Activation of metabotropic glutamate receptor 1 regulates hippocampal CA1 region excitability in rats with status epilepticus by suppressing the HCN1 channel

Dysregulation of hyperpolarization-activated cyclic nucleotide-gated cation(HCN)channels alters neuronal excitability.However,the role of HCN channels in status epilepticus is not fully understood.In this study,we established rat models of pentylenetetrazole-induced status epilepticus.We performed western blot assays and immunofluorescence staining.Our results showed that HCN1 channel protein expression,particularly HCN1 surface protein,was significantly decreased in the hippocampal CA1 region,whereas the expression of HCN2 channel protein was unchanged.Moreover,metabolic glutamate receptor 1(mGluR1)protein expression was increased after status epilepticus.The mGluR1 agonist(RS)-3,5-dihydroxyphenylglycine injected intracerebroventricularly increased the sensitivity and severity of pentylenetetrazole-induced status epilepticus,whereas application of the mGluR1 antagonist(+)-2-methyl-4-carboxyphenylglycine(LY367385)alleviated the severity of pentylenetetrazole-induced status epilepticus.The results from double immunofluorescence labeling revealed that mGluR1 and HCN1 were co-localized in the CA1 region.Subsequently,a protein kinase A inhibitor(H89)administered intraperitoneally successfully reversed HCN1 channel inhibition,thereby suppressing the severity and prolonging the latency of pentylenetetrazole-induced status epilepticus.Furthermore,H89 reduced the level of mGluR1,downregulated cyclic adenosine monophosphate(cAMP)/protein kinase A expression,significantly increased tetratricopeptide repeat-containing Rab8b-interacting protein(TRIP8b)(1a-4)expression,and restored TRIP8b(1b-2)levels.TRIP8b(1a-4)and TRIP8b(1b-2)are subunits of Rab8b interacting protein that regulate HCN1 surface protein.

Cranial irradiation impairs intrinsic excitability and synaptic plasticity of hippocampal CA1 pyramidal neurons with implications for cognitive function

Radiation therapy is a standard treatment for head and neck tumors.However,patients often exhibit cognitive impairments following radiation therapy.Previous studies have revealed that hippocampal dysfunction,specifically abnormal hippocampal neurogenesis or neuroinflammation,plays a key role in radiation-induced cognitive impairment.However,the long-term effects of radiation with respect to the electrophysiological adaptation of hippocampal neurons remain poorly characterized.We found that mice exhibited cognitive impairment 3 months after undergoing 10 minutes of cranial irradiation at a dose rate of 3 Gy/min.Furthermore,we observed a remarkable reduction in spike firing and excitatory synaptic input,as well as greatly enhanced inhibitory inputs,in hippocampal CA1 pyramidal neurons.Corresponding to the electrophysiological adaptation,we found reduced expression of synaptic plasticity marker VGLUT1 and increased expression of VGAT.Furthermore,in irradiated mice,long-term potentiation in the hippocampus was weakened and GluR1 expression was inhibited.These findings suggest that radiation can impair intrinsic excitability and synaptic plasticity in hippocampal CA1 pyramidal neurons.

Brain cell apoptosis and enhancement of nervous excitability in pregnant rats with high plasma levels of homocysteine

Hyperhomocysteinemia is an important risk factor for preeclampsia-eclampsia. This study established a pregnant rat model of hyperhomocysteinemia, in which blood plasma homocysteine concentrations were twice or three times greater than that of normal pregnant rats. TUNEL revealed an increase in the number of apoptotic cells in the frontal cortex of pregnant rats with hyperhomocysteinemia. In addition, immunohistochemical staining detected activated nuclear factor-KB-positve cells in the frontal cortex. Reverse transcription-PCR detected that mRNA expression of the anti-apoptotic gene bcl-2 diminished in the frontal cortex. In situ hybridization and western blotting revealed that N-methyi-D- aspartate receptor 1 mRNA and protein expression was upregulated in the frontal cortex and hippocampus. These results indicate that hyperhomocysteinemia can induce brain cell apoptosis, increase nerve excitability, and promote the occurrence of preeclampsia in pregnant rats.

