "active" Cl- homeostasis (Cl- homeodynamics), alternating inhibition and excitation, and could be the underlying mechanism of modal shifts in cellular and network oscillations. An ontogenic modal shift in GABA actions is required for normal development, but an aversive reverse modal shift in adults could occur occasionally. Thus any disturbance in this ordinal developmental GABA modal shift, resulting in an abnormal temporal window of depolarizing (excitatory) GABA action, could be the underlying pathogenesis of diverse neurodevelopmental disorders and neurological diseases.


Assuntos
Neurônios , Ácido gama-Aminobutírico , Humanos
5.
Brain Nerve ; 72(11): 1151-1157, 2020 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-33191294

RESUMO

Current inputs with a specific frequency tend to be output as a large voltage response in some neurons. This property is called resonance and is thought to be the basis for the frequency response of neurons. In this review, I summarize the molecules required for generating resonance.


Assuntos
Modelos Neurológicos , Neurônios , Humanos , Potenciais da Membrana
6.
Brain Nerve ; 72(11): 1159-1171, 2020 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-33191295

RESUMO

Network disorders of the basal ganglia may underlie the pathophysiology of movement disorders, such as Parkinson's disease and dystonia. The following models have been proposed to explain network disorders: (1) the firing rate model: an activity imbalance between the direct, indirect, and hyperdirect pathways induces changes in the mean firing rate of the output nuclei of the basal ganglia and causes hypokinetic or hyperkinetic movement disorders, (2) the firing pattern model: oscillatory and/or synchronized activity in the basal ganglia disturbs information processing in this area, resulting in motor symptoms and, (3) the dynamic activity model: abnormal neuronal modulations through the direct, indirect, and hyperdirect pathways disrupt the balance between movement-related inhibition and surrounding excitation in the output nuclei, which leads to motor symptoms. We present a critical analysis of these models in this review. Stereotactic surgery, which involves the application of high-frequency electrical stimulation (deep brain stimulation) or coagulation of a small area in the basal ganglia is an effective therapeutic strategy to treat movement disorders. We have also discussed the mechanism underlying the beneficial effects of stereotactic surgery.


Assuntos
Doença de Parkinson , Gânglios da Base , Humanos , Movimento , Neurônios , Doença de Parkinson/terapia
7.
Brain Nerve ; 72(11): 1183-1194, 2020 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-33191297

RESUMO

Oscillatory neuronal (electrical) activity in defined frequency ranges supports synchronous interactions between anatomically distinct regions of the human brain during cognitive tasks. Here in, this study presents a review of our previous studies, focusing on the neural oscillations in the sensory systems in response to external stimuli in normal healthy subjects and those with neurological disorders. Event-related evoked responses, using magnetoencephalography and high-density electroencephalography, were applied to evaluate neuromagnetic oscillations. This study demonstrated that altered neural synchronization plays an important role in distributed cortico-cortical processing. Therefore, some neuropsychiatric disorders can be conceptualized as network diseases.


Assuntos
Encéfalo , Magnetoencefalografia , Eletroencefalografia , Humanos , Neurônios
8.
Brain Nerve ; 72(11): 1207-1221, 2020 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-33191299

RESUMO

The brain is a kind of very large-scale integration circuit or its beyond that produces extremely various ranges of electroencephalogram. Epilepsy is a state caused by explosively hyperexcitable brain activities. Recently, it has been suggested that not only the hyperexcitability of neurons but also glial cells, which were previously thought to be silent or plain, play a crucial role in the acquisition of epileptogenicity. In this review article, we will comprehensively describe the utility of the analysis of brain activities from extremely low to high frequency oscillations. Our multi-institute study confirmed that ictal direct current shifts (ictal DC) precedes ictal high-frequency oscillations (ictal HFOs), being more prominent in neocortical epilepsy than in temporal lobe epilepsy. Moreover, we revealed that the complete resection of the core regions of ictal DC shifts significantly correlated with favorable outcomes after epileptic surgery. Taking our findings and previous knowledge into account, we will address the importance of not only neuronal but also glial functions towards the better understanding of pathogenesis of the so-called "chronic" state of epilepsy.


