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.

Effect of Neuronal Excitability in Hippocampal CA1 Area on Auditory Pathway in a Rat Model of Tinnitus

Background： Tinnitus is a common disorder that causes significant morbidity; however, the neurophysiological mechanism is not yet fully understood. A relationship between tinnitus and limbic system has been reported. As a significant component of the l imbic system, the hippocampus plays an important role in various pathological processes, such as emotional disturbance, decreased learning ability, and deterioration of memory. This study was aimed to explore the role of the hippocampus in the generation oftinnitus by electrophysiological technology. Methods： A tinnitus model was established in rats through intraperitoneal injection of salicylate （SA）. Subsequently, the spontaneous firing rate （SFR） of neurons in the hippocampal CAI area was recorded with in vivo multichannel recording technology to assess changes in excitability induced by SA. To investigate the effect of excitability changes ofhippocampus on the auditory pathway, the hippocampus was electrically stimulated and neural excitability in the auditory cortex （AC） was monitored. Results： Totally 65 neurons in the hippocampal CAI area were recorded, 45 from the SA group （n = 5）, and 20 from the saline group （n = 5）. Two hours after treatment, mean SFR of neurons in the hippocampal CA1 area had significantly increased from 3.06 ± 0.36 Hz to 9.18 ±1.30 Hz in the SA group （t = -4.521, P 〈 0.05）, while no significant difference was observed in the saline group （2.66 ± 0.36 Hz vs. 2.16 ± 0.36 Hz, t = 0.902, P 〉 0.05）. In the AC, 79.3% （157/198） of recorded neurons showed responses to electrical stimulation of the hippocampal CA1 area. Presumed pyramidal neurons were excited, while intermediate neurons were inhibited after electrical stimulation of the hippocampus. Conclusions： The study shows that the hippocampus is excited in SA-induced tinnitus, and stimulation of hippocampus could modulate neuronal excitability of the AC. The hippocampus is involved in tinnitus and may also have a regulatory effect on the neural center.

HMGB1,neuronal excitability and epilepsy

Epilepsy is a common neurological disease caused by synchronous firing of hyperexcitable neurons.Currently,antiepileptic drugs remain the main choice to control seizure,but 30%of patients are resistant to the drugs,which calls for more research on new promising targets.Neuroinflammation is closely associated with the development of epilepsy.As an important inflammatory factor,high mobility group protein B1(HMGB1)has shown elevated expression and an increased proportion of translocation from the nucleus to the cytoplasm in patients with epilepsy and in multiple animal models of epilepsy.HMGB1 can act on downstream receptors such as Toll-like receptor 4 and receptor for advanced glycation end products,thereby activating interleukin(IL)-1βand nuclear factor kappa-B(NF-κB),which in turn act with glutamate receptors such as the N-methyl-D-aspartate(NMDA)receptors to aggravate hyperexcitability and epilepsy.The hyperexcitability can in turn stimulate the expression and translocation of HMGB1.Blocking HMGB1 and its downstream signaling pathways may be a direction for antiepileptic drug therapy.Here,we review the changes of HMGB1-related pathway in epileptic brains and its role in the modulation of neuronal excitability and epileptic seizure.Furthermore,we discuss the potentials of HMGB1 as a therapeutic target for epilepsy and provide perspective on future research on the role of HMGB1 signaling in epilepsy.

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.

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.

Deficiency of anti-inflammatory cytokine IL-4 leads to neural hyperexcitability and aggravates cerebral ischemia-reperfusion injury

Systematic administration of anti-inflammatory cytokine interleukin 4(IL-4)has been shown to improve recovery after cerebral ischemic stroke.However,whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown.Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia-repertusion(I/R)injury.In multi-electrode array(MEA)recordings,IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons.IL-4 mRNA and protein expressions are upregulated after I/R injury.Genetic deletion of 11-4 gene aggravates I/R injury in vivo and exacerbates oxygen-glucose deprivation(OGD)injury in cortical neurons.Conversely,supplemental IL-4 protects 11-4-/-cortical neurons against OGD injury.Mechanistically,cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in Il-4-/-mice.Furthermore,upregulation of Nav1.1 channel,and downregulations of KCa3.1 channel and a6 subunit of GABAA receptors are detected in the cortical tissues and primary cortical neurons from Il-4-/-mice.Taken together,our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury,thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.