Distinct neuronal excitability alterations of medial prefrontal cortex in early-life neglect model of rats

Object:Early-life neglect has irreversible emotional effects on the central nervous system.In this work,we aimed to elucidate distinct functional neural changes in me-dial prefrontal cortex(mPFC)of model rats.Methods:Maternal separation with early weaning was used as a rat model of early-life neglect.The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole-cell patch clamp.Results:Glutamatergic and GABAergic neurons of mPFC were distinguished by typi-cal electrophysiological properties.The excitation of mPFC glutamatergic neurons was significantly increased in male groups,while the excitation of mPFC GABAergic neurons was significant in both female and male groups,but mainly in terms of rest membrane potential and amplitude,respectively.Conclusions:Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early-life neglect,which can contribute to distinct mechanisms for emotional and cognitive manifestations.

Effects of rhubarb extracts on hyperexcitability of hippocampal CA1 neurons after fluid percussion injury

Objective To investigate the effects of rhubarb extracts,i.e.rhein and emodin,on the neuronal hyperexcitability and synaptic transmission,and to further reveal the mechanism of the secondary brain damage.Methods The fluid percussion injury(FPI) rat model and extracellular recording method were used.The evoked field potentials by stimulating Schaffer collaterals were collected from the ipsilateral(impact side) and the contralateral hippocampal CA1 areas of rat in vitro.And the field potentials,including the field excitatory postsynaptic potential and the population spike,were analyzed.Results After the impact was performed on the rat parietal cortex,the evoked field potentials in the ipsilateral hippocampus CA1 area were enhanced obviously.Rhubarb extracts reduced the slope of the field excitatory postsynaptic potential and the number of the population spike significantly while rhein and emodin increased the latency of the population spike obviously.Conclusion Rhubarb extracts,i.e. rhein and emodin,can depress the neuronal hyperexcitability,which suggests that rhein and emodin play an important role in protecting the central nervous system from neuronal damage after traumatic brain injury.FPI produces hyperexcitability of hippocampal CA1 neurons,probably by enhancing excitatory synaptic transmission.

Dual face of axonal inhibitory inputs in the modulation of neuronal excitability in cortical pyramidal neurons

Limited by the tiny structure of axons,the effects of these axonal hyperpolarizing inputs on neuronal activity have not been directly elucidated.Here,we imitated these processes by simultaneously recording the activities of the somas and proximal axons of cortical pyramidal neurons.We found that spikes and subthreshold potentials propagate between somas and axons with high fidelity.Furthermore,inhibitory inputs on axons have opposite effects on neuronal activity according to their temporal integration with upstream signals.Concurrent with somatic depolarization,inhibitory inputs on axons decrease neuronal excitability and impede spike generation.In addition,following action potentials,inhibitory inputs on an axon increase neuronal spike capacity and improve spike precision.These results indicate that inhibitory inputs on proximal axons have dual regulatory functions in neuronal activity（suppression or facilitation）according to neuronal network patterns.

Somatosensory stimulation suppresses the excitability of pyramidal cells in the hippocampal CA1 region in rats

The hippocampal region of the brain is important for encoding environment inputs and memory formation. However, the underlying mechanisms are unclear. To investigate the behavior of indi-vidual neurons in response to somatosensory inputs in the hippocampal CA1 region, we recorded and analyzed changes in local ifeld potentials and the ifring rates of individual pyramidal cells and interneurons during tail clamping in urethane-anesthetized rats. We also explored the mechanisms underlying the neuronal responses. Somatosensory stimulation, in the form of tail clamping, chan-ged local ifeld potentials into theta rhythm-dominated waveforms, decreased the spike ifring of py-ramidal cells, and increased interneuron ifring. In addition, somatosensory stimulation attenuated orthodromic-evoked population spikes. These results suggest that somatosensory stimulation sup-presses the excitability of pyramidal cells in the hippocampal CA1 region. Increased inhibition by local interneurons might underlie this effect. These ifndings provide insight into the mechanisms of signal processing in the hippocampus and suggest that sensory stimulation might have thera-peutic potential for brain disorders associated with neuronal hyperexcitability.

