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1.
Cell Physiol Biochem ; 54(1): 15-26, 2020 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-31916734

RESUMEN

BACKGROUND/AIMS: The primary cilium is a nanoscale membrane protrusion believed to act as a mechano-chemical sensor in a range of different cell types. Disruptions in its structure and signalling have been linked to a number of medical conditions, referred to as ciliopathies, but remain poorly understood due to lack of techniques capable of investigating signal transduction in cilia at nanoscale. Here we set out to use latest advances in nanopipette technology to address the question of ion channel distribution along the structure of primary cilium. METHODS: We used glass nanopipettes and Scanning Ion Conductance Microscopy (SICM) to image 3D topography of intact primary cilia in inner medullary collecting duct (IMCD) cells with nanoscale resolution. The high-resolution topographical images were then used to navigate the nanopipette along the structure of each cilium and perform spatially resolved single-channel recordings under precisely controlled mechanical and chemical stimulation. RESULTS: We have successfully obtained first single-channel recordings at specific locations of intact primary cilia. Our experiments revealed significant differences between the populations of channels present at the ciliary base, tip and within extra-ciliary regions in terms of mean conductance and sensitivity to membrane displacement as small as 100 nm. Ion channels at the base of cilium, where mechanical strain is expected to be the highest, appeared particularly sensitive to the mechanical displacement. CONCLUSION: Our results suggest the distribution of ion channels in the membrane of primary cilia is non-homogeneous. The relationship between the location and function of ciliary ion channels could be key to understanding signal transduction in primary cilia.


Asunto(s)
Membrana Celular/metabolismo , Cilios/metabolismo , Canales Iónicos/metabolismo , Nanotecnología/métodos , Potenciales de Acción/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/farmacología , Animales , Células Cultivadas , Células Epiteliales/citología , Células Epiteliales/metabolismo , Mecanotransducción Celular , Ratones
2.
Life Sci ; 244: 117333, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31962132

RESUMEN

AIMS: Detect the antiarrhythmic effect of crotonoside (Cro). MAIN METHODS: We used whole-cell patch-clamp techniques to detect the effects of Cro on action potentials (APs) and transmembrane ion currents in isolated rabbit left ventricular myocytes. We also verified the effect of Cro on ventricular arrhythmias caused by aconitine in vivo. KEY FINDINGS: Cro reduced the maximum depolarization velocity (Vmax) of APs and shortened the action potential duration (APD) in a concentration-dependent manner, but it had no significant effect on the resting membrane potential (RMP) or action potential amplitude (APA). It also inhibited the peak sodium current (INa) and L-type calcium current (ICaL) in a concentration-dependent manner with half-maximal inhibitory concentrations (IC50) of 192 µmol/L and 159 µmol/L, respectively. However, Cro had no significant effects on the inward rectifier potassium current (IK1) or rapidly activating delayed rectifier potassium current (IKr). Sea anemone toxin II (ATX II) increased the late sodium current (INaL), but Cro abolished this effect. Moreover, Cro significantly abolished ATX II-induced early afterdepolarizations (EADs) and high extracellular Ca2+ concentration (3.6 mmol/L)-induced delayed afterdepolarizations (DADs). We also verified that Cro effectively delayed the onset time and reduced the incidence of ventricular arrhythmias caused by aconitine in vivo. SIGNIFICANCE: These results revealed that Cro effectively inhibits INa, INaL, and ICaL in ventricular myocytes. Cro has antiarrhythmic potential and thus deserves further study.


Asunto(s)
Guanina/farmacología , Miocitos Cardíacos/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Antiarrítmicos/metabolismo , Antiarrítmicos/farmacología , Arritmias Cardíacas/fisiopatología , Calcio/metabolismo , Canales de Calcio/efectos de los fármacos , China , Femenino , Guanina/metabolismo , Ventrículos Cardíacos/metabolismo , Técnicas de Placa-Clamp/métodos , Conejos , Sodio/metabolismo , Canales de Sodio/efectos de los fármacos
3.
DNA Cell Biol ; 39(2): 289-298, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31916853