Assuntos
Mapeamento Encefálico , Epilepsia , Encéfalo , Eletroencefalografia , Humanos , Neuroglia , Neurônios , Convulsões
9.
Brain Nerve ; 72(11): 1223-1237, 2020 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-33191300

RESUMO

Electroencephalographic recordings of human brain oscillations have been performed over approximately a century. Noninvasive methods for manipulation of brain oscillations are currently available. Reportedly, the manipulation of brain oscillations alters human behavior and cognition and is also used for "oscillotherapy" to treat many neurological diseases. In this review, we summarize the physiological mechanisms of brain oscillations, human behavioral and cognitive changes, and oscillotherapy; we have focused on our recent findings of the manipulation of human brain oscillations during bipedal walking and gait disorder recovery.


Assuntos
Encéfalo , Neurônios , Cognição , Eletroencefalografia , Humanos , Caminhada
10.
Nat Commun ; 11(1): 5073, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033238

RESUMO

Brain cells continuously produce and release protons into the extracellular space, with the rate of acid production corresponding to the levels of neuronal activity and metabolism. Efficient buffering and removal of excess H+ is essential for brain function, not least because all the electrogenic and biochemical machinery of synaptic transmission is highly sensitive to changes in pH. Here, we describe an astroglial mechanism that contributes to the protection of the brain milieu from acidification. In vivo and in vitro experiments conducted in rodent models show that at least one third of all astrocytes release bicarbonate to buffer extracellular H+ loads associated with increases in neuronal activity. The underlying signalling mechanism involves activity-dependent release of ATP triggering bicarbonate secretion by astrocytes via activation of metabotropic P2Y1 receptors, recruitment of phospholipase C, release of Ca2+ from the internal stores, and facilitated outward HCO3- transport by the electrogenic sodium bicarbonate cotransporter 1, NBCe1. These results show that astrocytes maintain local brain extracellular pH homeostasis via a neuronal activity-dependent release of bicarbonate. The data provide evidence of another important metabolic housekeeping function of these glial cells.


Assuntos
Astrócitos/metabolismo , Bicarbonatos/metabolismo , Encéfalo/metabolismo , Espaço Extracelular/metabolismo , Acetazolamida/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Anidrases Carbônicas/metabolismo , Células Cultivadas , Estimulação Elétrica , Fluorescência , Hipocampo/metabolismo , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Antagonistas Purinérgicos/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores Purinérgicos/metabolismo , Transdução de Sinais , Simportadores de Sódio-Bicarbonato/metabolismo
11.
Nat Commun ; 11(1): 5074, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033265

RESUMO

Touch and itch sensations are crucial for evoking defensive and emotional responses, and light tactile touch may induce unpleasant itch sensations (mechanical itch or alloknesis). The neural substrate for touch-to-itch conversion in the spinal cord remains elusive. We report that spinal interneurons expressing Tachykinin 2-Cre (Tac2Cre) receive direct Aß low threshold mechanoreceptor (LTMR) input and form monosynaptic connections with GRPR neurons. Ablation or inhibition markedly reduces mechanical but not acute chemical itch nor noxious touch information. Chemogenetic inhibition of Tac2Cre neurons also displays pronounced deficit in chronic dry skin itch, a type of chemical itch in mice. Consistently, ablation of gastrin-releasing peptide receptor (GRPR) neurons, which are essential for transmitting chemical itch, also abolishes mechanical itch. Together, these results suggest that innocuous touch and chemical itch information converge on GRPR neurons and thus map an exquisite spinal circuitry hard-wired for converting innocuous touch to irritating itch.