Transcranial magnetic stimulation probes the excitability of the primary motor cortex:A framework to account for the facilitating effects of acute whole-body exercise on motor processes

The effects of exercise on decision-making performance have been studied using a wide variety of cognitive tasks and exercise interventions. Although the current literature supports a beneficial influence of acute exercise on cognitive performance, the mechanisms underlying this phenomenon have not yet been elucidated. We review studies that used single-pulse transcranial magnetic stimulation （TMS） to probe the excitability of motor structures during whole-body exercise and present a framework to account for the facilitating effects of acute exercise on motor processes. Recent results suggest that, even in the absence of fatigue, the increase in corticospinal excitability classically reported during submaximal and exhausting exercises may be accompanied by a reduction in intracortical inhibition. We propose that reduced intracortical inhibition elicits an adaptive central mechanism that counteracts the progressive reduction in muscle responsiveness caused by peripheral fatigue. Such a reduction would render the motor cortex more sensitive to upstream influences, thus causing increased corticospinal excitability. Furthermore, reduction of intracortical inhibition may account for the more efficient descending drive and for the improvement of reaction time performance during exercise. The adaptive modulation in intracortical inhibition could be implemented through a general increase in reticular activation that would further account for enhanced sensory sensitivity.

Chronic fatigue syndrome with history of severe infection combined altered blood oxidant status, and reduced potassium efflux and muscle excitability at exercise

It is documented that chronic fatigue syndrome (CFS) combines enhanced oxidative stress with altered muscle excitability. We hypothesized that these disorders may be accentuated when severe infection preceded the CFS symptoms. This case-control study compared 55 CFS patients to a matched control group of 40 healthy subjects. In twenty-five CFS patients, severe infection was reported within the three to seven?month period preceding the CFS symptoms. The others had practiced sport at high level. Plasma concentrations of potassium, a marker of lipid peroxidation (thiobarbituric acid reactive substances, TBARS), and an endogenous antioxidant (reduced ascorbic acid, RAA) were measured. Action potential (M-wave) was evoked in the vastus lateralis muscle to explore the muscle membrane excitability. All subjects performed a maximal incremental cycling exercise. Compared to control subjects, all CFS patients presented an elevated resting TBARS level and, during and after exercise, an altered M-wave configuration. History of infection was associated with marked significant increase in resting TBARS level, enhanced M-wave alterations, and also reduced exercise-induced potassium efflux. The magnitude of exercise-induced M-wave alterations was proportional to the baseline TBARS level. Severe infection preceding CFS seems to constitute a stressor inducing altered blood oxidant status and a reduced muscle excitability at work.

Corticospinal excitability during motor imagery is diminished by continuous repetition-induced fatigue

Application of continuous repetition of motor imagery can improve the performance of exercise tasks.However,there is a lack of more detailed neurophysiological evidence to support the formulation of clear standards for interventions using motor imagery.Moreover,identification of motor imagery intervention time is necessary because it exhibits possible central fatigue.Therefore,the purpose of this study was to elucidate the development of fatigue during continuous repetition of motor imagery through objective and subjective evaluation.The study involved two experiments.In experiment 1,14 healthy young volunteers were required to imagine grasping and lifting a 1.5-L plastic bottle using the whole hand.Each participant performed the motor imagery task 100 times under each condition with 48 hours interval between two conditions:500 mL or 1500 mL of water in the bottle during the demonstration phase.Mental fatigue and a decrease in pinch power appeared under the 1500-mL condition.There were changes in concentration ability or corticospinal excitability,as assessed by motor evoked potentials,between each set with continuous repetition of motor imagery also under the 1500-mL condition.Therefore,in experiment 2,12 healthy volunteers were required to perform the motor imagery task 200 times under the 1500-mL condition.Both concentration ability and corticospinal excitability decreased.This is the first study to show that continuous repetition of motor imagery can decrease corticospinal excitability in addition to producing mental fatigue.This study was approved by the Institutional Ethics Committee at the Nagasaki University Graduate School of Biomedical and Health Sciences(approval No.18121302)on January 30,2019.