Cyproheptadine Regulates Pyramidal Neuron Excitability in Mouse Medial Prefrontal Cortex

Cyproheptadine （CPH）, a first-generation anti- histamine, enhances the delayed rectifier outward K＋ current （IK） in mouse cortical neurons through a sigma-1 receptor-mediated protein kinase A pathway. In this study, we aimed to determine the effects of CPH on neuronal excitability in current-clamped pyramidal neurons in mouse medial prefrontal cortex slices. CPH （10 μmol/L） significantly reduced the current density required to generate action potentials （APs） and increased the instan- taneous frequency evoked by a depolarizing current. CPH also depolarized the resting membrane potential （RMP）, decreased the delay time to elicit an AP, and reduced the spike threshold potential. This effect of CPH was mim- icked by a sigma-1 receptor agonist and eliminated by an antagonist. Application of tetraethylammonium （TEA） to block IK channels hyperpolarized the RMP and reduced the instantaneous frequency of APs. TEA eliminated the effects of CPH on AP frequency and delay time, but had no effect on spike threshold or RMP. The current-voltage relationship showed that CPH increased the membrane depolarization in response to positive current pulses and hyperpolarization in response to negative current pulses, suggesting that other types of membrane ion channels might also be affected by CPH. These results suggest that CPH increases the excitability of medial prefrontal cortex neurons by regulating TEA-sensitive IK channels as well as other TEA-insensitive K＋ channels, probably ID and inward-rectifier Kir channels. This effect of CPH may explain its apparent clinical efficacy as an antidepressant and antipsychotic.

Neural Mechanism Underlying Task-Specific Enhancement of Motor Learning by Concurrent Transcranial Direct Current Stimulation

The optimal protocol for neuromodulation by transcranial direct current stimulation(tDCS)remains unclear.Using the rotarod paradigm,we found that mouse motor learning was enhanced by anodal tDCS(3.2 mA/cm^(2))during but not before or after the performance of a task.Dual-task experiments showed that motor learning enhancement was specific to the task accompanied by anodal tDCS.Studies using a mouse model of stroke induced by middle cerebral artery occlusion showed that concurrent anodal tDCS restored motor learning capability in a task-specific manner.Transcranial in vivo Ca^(2+)imaging further showed that anodal tDCS elevated and cathodal tDCS suppressed neuronal activity in the primary motor cortex(M1).Anodal tDCS specifically promoted the activity of task-related M1 neurons during task performance,suggesting that elevated Hebbian synaptic potentiation in task-activated circuits accounts for the motor learning enhancement.Thus,application of tDCS concurrent with the targeted behavioral dysfunction could be an effective approach to treating brain disorders.

Anticonvulsant Effect of Xingnaojing Injection on Acute Seizure Models in Mice

Background:Epilepsy is characterized by acute recurrent seizures.The control of seizures is largely hampered by the tolerance to current anti-seizure drugs.Complementary anti-convulsant pharmacotherapies are urgently needed.Objective:Here,we aimed to investigate the anti-convulsant effects of Xingnaojing Injection(XNJ)which is an approved Traditional Chinese Medicine injection on different acute seizure models in mice.Methods:The effects of XNJ were tested on the maximal electroshock(MES),pentylenetetrazol(PTZ)and kainic acid(KA)acute seizure models.Also,whether XNJ can directly inhibit hippocampal neuronal firings were exam-ined by in vitro electrophysiology.Results:XNJ could shorten the durations of generalized tonic-clonic seizures in the MES model.It also significantly prolonged the latencies to generalized myo-clonic seizures in the PTZ model.In the KA model,XNJ showed various efficacies including inhibiting the seizure stages,prolonging the latency to the occurrence of the first seizures or generalized seizures,shortening the seizure durations,decreasing the numbers of generalized seizures.In vitro electrophysiological recordings further verified XNJ directly inhibited both the spontaneous and evoked action potentials of hippocampal pyramidal neurons,but did not influence the excitatory or inhibitory synaptic transmissions.Conclusion:These findings proposed XNJ as an alternative anti-convulsant pharmacotherapy for controlling acute epileptic seizures.