Assuntos
Rede Nervosa/fisiopatologia , Prurido/fisiopatologia , Tato/fisiologia , Animais , Comportamento Animal , Injeções Espinhais , Luz , Potenciais da Membrana , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Precursores de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores da Bombesina/metabolismo , Pele/patologia , Medula Espinal/fisiopatologia , Sinapses/metabolismo , Taquicininas/metabolismo
12.
Zh Nevrol Psikhiatr Im S S Korsakova ; 120(9. Vyp. 2): 26-33, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33076642

RESUMO

OBJECTIVE: To describe the changes in temporal characteristics of sleep-wake cycle, which can serve as non-motor manifestations of an early stage of Parkinson's disease (PD), using the model of preclinical PD in rats of two age groups. MATERIAL AND METHODS: A prolonged (up to 21 days) model of preclinical PD in middle-aged (7-8 month) and aged (19-20 month) rats was created. The model was based on cumulative inhibition of proteasomal system of the brain caused by intranasal administration of lactacystin, a specific proteasome inhibitor. Polysomnographic data were recorded daily using telemetric Dataquest A.R.T. System (DSI, USA) in unrestrained animals. RESULTS AND CONCLUSION: Aging was accompanied with increased sleepiness during the active (dark) phase of the day (as was implied by a two-fold increase in the total time of drowsiness) and with 1.5-fold growth of light sleep during the inactive phase of the day. A common feature of sleep disturbances in the model of preclinical PD in both middle-aged and aged rats was hypersomnia during the active phase of the day. It was suggested to be similar to the excessive daytime sleepiness in humans. Hypersomnolence was more pronounced in aged rats because it added to sleepiness developing with aging. In both age groups, the model of preclinical PD was also associated with a decrease in EEG delta power during slow-wave sleep. It is considered dangerous because it might represent the decrease in protein synthesis rate and the weakening of restorative processes in neurons, occurring with the prolonged inhibition of proteasomal system of the brain. Sleep disturbances, identified the model of preclinical PD in rats of different age, may be recommended for clinical validation as low-cost early signs indicating the initial stage of PD.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Doença de Parkinson , Transtornos do Sono-Vigília , Animais , Humanos , Pessoa de Meia-Idade , Neurônios , Ratos , Transtornos do Sono-Vigília/etiologia , Vigília
13.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 365-368, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018004

RESUMO

Edge information is essential for object recognition and motion detection. It is reported that photoreceptors, horizontal cells and bipolar cells in the outer retina involved for edge detection. Moreover, it is known that the center and the surround receptive field structure found in the bipolar cell layer is thought to be related to an initial process of edge detection. In the present study, we constructed retinal network models including photoreceptors, horizontal cells, and bipolar cells using single-compartment neurons to investigate those contributions for edge detection. We simulate fixation of a natural image with changing the size of the horizontal cell receptive field and confirmed that the constructed model successfully extracts edges in the image. Furthermore, most of the edge in the scene is extracted when the size of the horizontal cell receptive field matched with that reported in anatomical evidence. To evaluate the performance of edge detection, we compare the result of edge detection with the Canny algorithm. As a result, we conformed that the model well detects fine edges similar to the Canny edge detection.


Assuntos
Células Fotorreceptoras , Retina , Algoritmos , Modelos Teóricos , Neurônios
14.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 1051-1054, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018166

RESUMO

Oxygen deprivation (hypoxia) and reduced blood supply (ischemia) can occur before, during or shortly after birth and can result in death, brain damage and long-term disability. Assessing neuronal survival after hypoxia-ischemia in the near-term fetal sheep brain model is essential for the development of novel treatment strategies. As manual quantification of neurons in histological images varies between different assessors and is extremely time-consuming, automation of the process is needed and has not been currently achieved. To achieve automation, successfully segmenting the neurons from the background is very important. Due to presence of densely populated overlapping cells and with no prior information of shapes and sizes, the segmentation of neurons from the image is complex. Initially, we segmented the RGB images by using K-means clustering to primarily segment the neurons from the background based on their colour value, a distance transform for seed detection and watershed method for separating overlapping objects. However, this resulted in unsatisfactory sensitivity and performance due to over-segmentation if we use the RGB image directly. In this paper, we propose a semi-automated modified approach to segment neurons that tackles the over-segmentation issue that we encountered. Initially, we separated the red, green and blue colour channel information from the RGB image. We determined that by applying the same segmentation method first to the blue channel image, then by performing segmentation on the green channel for the neurons that remain unsegmented from the blue channel segmentation and finally by performing segmentation on red channel for neurons that were still unsegmented from the green channel segmentation, improved performance results could be achieved. The modified approach increased performance for the healthy and ischemic animal images from 89.7% to 98.08% and from 94.36% to 98.06% respectively as compared to using RGB image directly.