Quantitative evaluation of extrinsic factors influencing electrical excitability in neuronal networks： Voltage Threshold Measurement Method(VTMM)

The electrical excitability of neural networks is influenced by different environmental factors. Effective and simple methods are required to objectively and quantitatively evaluate the influence of such factors, including variations in temperature and pharmaceutical dosage. The aim of this paper was to introduce ‘the voltage threshold measurement method＇, which is a new method using microelectrode arrays that can quantitatively evaluate the influence of different factors on the electrical excitability of neural networks. We sought to verify the feasibility and efficacy of the method by studying the effects of acetylcholine, ethanol, and temperature on hippocampal neuronal networks and hippocampal brain slices. First, we determined the voltage of the stimulation pulse signal that elicited action potentials in the two types of neural networks under normal conditions. Second, we obtained the voltage thresholds for the two types of neural networks under different concentrations of acetylcholine, ethanol, and different temperatures. Finally, we obtained the relationship between voltage threshold and the three influential factors. Our results indicated that the normal voltage thresholds of the hippocampal neuronal network and hippocampal slice preparation were 56 and 31 m V, respectively. The voltage thresholds of the two types of neural networks were inversely proportional to acetylcholine concentration, and had an exponential dependency on ethanol concentration. The curves of the voltage threshold and the temperature of the medium for the two types of neural networks were U-shaped. The hippocampal neuronal network and hippocampal slice preparations lost their excitability when the temperature of the medium decreased below 34 and 33°C or increased above 42 and 43°C, respectively. These results demonstrate that the voltage threshold measurement method is effective and simple for examining the performance/excitability of neuronal networks.

Negative self-feedback induced enhancement and transition of spiking activity for class-3 excitability

Post-inhibitory rebound(PIR)spike,which has been widely observed in diverse nervous systems with different physiological functions and simulated in theoretical models with class-2 excitability,presents a counterintuitive nonlinear phenomenon in that the inhibitory effect can facilitate neural firing behavior.In this study,a PIR spike induced by inhibitory stimulation from the resting state corresponding to class-3 excitability that is not related to bifurcation is simulated in the Morris–Lecar neuron.Additionally,the inhibitory self-feedback mediated by an autapse with time delay can evoke tonic/repetitive spiking from phasic/transient spiking.The dynamical mechanism for the PIR spike and the tonic/repetitive spiking is acquired with the phase plane analysis and the shape of the quasi-separatrix curve.The result extends the counterintuitive phenomenon induced by inhibition to class-3 excitability,which presents a potential function of inhibitory autapse and class-3 neuron in many neuronal systems such as the auditory system.

Exogeneous energy supply and excitability of cells in embryonic atypical epidermis of Cynops cultured in vitro

Cells of in vitro cultured epidermis explants of ectoderm isolated at early gastrula stage,showed only weak excitability or even non-excitable at 6V when examined electrophysiologically.If non-excitable explants were treated with 100 mM glucose,the action potential (AP) appeared and within 1 hr reached its maximum.At the same time,their stimulus threshold became lowered gradually.And,if the glucose was washed out,AP gradually disappeared.If explants were treated with glucose of different concentrations,the percentage of explants which displayed AP increased with the increase of glucose concentration.When explants with approximately the same original stimulus threshold were treated with glucose of different concentrations,the stimulus threshold became lowered more in the more concentrated solution.If explants with different original stimulus thresholds were treated with glucose of the same concentration,the lowering of stimulus threshold was more obvious in those with higher original stimulus threshold.Other energy supplying substances used showed similar effect.

Enhanced motor cortex excitability after spinal cord injury

Transcranial magnetic stimulation（TMS）represents a useful non-invasive approach to studying cortical physiology,in addition to the descending motor pathways（Hallett,2000）,and may also be used to investigate the intracortical facilitatory and inhibitory mechanisms.

Changes in Excitability of the Motor Cortex Associated with Internal Model Formation during Intrinsic Visuomotor Learning in the Upper Arm

Previous studies have shown that the primary motor cortex (M1) may drive part of the feed forward control of well learnt simple movements by specifying patterns of muscle activation. This study explored the role of the M1 in the feed forward control of newly formed movement patterns after motor adaptation. Ten healthy right-handed subjects performed planar, centre-out arm reaching movement trials with a robotic manipulandum in three phases: a null force field (baseline), a velocity-dependent force field (adaptation;25 Nsm-1) and again in a null force field (deadaptation). Reaching error and voluntary EMG were recorded from the biceps and triceps before, during and after motor adaptation. We also explored the effects of motor adaptation on evoked responses to single and paired pulse Transcranial Magnetic Stimulation from the same muscles at different delays after a visual go command, but before the onset of voluntary muscle activity. After the force field was removed, subjects produced reaching overshoot characteristic of adaptive internal model formation. Following motor adaptation, there was a significant increase in corticospinal excitability, reduction in short interval intracortical inhibition and increase in short interval intracortical facilitation that was associated with a sustained increase in voluntary muscle activity in the biceps. The adaptation-driven increase in reaching overshoot coupled with the increase in voluntary activity, corticospinal and intracortical excitability in the biceps suggests that the M1 may specify some of the feed forward components of newly learnt internal models through the control of specific muscles.