Astrocyte-Derived Lactate Modulates the Passive Coping Response to Behavioral Challenge in Male Mice

Every organism inevitably experiences stress. In the face of acute, intense stress, for example, periods of passivity occur when an organism's actions fail to overcome the challenge. The occurrence of inactive behavior may indicate that struggling would most likely be fruitless.Repeated serious stress has been associated with mood disorders such as depression. The modulation of passive coping response patterns has been explored with a focus on the circuit level. However, the cellular and molecular mechanisms are largely uncharacterized. Here, we report that lactate is a key factor in the astrocytic modulation of the passive coping response to behavioral challenge in adult mice. We found increased extracellular lactate in the medial prefrontal cortex(mPFC) when mice experienced the forced swimming test(FST). Furthermore, we discovered that disturbing astrocytic glycogenolysis, which is a key step for lactate production in the mPFC, decreased the duration of immobility in the FST. Knocking down monocarboxylate transporter 4(MCT4), which is expressed exclusively in astrocytes and transports lactate from astrocytes to the extracellular space, caused similar results in the FST. The behavioral effect of both the pharmacological disturbance of astrocytic glycogenolysis and viral disruption of MCT4 expression was rescued via the administration of L-lactate. Moreover, we found that both pharmacological and viral modulation of astrocytederived lactate in mPFC slices increased the excitability of layer V pyramidal neurons, and this enhancement was reversed by exogenous L-lactate administration. These results highlight astrocyte-derived lactate as a biological mechanism underlying the passive coping response to behavioral challenge and may provide new strategies to prevent mood disorders.

Revealing the Precise Role of Calretinin Neurons in Epilepsy: We Are on the Way

Epilepsy is a common neurological disorder characterized by hyperexcitability in the brain.Its pathogenesis is classically associated with an imbalance of excitatory and inhibitory neurons.Calretinin(CR)is one of the three major types of calcium-binding proteins present in inhibitory GABAergic neurons.The functions of CR and its role in neural excitability are still unknown.Recent data suggest that CR neurons have diverse neurotransmitters,morphologies,distributions,and functions in different brain regions across various species.Notably,CR neurons in the hippocampus,amygdala,neocortex,and thalamus are extremely susceptible to excitotoxicity in the epileptic brain,but the causal relationship is unknown.In this review,we focus on the heterogeneous functions of CR neurons in different brain regions and their relationship with neural excitability and epilepsy.Importantly,we provide perspectives on future investigations of the role of CR neurons in epilepsy.

Spatiotemporal dynamics in a network composed of neurons with different excitabilities and excitatory coupling

Spiral waves have been observed in the biological experiments on rat cortex perfused with drugs which can block inhibitory synapse and switch neuron excitability from type II to type I. To simulate the spiral waves observed in the experiment, the spatiotemporal patterns are investigated in a network composed of neurons with type I and II excitabilities and excitatory coupling. Spiral waves emerge when the percentage(p) of neurons with type I excitability in the network is at middle levels, which is dependent on the coupling strength. Compared with other spatial patterns which appear at different p values, spiral waves exhibit optimal spatial correlation at a certain spatial frequency, implying the occurrence of spatial coherence resonance-like phenomenon. Some dynamical characteristics of the network such as mean firing frequency and synchronous degree can be well interpreted with distinct properties between type I excitability and type II excitability. The results not only identify dynamics of spiral waves in neuronal networks composed of neurons with different excitabilities, but also are helpful to understanding the emergence of spiral waves observed in the biological experiment.

Effect of initial phase diversity on signal detection in excitable systems

Undoubtedly, the sensory organs of biological systems have been evolved to accurately detect and locate the external stimuli, even if they are very weak. However, the mechanism underlying this ability is still not fully understood. Previously, it had been shown that stochastic resonance may be a good candidate to explain this ability, by which the response of a system to an external signal is amplified by the presence of noise. Recently, it is pointed out that the initial phase diversity in external signals can be also served as a simple and feasible mechanism for weak signal detection or amplification in excitable neurons. We here make a brief review on this progress. We will show that there are two kinds of effects of initial phase diversity: one is the phase disorder, i.e., the initial phases are different and static, and the other is the phase noise, i.e., the initial phases are time-varying like noise. Both cases show that initial phase diversity in subthreshold periodic signals can indeed play a constructive role in the emergence of sustained spiking activity. As initial phase diversity can mimic different arrival times from source signal to sensory organs, these findings may provide a cue for understanding the hunting behaviors of some biological systems.

Postsynaptic Excitation of Prefrontal Cortical Pyramidal Neurons by Hypocretins/Orexins

Hypocretins/orexins are crucial for the regulation of wakefulness by the excitatory actions on multiple subcortical arousal systems. In prefrontal cortex,