RESUMEN

TBX3 reprograms cardiac myocytes into cells that possess sinoatrial node phenotype, but no specific funny current (If) was detected. We explore whether overexpression of TBX3 alone or combined with HCN2 can reprogram human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) into pacemaker-like cells. HiPSC-CMs were transfected with TBX3 and/or HCN2 in this study. Expression analysis showed that overexpression of TBX3 induces a reduced reduction expression profile of working cardiomyocytes into that of pacemaker cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and electrophysiological analyses showed a reduced expression of connexins subunits (CX40, CX43), the sodium current (SCN5A, INa), the inward rectified potassium channels (Kir2.1, IK1), and an increased expression of connexins subunits (CX30.2, CX45). No If was detected. The reduction of IK1 resulted in a more depolarized maximum diastolic potential together with an expression of If (generated by HCN2), which they work in synergy to generate spontaneous diastolic depolarization that was the most typical characteristic of pacemaker cells. In conclusion, overexpression of TBX3 and HCN2 could reprogram hiPSC-CMs into pacemaker-like cells. The ability to enable diastolic depolarization formation provides a new strategy for the construction of a biological pacemaker.


Asunto(s)
Diferenciación Celular/genética , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Células Madre Pluripotentes Inducidas/metabolismo , Canales de Potasio/genética , Proteínas de Dominio T Box/genética , Potenciales de Acción/fisiología , Relojes Biológicos/genética , Humanos , Miocitos Cardíacos/metabolismo
4.
Toxicol Lett ; 322: 98-103, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-31954869

RESUMEN

Patients intoxicated with organophosphorous compounds may need general anaesthesia to enable mechanical ventilation or for control of epileptiform seizures. It is well known that cholinergic overstimulation attenuates the efficacy of general anaesthetics to reduce spontaneous network activity in the cortex. However, it is not clear how propofol, the most frequently used intravenous anaesthetic today, is affected. Here, we investigated the effects of cholinergic overstimulation induced by soman and acetylcholine on the ability of propofol to depress spontaneous action potential activity in organotypic cortical slices measured by extracellular voltage recordings. Cholinergic overstimulation by co-application of soman and acetylcholine (10 µM each) did not reduce the relative inhibition of propofol (1.0 µM; mean normalized action potential firing rate 0.49 ± 0.06 of control condition, p < 0.001, Wilcoxon signed rank test) but clearly reduced its efficacy. Co-application of atropine (10 nM) did not improve the efficacy. Propofol preserved its relative inhibitory potential but did not produce a degree of neuronal depression which can be expected to assure hypnosis in humans. Since a combination with atropine did not improve its efficacy, an increase in dosage will probably be necessary when propofol is used in victims suffering from organophosphorous intoxication.


Asunto(s)
Acetilcolina/toxicidad , Potenciales de Acción/efectos de los fármacos , Anestésicos Intravenosos/farmacología , Red Nerviosa/efectos de los fármacos , Propofol/farmacología , Soman/toxicidad , Acetilcolina/administración & dosificación , Anestesia General , Anestésicos Intravenosos/administración & dosificación , Animales , Ratones Endogámicos C57BL , Neocórtex/efectos de los fármacos , Neocórtex/fisiología , Red Nerviosa/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Técnicas de Cultivo de Órganos , Intoxicación por Organofosfatos , Propofol/administración & dosificación , Soman/administración & dosificación
5.
Life Sci ; 240: 117068, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31751583

RESUMEN

AIMS: Bradycardia contributes to tachy-brady arrhythmias or sinus arrest during heart failure (HF). Sinoatrial node (SAN) adenosine A1 receptors (ADO A1Rs) are upregulated in HF, and adenosine is known to exert negative chronotropic effects on the SAN. Here, we investigated the role of A1R signaling at physiologically relevant ADO concentrations on HF SAN pacemaker cells. MAIN METHODS: Dogs with tachypacing-induced chronic HF and normal controls (CTL) were studied. SAN tissue was collected for A1R and GIRK mRNA quantification. SAN cells were isolated for perforated patch clamp recordings and firing rate (bpm), slope of slow diastolic depolarization (SDD), and maximum diastolic potential (MDP) were measured. Action potentials (APs) and currents were recorded before and after addition of 1 and 10 µM ADO. To assess contributions of A1R and G protein-coupled Inward Rectifier Potassium Current (GIRK) to ADO effects, APs were measured after the addition of DPCPX (selective A1R antagonist) or TPQ (selective GIRK blocker). KEY FINDINGS: A1R and GIRK mRNA expression were significantly increased in HF. In addition, ADO induced greater rate slowing and membrane hyperpolarization in HF vs CTL (p < 0.05). DPCPX prevented ADO-induced rate slowing in CTL and HF cells. The ADO-induced inward rectifying current, IKado, was observed significantly more frequently in HF than in CTL. TPQ prevented ADO-induced rate slowing in HF. SIGNIFICANCE: An increase in A1R and GIRK expression enhances IKAdo, causing hyperpolarization, and subsequent negative chronotropic effects in canine chronic HF at relevant [ADO]. GIRK blockade may be a useful strategy to mitigate bradycardia in HF.