Research progress on the correlation between ion channel and excitability of striatum neurons in Parkinson's disease

Parkinson's disease(PD)is a neurodegenerative disorder due to gradual loss of dopaminergic neurons in the substantia nigra in the midbrain,however the pathogenesis is unclear.There is a correlation between the excitability of striatal neurons and PD.Ion channels are important to maintain membrane potential and regulate excitability of neurons,while ionic mechanisms for modulation of neurons excitability are not fully understood.This article reviews the relationship between ion channels and excitability of striatal neurons in PD and ion channel changes in the pathogenesis of PD.In order to find new targets to treatment PD by intervening ion channels.

A Neural Excitability Based Coding Strategy for Cochlear Implants

A novel cochlear implant coding strategy based on the neural excitability has been developed and implemented using Matlab/Simulink. Unlike present day coding strategies, the Excitability Controlled Coding (ECC) strategy uses a model of the excitability state of the target neural population to determine its stimulus selection, with the aim of more efficient stimulation as well as reduced channel interaction. Central to the ECC algorithm is an excitability state model, which takes into account the supposed refractory behaviour of the stimulated neural populations. The excitability state, used to weight the input signal for selecting the stimuli, is estimated and updated after the presentation of each stimulus, and used iteratively in selecting the next stimulus. Additionally, ECC regulates the frequency of stimulation on a given channel as a function of the corresponding input stimulus intensity. Details of the model, implementation and results of benchtop plus subjective tests are presented and discussed. Compared to the Advanced Combination Encoder (ACE) strategy, ECC produces a better spectral representation of an input signal, and can potentially reduce channel interactions. Pilot test results from 4 CI recipients suggest that ECC may have some advantage over ACE for complex situations such as speech in noise, possibly due to ECC’s ability to present more of the input spectral contents compared to ACE, which is restricted to a fixed number of maxima. The ECC strategy represents a neuro-physiological approach that could potentially improve the perception of more complex sound patterns with cochlear implants.

Regulating Neuronal Hyper-Excitability and Hyper-Synchrony in Epileptic Patients by Using PUFA, Calcium and ATP Buffering

Epilepsy is a severe neurological disorder clinically identified by hyper-excitability and/or hyper-synchrony in the cortex and other subcortical regions of the brain. To regulate such excitability and synchrony, Hodgkin and Huxley model has been deployed with either PUFA or calcium buffering coupled with ATP modulate neurotransmitter release. We formulate and analyze a system of differential equations that describe the effects of PUFA, ATP, and calcium buffering in regulating neuronal hyper-excitability and hyper-synchrony in epileptic patients. We observed that PUFA had diverse effects on the gating variables. Specifically, there was a significant reduction in the inhibitory potency of PUFA on the m-gates which may cause a direct inhibition of the voltage-gated Na＋ channels and thus reduce neuronal excitability in epileptic patients. Also, the activation of the potassium channels by PUFA directly limited the neuronal hyper-excitability, while a small change in voltage potential coupled with PUFA restraint activated the voltage dependent ion channels which aided in lowering epileptic excitability in patients. In addition, higher ATP buffer levels in the presence of PUFA caused a significant hyperpolarization which may decrease neuronal excitability while lower ATP level initiated neuron depolarization. These results clearly suggest that PUFA coupled with calcium and ATP buffering could be used to modulate neuronal excitability excessive synchrony in epileptic patients.