Assuntos
Feto , Fenômenos Fisiológicos do Sistema Nervoso , Animais , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Neurônios , Gravidez , Cuidado Pré-Natal , Ovinos
15.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 1836-1839, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018357

RESUMO

Measuring neural activity from well-defined neural populations deep inside the brain has an important value in neuroscience. Fiber photometry is an important technique for evaluating neuron activity inside the brain. Besides, miniature wireless systems to record neuronal activity in a fully untethered experimental setting have recently become extremely interesting for experimenters. Still, a noise-robust wireless fiber photometry system for this purpose does not exist. Using an isosbestic excitation wavelength for recording with GCaMP6 has recently been suggested to reduce the different types of noises. We present the design of a wireless fiber photometry system at 470 nm for calcium-dependent fluorescence emission of GCaMP6 using a calcium-independent isosbestic excitation wavelength of 410 nm. Synthetic emission fluorescence light was played from a function generator to drive an LED at 530 nm at test the photometry platform. The setup has been fixed at 4.18 mW light power after linearity assessment while the analog circuit has THD of 0.35%. Then, the recorded synthetic neuronal activity was transmitted wirelessly to the base station. Finally, the isosbestic response has been aligned and removed from the calcium-dependent fluorescence signal to have a noiseless neuronal activity.


Assuntos
Fibras na Dieta , Fotometria , Animais , Encéfalo , Laxantes , Neurônios
16.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2287-2290, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018464

RESUMO

Mitochondria play a critical role in regulating cellular processes including ATP production, intracellular calcium signaling and generation of reactive oxidative species (ROS). Neurons rely on mitochondrial function to perform a range of complex processes, and mitochondrial dysfunctions have been shown to have an impact in pathologies of the nervous system. Yet, neurons contain a finite number of mitochondria, and their location is known to change in response to a number of factors including age and cellular activity, thereby impacting neuronal response. In this paper, we introduce a novel computational model of mitochondria motility that focuses on their movements along the axon. We describe the biological processes involved and the main parameters of the model. We use the model to investigate how some of these parameters affect the ability of mitochondria to position themselves in regions of high energy demand. Finally, we discuss the significance of our work and its downstream applications in further understanding pathologies of the nervous system such as Alzheimer's disease, and help identify potential novel therapeutic targets.


Assuntos
Axônios , Mitocôndrias , Sinalização do Cálcio , Movimento Celular , Mitocôndrias/metabolismo , Neurônios
17.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2368-2371, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018482

RESUMO

It has been widely accepted that Parkinson's disease (PD) is triggered and shaped by propagation of misfolded α-synuclein. Converging neurophysiological evidence suggests that leucine-rich repeat kinase 2 (LRRK2) is involved in membrane transport of PD pathogenesis. This study proposed an agent-based computational model by integrating structural connections and gene expression to investigate whether LRRK2 would affect the PD pathology propagation in central nervous system. Gene expression profiles from the Allen Human Brain Atlas (AHBA) and multimodal brain MRI images from Parkinson's Progression Markers Initiative (PPMI) and Human Connectome Project (HCP) were employed for the model construction. The model results exhibit the involvement of LRRK2 gene expression remarkably elevated model fitting (r = 0.73) compared with the traditional susceptible-infected-removed (S-I-R) model (r=0.60). Specifically, our model revealed that LRRK2 is more likely to modulate pathology secretion out of neurons, rather than spreading into neurons. The findings support the theory of LRRK2 gene expression modulating cell-to-cell propagation of misfolded proteins. As a result, the proposed model would bring new insights of understanding PD mechanism in terms of misfolded α-synuclein propagation.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Encéfalo/diagnóstico por imagem , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Neurônios/metabolismo , Doença de Parkinson/genética , alfa-Sinucleína/genética
18.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2491-2495, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018512