Asunto(s)
Agonistas del Receptor de Adenosina A1/farmacología , Adenosina/farmacología , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/agonistas , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Receptor de Adenosina A1/metabolismo , Nodo Sinoatrial/citología , Nodo Sinoatrial/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Antagonistas del Receptor de Adenosina A1/farmacología , Animales , Venenos de Abeja/farmacología , Relojes Biológicos , Enfermedad Crónica , Perros , Femenino , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/antagonistas & inhibidores , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/efectos de los fármacos , Técnicas In Vitro , Masculino , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Receptor de Adenosina A1/efectos de los fármacos , Xantinas/farmacología
6.
Nat Rev Cardiol ; 17(1): 22-36, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31249403

RESUMEN

Conventional right ventricular (RV) pacing, particularly RV apical pacing, can have deleterious effects on cardiac function. Long-term RV apical pacing has been associated with increased risk of atrial fibrillation, hospitalization for heart failure, pacing-induced cardiomyopathy and associated death. His bundle pacing (HBP) results in physiological ventricular activation and has generated tremendous research interest and enthusiasm. By stimulating the His-Purkinje network directly, HBP results in synchronized ventricular activation, which might translate into improved clinical outcomes compared with dyssynchronous ventricular activation with RV apical pacing. HBP can also overcome bundle branch block patterns, and data are accumulating on the benefit of HBP for cardiac resynchronization therapy. In this Review, we summarize the anatomy of the His bundle and early clinical observations, implantation techniques and available outcome data associated with permanent HBP. We also highlight the challenges with HBP and the need for additional tools and more randomized data before widespread application of permanent HBP.


Asunto(s)
Arritmias Cardíacas/terapia , Fascículo Atrioventricular/fisiopatología , Estimulación Cardíaca Artificial/tendencias , Insuficiencia Cardíaca/terapia , Potenciales de Acción , Animales , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/mortalidad , Arritmias Cardíacas/fisiopatología , Estimulación Cardíaca Artificial/efectos adversos , Estimulación Cardíaca Artificial/mortalidad , Difusión de Innovaciones , Predicción , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca , Humanos , Factores de Riesgo , Resultado del Tratamiento
7.
Toxicol Lett ; 318: 57-64, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31585160

RESUMEN

3-Bromopyruvate (3-BrPA) is a promising agent that has been widely studied in the treatment of cancer and pulmonary hypertension. Rotenone is a pesticide commonly used on farms and was shown to have anti-cancer activity and delay fibrosis progression in chronic kidney disease in a recent study. However, there are few studies showing the toxicity of rotenone and 3-BrPA in the myocardium. To support further medical exploration, it is necessary to clarify the side effects of these compounds on the heart. This study was designed to examine the cardiotoxicity of 3-BrPA and rotenone by investigating electrical and structural cardiac remodeling in rats. Forty male rats were divided into 4 groups (n = 10 in each group) and injected intraperitoneally with 3-BrPA, rotenone or a combination of 3-BrPA and rotenone. The ventricular effective refractory period (VERP), corrected QT interval (QTc), and ventricular tachycardia/ventricular fibrillation (VT/VF) inducibility were measured. The expression of Cx43, Kir2.1, Kir6.2, DHPRα1, KCNH2, caspase3, caspase9, Bax, Bcl2, and P53 was detected. Masson's trichrome, TUNEL, HE, and PAS staining and transmission electron microscopy were used to detect pathological and ultrastructural changes. Our results showed that rotenone alone and rotenone combined with 3-BrPA significantly increased the risk of ventricular arrhythmias. Rotenone combined with 3-BrPA caused myocardial apoptosis, and rotenone alone and rotenone combined with 3-BrPA caused electrical and structural cardiac remodeling in rats.