Control of cardiac excitability and arrhythmias by microRNAs

Recent studies revealing the important roles of microRNAs（miRNAs） in regulating expression of ion channel genes have opened up a research field for extending and deepening our investi- gation into the cardiac excitability and the associated arrhythmogenesis.Cardiac excitability,the fundamental property of the cardiac myocytes,defines the cardiac conduction,repolarization,automaticity,intracellular calcium handling,and their regional heterogeneity. Our previous and ongoing studies and the work from other laboratories have demonstrated the significant involvement of miRNAs in regulating every aspects of cardiac excitability.We have found earlier that the muscle-specific miRNA miR-1 boosts up the arrhythmogenic potential through targeting gap junction channel connexin 43 in myocardial infarction.A subsequent study revealed that miR-1 can also cause arrhythmias by impairing Ca2+ handling by targeting phosphatase.We then identified another muscle-specific miRNA miR-133 promotes abnormal QT prolongation by repressing HERG K+ channel expression in diabetic cardiomyopathy. Subsequently,we discovered that both miR- 1 and miR-133 are involved in the reexpression of pacemaker channels HCN2/HCN4 to enhance abnormal automaticity in cardiac hypertrophy.Recently, we further identified miR-328 as an important determinant for atrial fibrillation（AF） and the associated adverse atrial electrical remodeling via targeting L-type Ca2+ channels.While all the above-mentioned miRNAs are proarrhythmic,we have newly identified for the first time a natural antiarrhythmic miRNA miR-26.We found that all three members of the miR-26 family is downregulated in their expression in AF tissues and this downregulation increases AF vulnerability as a result of removal of an endogenous antiarrhythmic factor.miR-26 downregulation shortens atrial action potential favoring AF by increasing inward rectifier K+ current（IK1） density. This is caused by an upregulation of Kir2.1 K+ channel subunit due to derepression of its encoding gene KCNJ2 as we have validated KCNJ2 as a target gene for miR-26.Administration of a LNA-modified antimiR-26 antisense through tail vein injection increases AF vulnerability as indicated by increased number of mice with AF induction by intracardiac pacing.And this effect is blunted by co-injection of either an adenovirus vector carrying miR-26 precursor sequence or a LNA-modified miR-26 mimic to specifically target KCNJ2.We further discovered that the activity of NFAT transcription factor is enhanced in AF which represses the transcription of miR-26. We characterized the promoter region of the host genes of all three members of the miR-26 miRNA family and identified a common cis-acting element for NFAT binding.Thus,our study unraveled a novel miRNA signaling pathway AF NFAT miR-26 KC-NJ2 /Kir2.1/IK1 AF as a positive feedback loop favoring AF and the remodeling process.

Soleus arthrogenic muscle inhibition following acute lateral ankle sprain correlates with symptoms and ankle disability but not with postural control

Background:Acute lateral ankle sprains(ALAS)are associated with long-term impairments and instability tied to altered neural excitability.Arthrogenic muscle inhibition(AMI)has been observed in this population;however,relationships with injury-related impairments are unclear,potentially due to the resting,prone position in which AMI is typically measured.Assessing AMI during bipedal stance may provide a better understanding of this relationship.Methods:AMI was assessed in 38 young adults(19 ALAS within 72 h of injury:10 males,21.4±2.7 years;19 healthy controls:10 males,21.9±2.2 years;mean±SD)using the Hoffmann reflex(H-reflex)during bipedal stance.Electrical stimulation was administered to identify the _(max)imal H-reflex(H_(max))and _(max)imal motor response(M_(max))from the soleus,fibularis longus,and tibialis anterior muscles.The primary outcome measure was the H_(max)/M_(max) ratio.Secondary outcomes included acute symptoms(pain and swelling),postural control during bipedal stance,and self-reported function.Results:No significant group-by-limb interactions were observed for any muscle.However,a significant group main effect was observed in the soleus muscle(F(1,35)=6.82,p=0.013),indicating significantly lower H_(max)/M_(max) ratios following ALAS(0.38±0.20)compared to healthy controls(0.53±0.16).Furthermore,lower H_(max)/M_(max) ratios in the soleus significantly correlated with acute symptoms and self-reported function but not with postural control.Conclusion:This study supports previous evidence of AMI in patients with ALAS,providing insight into neurophysiologic impacts of musculoskeletal injury.Our results suggest that assessing AMI in a standing position following acute injury may provide valuable insight into how AMI develops and guide potential therapeutic options to curb and offset the formation of joint instability.