RESUMO

Cortical spreading depression (CSD) is a slowly propagating wave of depolarization of brain cells, followed by temporary silenced electrical brain activity. Major structural changes during CSD are linked to neuronal and possibly glial swelling. However, basic questions still remain unanswered. In particular, there are open questions regarding whether neurons or glial cells swell more, and how the cellular swelling affects the CSD wave propagation.In this study, we computationally explore how different parameters affect the swelling of neurons and astrocytes (starshaped glial cells) during CSD and how the cell swelling alters the CSD wave spatial distribution. We apply a homogenized mathematical model that describes electrodiffusion in the intraand extracellular space, and discretize the equations using a finite element method. The simulations are run with a twocompartment (extracellular space and neurons) and a threecompartment version of the model with astrocytes added. We consider cell swelling during CSD in four scenarios: (A) incorporating aquaporin-4 channels in the astrocytic membrane, (B) increasing the neuron/astrocyte ratio to 2:1, (C) blocking and increasing the Na+/K+-ATPase rate in the astrocytic compartment, and (D) blocking the Cl- channels in astrocytes. Our results show that increasing the water permeability in the astrocytes results in a higher astrocytic swelling and a lower neuronal swelling than in the default case. Further, elevated neuronal density increases the swelling in both neurons and astrocytes. Blocking the Na+/K+-ATPase in the astrocytes leads to an increased wave width and swelling in both compartments, which instead decreases when the pump rate is raised. Blocking the Cl- channels in the astrocytes results in neuronal swelling, and a shrinkage in the astrocytes. Our results suggest a supporting role of astrocytes in preventing cellular swelling and CSD, as well as highlighting how dysfunctions in astrocytes might elicit CSD.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Aquaporina 4 , Astrócitos , Neurônios , ATPase Trocadora de Sódio-Potássio
19.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2938-2941, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018622

RESUMO

Electrical brain stimulation (EBS) has been actively researched because of its clinical application and usefulness in brain research. However, its effect on individual neurons remains uncertain, as each neuron's response to EBS is highly variable and dependent on its morphology and the axis in which a neuron lies. Hence, our goal was to investigate the way that neuronal morphology affects the cellular response to extracellular stimulation from multiple directions. In this computational study, we observed that the varying neuronal morphology and direction of applied electrical field (EF) had some influence on the excitation threshold, which generates an action potential. Further, change of the excitation threshold depending on EF directions was observed.Clinical Relevance- These findings would help us to understand the variability in the modulatory effects of EBS at the cellular level and would be the basis for understanding the packed fibers' responses to EBS. Ultimately, considering EBS' clinical application, it may also help to predict patient's results from EBS treatment.


Assuntos
Modelos Neurológicos , Neurônios , Encéfalo , Estimulação Elétrica , Eletricidade , Humanos
20.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 3046-3049, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018647

RESUMO

In the design of brain-machine interface (BMI), as the number of electrodes used to collect neural spike signals declines slowly, it is important to be able to decode with fewer units. We tried to train a monkey to control a cursor to perform a two-dimensional (2D) center-out task smoothly with spiking activities only from two units (direct units). At the same time, we studied how the direct units did change their tuning to the preferred direction during BMI training and tried to explore the underlying mechanism of how the monkey learned to control the cursor with their neural signals. In this study, we observed that both direct units slowly changed their preferred directions during BMI learning. Although the initial angles between the preferred directions of 3 pairs units are different, the angle between their preferred directions approached 90 degrees at the end of the training. Our results imply that BMI learning made the two units independent of each other. To our knowledge, it is the first time to demonstrate that only two units could be used to control a 2D cursor movements. Meanwhile, orthogonalizing the activities of two units driven by BMI learning in this study implies that the plasticity of the motor cortex is capable of providing an efficient strategy for motor control.


Assuntos
Interfaces Cérebro-Computador , Córtex Motor , Animais , Macaca mulatta , Movimento , Neurônios
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