Asunto(s)
Antineoplásicos/toxicidad , Ventrículos Cardíacos/efectos de los fármacos , Insecticidas/toxicidad , Piruvatos/toxicidad , Rotenona/toxicidad , Taquicardia Ventricular/inducido químicamente , Fibrilación Ventricular/inducido químicamente , Remodelación Ventricular/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Cardiotoxicidad , Conexina 43/genética , Conexina 43/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/ultraestructura , Masculino , Canales de Potasio de Rectificación Interna/genética , Canales de Potasio de Rectificación Interna/metabolismo , Ratas Wistar , Periodo Refractario Electrofisiológico/efectos de los fármacos , Medición de Riesgo , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/patología , Taquicardia Ventricular/fisiopatología , Fibrilación Ventricular/metabolismo , Fibrilación Ventricular/patología , Fibrilación Ventricular/fisiopatología
8.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 36(6): 902-910, 2019 Dec 25.
Artículo en Chino | MEDLINE | ID: mdl-31875362

RESUMEN

Biological neural networks have dual properties of small-world attributes and scale-free attributes. Most of the current researches on neural networks are based on small-world networks or scale-free networks with lower clustering coefficient, however, the real brain network is a scale-free network with small-world attributes. In this paper, a scale-free spiking neural network with high clustering coefficient and small-world attribute was constructed. The dynamic evolution process was analyzed from three aspects: synaptic regulation process, firing characteristics and complex network characteristics. The experimental results show that, as time goes by, the synaptic strength gradually decreases and tends to be stable. As a result, the connection strength of the network decreases and tends to be stable; the firing rate of neurons gradually decreases and tends to be stable, and the synchronization becomes worse; the local information transmission efficiency is stable, the global information transmission efficiency is reduced and tends to be stable, and the small-world attributes are relatively stable. The dynamic characteristics vary with time and interact with each other. The regulation of synapses is based on the firing time of neurons, and the regulation of synapses will affect the firing of neurons and complex characteristics of networks. In this paper, a scale-free spiking neural network was constructed, which has biological authenticity. It lays a foundation for the research of artificial neural network and its engineering application.


Asunto(s)
Modelos Neurológicos , Plasticidad Neuronal , Potenciales de Acción , Sinapsis
9.
Nat Neurosci ; 22(12): 2050-2059, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31768054

RESUMEN

Affective learning and memory are essential for daily behavior, with both adaptive and maladaptive learning depending on stimulus-evoked activity in the amygdala circuitry. Behavioral studies further suggest that post-association offline processing contributes to memory formation. Here we investigated spike sequences across simultaneously recorded neurons while monkeys learned to discriminate between aversive and pleasant tone-odor associations. We show that triplets of neurons exhibit consistent temporal sequences of spiking activity that differed from firing patterns of individual neurons and pairwise correlations. These sequences occurred throughout the long post-trial period, contained valence-related information, declined as learning progressed and were selectively present in activity evoked by the recent pairing of a conditioned stimulus with an unconditioned stimulus. Our findings reveal that temporal sequences across neurons in the primate amygdala serve as a coding mechanism and might aid memory formation through the rehearsal of the recently experienced association.


Asunto(s)
Amígdala del Cerebelo/fisiología , Memoria/fisiología , Neuronas/fisiología , Potenciales de Acción/fisiología , Animales , Condicionamiento Clásico/fisiología , Aprendizaje Discriminativo/fisiología , Macaca fascicularis , Factores de Tiempo
10.
Zhonghua Yi Xue Za Zhi ; 99(43): 3413-3416, 2019 Nov 19.
Artículo en Chino | MEDLINE | ID: mdl-31752469

RESUMEN

Objective: To investigate the application value of motor unit number index (MUNIX) for diagnosis and assessment progress in patients with amyotrophic lateral sclerosis (ALS). Method: Sixty healthy controls and 60 ALS patients in the clinic were enrolled from May 2017 to December 2018. The bilateral deltoid, abductor digiti minimi, quadriceps femoris and tibialis anterior muscles of the subjects were detected by MUNIX method, and the negative peak amplitude of compound muscle action potential (CMAP) of ulnar nerve, femoral nerve, peroneal nerve, axillary nerve in bilateral was collected. MUNIX and motor unit size index (MUSIX) of muscles were compared between ALS group and control group. The difference between the MUNIX abnormal rate of muscles and abnormal rate of the corresponding CMAP negative peak amplitude in ALS patients was further compared. Meanwhile, the correlation between the disease course of ALS patients and MUNIX and MUSIX was analyzed. Results: Compared with the control group, the MUNIX values of the deltoid, abductor digiti minimi, quadriceps femoris and tibialis anterior decreased significantly (97±24 vs 183±38, 48±17 vs 191±39, 54±15 vs 159±22, 49±16 vs 147±25, all P<0.05). MUSIX values increased ((175±32) µV vs (47±15) µV, (189±34) µV vs (54±16) µV, (170±30) µV vs (49±13) µV, (190± 36) µV vs (48± 14) µV, all P<0.05)). In ALS patients, the abnormal rate of MUNIX was respectively 81%, 87%, 75% and 89%. The negative peak amplitude abnormal rate of corresponding neuralCMAP was 35%, 40%, 31% and 36%, respectively, with a significant difference (P<0.05). There was a negative correlation between MUNIX value and the course of disease in ALS patients (P<0.05), and a positive correlation between MUSIX value and the course of disease (P<0.05). Conclusion: The MUNIX technique exhibits the features of quantifying the proximal upper and lower limb muscles and assessing the loss of motor units in motor neuron degeneration.


Asunto(s)
Esclerosis Amiotrófica Lateral , Potenciales de Acción , Electromiografía , Humanos , Neuronas Motoras , Músculo Esquelético , Nervio Peroneo
11.
Biochemistry (Mosc) ; 84(9): 1085-1092, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31693468

RESUMEN

Many motor disorders are associated with depolarization of the membrane of skeletal muscle fibers due to the impaired functioning of Na,K-ATPase. Here, we studied the role of ouabain (specific Na,K-ATPase ligand) and AMP-activated protein kinase (key regulator of muscle metabolism) in the maintenance of muscle electrogenesis; the levels of these endogenous factors are directly related to the motor activity. After 4-day intraperitoneal administration of ouabain (1 µg/kg daily), a hyperpolarization of sarcolemma was registered in isolated rat diaphragm muscles due to an increase in the electrogenic activity of Na,K-ATPase. In acute experiments, addition of nanomolar ouabain concentrations to the bathing solution resulted in the muscle membrane hyperpolarization within 15 min. The effect of ouabain reversed to membrane depolarization with the increase in the external potassium concentration. It is possible that Na,K-ATPase activation by ouabain may be regulated by such factors as specific subcellular location, interaction with molecular partners, and changes in the ionic balance. Preventive administration of the AMP-activated protein kinase activator AICAR (5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside; 400 mg/kg body weight daily for 7 days) in chronic experiments resulted in the stabilization of the endplate structure and abolishment of depolarization of the rat soleus muscle membrane caused by the motor activity cessation. The obtained data can be useful for creating approaches for correction of muscle dysfunction, especially at the early stages, prior to the development of muscle atrophy.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Potenciales de Acción/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Ouabaína/administración & dosificación , Ouabaína/farmacología , Aminoimidazol Carboxamida/administración & dosificación , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Masculino , Fibras Musculares Esqueléticas/enzimología , Fibras Musculares Esqueléticas/metabolismo , Ratas , Ratas Wistar , Ribonucleótidos/administración & dosificación , Ribonucleótidos/farmacología , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Relación Estructura-Actividad
12.
Nat Commun ; 10(1): 4745, 2019 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-31628322

RESUMEN

Measuring neuronal tuning curves has been instrumental for many discoveries in neuroscience but requires a priori assumptions regarding the identity of the encoded variables. We applied unsupervised learning to large-scale neuronal recordings in behaving mice from circuits involved in spatial cognition and uncovered a highly-organized internal structure of ensemble activity patterns. This emergent structure allowed defining for each neuron an 'internal tuning-curve' that characterizes its activity relative to the network activity, rather than relative to any predefined external variable, revealing place-tuning and head-direction tuning without relying on measurements of place or head-direction. Similar investigation in prefrontal cortex revealed schematic representations of distances and actions, and exposed a previously unknown variable, the 'trajectory-phase'. The internal structure was conserved across mice, allowing using one animal's data to decode another animal's behavior. Thus, the internal structure of neuronal activity itself enables reconstructing internal representations and discovering new behavioral variables hidden within a neural code.


Asunto(s)
Movimientos de la Cabeza/fisiología , Red Nerviosa/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Percepción Espacial/fisiología , Potenciales de Acción/fisiología , Algoritmos , Animales , Cognición/fisiología , Hipocampo/citología , Hipocampo/fisiología , Masculino , Ratones Endogámicos C57BL , Modelos Neurológicos , Red Nerviosa/citología , Orientación/fisiología , Corteza Prefrontal/citología
13.
Nat Commun ; 10(1): 4468, 2019 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-31578320

RESUMEN

State-of-the-art techniques allow researchers to record large numbers of spike trains in parallel for many hours. With enough such data, we should be able to infer the connectivity among neurons. Here we develop a method for reconstructing neuronal circuitry by applying a generalized linear model (GLM) to spike cross-correlations. Our method estimates connections between neurons in units of postsynaptic potentials and the amount of spike recordings needed to verify connections. The performance of inference is optimized by counting the estimation errors using synthetic data. This method is superior to other established methods in correctly estimating connectivity. By applying our method to rat hippocampal data, we show that the types of estimated connections match the results inferred from other physiological cues. Thus our method provides the means to build a circuit diagram from recorded spike trains, thereby providing a basis for elucidating the differences in information processing in different brain regions.


Asunto(s)
Potenciales de Acción/fisiología , Hipocampo/fisiología , Vías Nerviosas/fisiología , Neuronas/fisiología , Potenciales Sinápticos/fisiología , Algoritmos , Animales , Hipocampo/anatomía & histología , Hipocampo/citología , Modelos Lineales , Modelos Neurológicos , Neuronas/citología , Ratas
14.
Muscle Nerve ; 60(6): 679-686, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31566774

RESUMEN

INTRODUCTION: The purpose of this study was to comprehensively evaluate respiratory muscle function in adults with facioscapulohumeral muscular dystrophy (FSHD). METHODS: Fourteen patients with FSHD (9 men, 53 ± 16 years of age) and 14 matched controls underwent spirometry, diaphragm ultrasound, and measurement of twitch gastric and transdiaphragmatic pressures (twPgas and twPdi; n = 10) after magnetic stimulation of the lower thoracic nerve roots and the phrenic nerves. The latter was combined with recording of diaphragm compound muscle action potentials (CMAPs; n = 14). RESULTS: The following parameters were significantly lower in patients vs controls: forced vital capacity (FVC); maximum inspiratory and expiratory pressure; peak cough flow; diaphragm excursion amplitude; and thickening ratio on ultrasound, twPdi (11 ± 5 vs 20 ± 6 cmH2 O) and twPgas (7 ± 3 vs 25 ± 20 cmH2 O). Diaphragm CMAP showed no group differences. FVC correlated inversely with the clinical severity scale score (r = -0.63, P = .02). DISCUSSION: In FSHD, respiratory muscle weakness involves both the diaphragm and the expiratory abdominal muscles.


Asunto(s)
Diafragma/fisiopatología , Debilidad Muscular/fisiopatología , Distrofia Muscular Facioescapulohumeral/fisiopatología , Músculos Respiratorios/fisiopatología , Potenciales de Acción/fisiología , Adulto , Anciano , Estudios de Casos y Controles , Estudios Transversales , Diafragma/diagnóstico por imagen , Femenino , Humanos , Masculino , Presiones Respiratorias Máximas , Persona de Mediana Edad , Debilidad Muscular/etiología , Distrofia Muscular Facioescapulohumeral/complicaciones , Conducción Nerviosa , Nervio Frénico , Raíces Nerviosas Espinales , Espirometría , Vértebras Torácicas , Ultrasonografía , Capacidad Vital
15.
Nat Commun ; 10(1): 4325, 2019 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-31541103

RESUMEN

Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) are increasingly recognized as valuable for determining the effects of drugs on ion channels but they do not always accurately predict contractile responses of the human heart. This is in part attributable to their immaturity but the sensitivity of measurement tools may also be limiting. Measuring action potential, calcium flux or contraction individually misses critical information that is captured when interrogating the complete excitation-contraction coupling cascade simultaneously. Here, we develop an hypothesis-based statistical algorithm that identifies mechanisms of action. We design and build a high-speed optical system to measure action potential, cytosolic calcium and contraction simultaneously using fluorescent sensors. These measurements are automatically processed, quantified and then assessed by the algorithm. Multiplexing these three critical physical features of hiPSC-CMs allows identification of all major drug classes affecting contractility with detection sensitivities higher than individual measurement of action potential, cytosolic calcium or contraction.


Asunto(s)
Células Madre Pluripotentes Inducidas/metabolismo , Contracción Miocárdica , Miocitos Cardíacos/metabolismo , Potenciales de Acción , Algoritmos , Calcio/metabolismo , Biología Computacional , Colorantes Fluorescentes , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Canales Iónicos , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Imagen Óptica
16.
Chin J Physiol ; 62(4): 166-174, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31535632

RESUMEN

Although force steadiness varies with visuospatial information, accountable motor unit (MU) behaviors are not fully understood. This study investigated the modulation of MU discharges and force-discharge relation due to variations in the spatial resolution of visual feedback, with a particular focus on discharge variability among MUs. Fourteen young adults produced isometric force at 10% of maximal voluntary contraction (MVC) through index abduction, under the conditions of force trajectory displayed with low visual gain (LVG) and high visual gain (HVG). Together with smaller and more complex force fluctuations, HVG resulted in greater variabilities of the mean interspike interval and discharge irregularity among MUs than LVG did. Estimated via smoothening of a cumulative spike train of all MUs, global discharge rate was tuned to visual gain, with a more complex global discharge rate and a lower force-discharge relation in the HVG condition. These higher discharge variabilities were linked to larger variance of the common drive received by MUs for regulation of muscle force with higher visuospatial information. In summary, higher visuospatial information improves force steadiness with more complex force fluctuations, underlying joint effects of low-pass filter property of the musculotendon complex and central modulation of discharge variability among MUs.


Asunto(s)
Neuronas Motoras , Potenciales de Acción , Electromiografía , Humanos , Contracción Muscular , Músculo Esquelético , Alta del Paciente
17.
PLoS Comput Biol ; 15(9): e1007375, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31545787

RESUMEN

Dopaminergic neurons (DAs) of the rodent substantia nigra pars compacta (SNc) display varied electrophysiological properties in vitro. Despite this, projection patterns and functional inputs from DAs to other structures are conserved, so in vivo delivery of consistent, well-timed dopamine modulation to downstream circuits must be coordinated. Here we show robust coordination by linear parameter controllers, discovered through powerful mathematical analyses of data and models, and from which consistent control of DA subthreshold oscillations (STOs) and spontaneous firing emerges. These units of control represent coordinated intracellular variables, sufficient to regulate complex cellular properties with radical simplicity. Using an evolutionary algorithm and dimensionality reduction, we discovered metaparameters, which when regressed against STO features, revealed a 2-dimensional control plane for the neuron's 22-dimensional parameter space that fully maps the natural range of DA subthreshold electrophysiology. This plane provided a basis for spiking currents to reproduce a large range of the naturally occurring spontaneous firing characteristics of SNc DAs. From it we easily produced a unique population of models, derived using unbiased parameter search, that show good generalization to channel blockade and compensatory intracellular mechanisms. From this population of models, we then discovered low-dimensional controllers for regulating spontaneous firing properties, and gain insight into how currents active in different voltage regimes interact to produce the emergent activity of SNc DAs. Our methods therefore reveal simple regulators of neuronal function lurking in the complexity of combined ion channel dynamics.


Asunto(s)
Potenciales de Acción/fisiología , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/fisiología , Modelos Neurológicos , Algoritmos , Animales , Biología Computacional , Ratas , Sustancia Negra/citología , Sustancia Negra/metabolismo
18.
Nat Neurosci ; 22(11): 1925-1935, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31527803

RESUMEN

The thalamus is the central communication hub of the forebrain and provides the cerebral cortex with inputs from sensory organs, subcortical systems and the cortex itself. Multiple thalamic regions send convergent information to each cortical region, but the organizational logic of thalamic projections has remained elusive. Through comprehensive transcriptional analyses of retrogradely labeled thalamic neurons in adult mice, we identify three major profiles of thalamic pathways. These profiles exist along a continuum that is repeated across all major projection systems, such as those for vision, motor control and cognition. The largest component of gene expression variation in the mouse thalamus is topographically organized, with features conserved in humans. Transcriptional differences between these thalamic neuronal identities are tied to cellular features that are critical for function, such as axonal morphology and membrane properties. Molecular profiling therefore reveals covariation in the properties of thalamic pathways serving all major input modalities and output targets, thus establishing a molecular framework for understanding the thalamus.


Asunto(s)
Corteza Cerebral/anatomía & histología , Tálamo/anatomía & histología , Potenciales de Acción , Animales , Atlas como Asunto , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiología , Humanos , Ratones , Ratones Transgénicos , Vías Nerviosas/anatomía & histología , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiología , Tálamo/metabolismo , Tálamo/fisiología , Transcriptoma
19.
Nat Commun ; 10(1): 3969, 2019 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-31481671

RESUMEN

Analyses of idealized feedforward networks suggest that several conditions have to be satisfied in order for activity to propagate faithfully across layers. Verifying these concepts experimentally has been difficult owing to the vast number of variables that must be controlled. Here, we cultured cortical neurons in a chamber with sequentially connected compartments, optogenetically stimulated individual neurons in the first layer with high spatiotemporal resolution, and then monitored the subthreshold and suprathreshold potentials in subsequent layers. Brief stimuli delivered to the first layer evoked a short-latency transient response followed by sustained activity. Rate signals, carried by the sustained component, propagated reliably through 4 layers, unlike idealized feedforward networks, which tended strongly towards synchrony. Moreover, temporal jitter in the stimulus was transformed into a rate code and transmitted to the last layer. This novel mode of propagation occurred in the balanced excitatory-inhibitory regime and is mediated by NMDA-mediated receptors and recurrent activity.


Asunto(s)
Neuronas/fisiología , Transducción de Señal , Potenciales de Acción , Animales , Células Cultivadas , Corteza Cerebral/citología , Femenino , Masculino , Ratones , Neuronas/citología , Optogenética , Tiempo de Reacción/fisiología , Receptores de N-Metil-D-Aspartato/fisiología
20.
Muscle Nerve ; 60(6): 687-692, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31478199

RESUMEN

INTRODUCTION: Nerve imaging has a limited role in axonal and muscle fiber loss. In this study, we sought to explore the utility of standardized muscle ultrasound (US) assessment in these clinical scenarios. METHODS: We performed a prospective study from March to August 2018 of patients attending the neuromuscular clinic. All patients underwent clinical evaluation and standardized muscle thickness measurement by US in seven muscles. RESULTS: The study cohort consisted of 114 participants, including patients with polyneuropathy, motor neuron disease, and myopathy. The smallest distal muscle thickness was found in patients with polyneuropathy, while the smallest proximal muscle thickness was found in patients with myopathy. Muscle thickness was strongly correlated with muscle strength (r 2 = 0.62), electrophysiological findings (r 2 : 0.44-0.55), and disability score (r 2 = 0.53). DISCUSSION: Standardized muscle thickness measured by US shows diagnostic usefulness in a spectrum of neuromuscular disorders and correlates with clinical and electrophysiological findings.


Asunto(s)
Músculo Esquelético/diagnóstico por imagen , Enfermedades Neuromusculares/diagnóstico por imagen , Potenciales de Acción/fisiología , Adulto , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/fisiopatología , Electromiografía , Femenino , Humanos , Masculino , Síntomas sin Explicación Médica , Persona de Mediana Edad , Fuerza Muscular , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Atrofia Muscular Espinal/diagnóstico por imagen , Atrofia Muscular Espinal/patología , Atrofia Muscular Espinal/fisiopatología , Enfermedades Musculares/diagnóstico por imagen , Enfermedades Musculares/patología , Enfermedades Musculares/fisiopatología , Conducción Nerviosa/fisiología , Enfermedades Neuromusculares/patología , Enfermedades Neuromusculares/fisiopatología , Tamaño de los Órganos , Polineuropatías/diagnóstico por imagen , Polineuropatías/patología , Polineuropatías/fisiopatología , Estudios Prospectivos , Radiculopatía/diagnóstico por imagen , Radiculopatía/patología , Radiculopatía/fisiopatología , Ultrasonografía
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