Could respiration-driven blood oxygen changes modulate neural activity?

Oxygen is critical for neural metabolism, but under most physiological conditions, oxygen levels in the brain are far more than are required. Oxygen levels can be dynamically increased by increases in respiration rate that are tied to the arousal state of the brain and cognition, and not necessarily linked to exertion by the body. Why these changes in respiration occur when oxygen is already adequate has been a long-standing puzzle. In humans, performance on cognitive tasks can be affected by very high or very low oxygen levels, but whether the physiological changes in blood oxygenation produced by respiration have an appreciable effect is an open question. Oxygen has direct effects on potassium channels, increases the degradation rate of nitric oxide, and is rate limiting for the synthesis of some neuromodulators. We discuss whether oxygenation changes due to respiration contribute to neural dynamics associated with attention and arousal.

Distinct Role of Mono-2-ethylhexyl Phthalate in Neuronal Transmission in Rat CA3 Hippocampal Neurons: Involvement of Ion Channels.

Mono-(2-ethylhexyl) phthalate (MEHP) is one of the main active metabolites of di-(2-ethylhexyl) phthalate (DEHP). In our previous works, by using rat and Drosophila models, we showed a disruption of neural function due to DEHP. However, the exact neural effects of MEHP are still unclear. To explore the effects of MEHP on the central nervous system, the electrophysiological properties of spontaneous action potential (sAP), mini-excitatory postsynaptic currents (mEPSCs), ion channels, including Na+, Ca2+, and K+ channels from rat CA3 hippocampal neurons area were assessed. Our data showed that MEHP (at the concentrations of 100 or 300 µM) decreased the amplitude of sAP and the frequency of mEPSCs. Additionally, MEHP (100 or 300 µM) significantly reduced the peak current density of Ca2+ channels, whereas only the concentration of 300 µM decreased the peak current density of Na+ and K+ channels. Therefore, our results indicate that exposure to MEHP could affect the neuronal excitability and synaptic plasticity of rat CA3 hippocampal neurons by inhibiting ion channels' activity, implying the distinct role of MEHP in neural transmission.

Glial Synaptobrevin mediates peripheral nerve insulation, neural metabolic supply, and is required for motor function.

Peripheral nerves contain sensory and motor neuron axons coated by glial cells whose interplay ensures function, but molecular details are lacking. SNARE-proteins mediate the exchange and secretion of cargo by fusing vesicles with target organelles, but how glial SNAREs contribute to peripheral nerve function is largely unknown. We, here, identify non-neuronal Synaptobrevin (Syb) as the essential vesicular SNARE in Drosophila peripheral glia to insulate and metabolically supply neurons. We show that tetanus neurotoxin light chain (TeNT-LC), which potently inhibits SNARE-mediated exocytosis from neurons, also impairs peripheral nerve function when selectively expressed in glia, causing nerve disintegration, defective axonal transport, tetanic muscle hyperactivity, impaired locomotion, and lethality. While TeNT-LC disrupts neural function by cleaving neuronal Synaptobrevin (nSyb), it targets non-neuronal Synaptobrevin (Syb) in glia, which it cleaves at low rates: Glial knockdown of Syb (but not nSyb) phenocopied glial TeNT-LC expression whose effects were reverted by a TeNT-LC-insensitive Syb mutant. We link Syb-necessity to two distinct glial subtypes: Impairing Syb function in subperineurial glia disrupted nerve morphology, axonal transport, and locomotion, likely, because nerve-isolating septate junctions (SJs) could not form as essential SJ components (like the cell adhesion protein Neurexin-IV) were mistargeted. Interference with Syb in axon-encircling wrapping glia left nerve morphology and locomotion intact but impaired axonal transport, likely because neural metabolic supply was disrupted due to the mistargeting of metabolite shuffling monocarboxylate transporters. Our study identifies crucial roles of Syb in various glial subtypes to ensure glial-glial and glial-neural interplay needed for proper nerve function, animal motility, and survival.

Effects of tDCS dose and electrode montage on regional cerebral blood flow and motor behavior.

We used three dose levels (Sham, 2 mA, and 4 mA) and two different electrode montages (unihemispheric and bihemispheric) to examine DOSE and MONTAGE effects on regional cerebral blood flow (rCBF) as a surrogate marker of neural activity, and on a finger sequence task, as a surrogate behavioral measure drawing on brain regions targeted by transcranial direct current stimulation (tDCS). We placed the anodal electrode over the right motor region (C4) while the cathodal or return electrode was placed either over a left supraorbital region (unihemispheric montage) or over the left motor region (C3 in the bihemispheric montage). Performance changes in the finger sequence task for both hands (left hand: p = 0.0026, and right hand: p = 0.0002) showed a linear tDCS dose response but no montage effect. rCBF in the right hemispheric perirolandic area increased with dose under the anodal electrode (p = 0.027). In contrast, in the perirolandic ROI in the left hemisphere, rCBF showed a trend to increase with dose (p = 0.053) and a significant effect of montage (p = 0.00004). The bihemispheric montage showed additional rCBF increases in frontomesial regions in the 4mA condition but not in the 2 mA condition. Furthermore, we found strong correlations between simulated current density in the left and right perirolandic region and improvements in the finger sequence task performance (FSP) for the contralateral hand. Our data support not only a strong direct tDCS dose effect for rCBF and FSP as surrogate measures of targeted brain regions but also indirect effects on rCBF in functionally connected regions (e.g., frontomesial regions), particularly in the higher dose condition and on FSP of the ipsilateral hand (to the anodal electrode). At a higher dose and irrespective of polarity, a wider network of sensorimotor regions is positively affected by tDCS.

Transcriptional Regulation of Voltage-Gated Sodium Channels Contributes to GM-CSF-Induced Pain.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the production of granulocyte and macrophage populations from the hematopoietic progenitor cells; it is one of the most common growth factors in the blood. GM-CSF is also involved in bone cancer pain development by regulating tumor-nerve interactions, remodeling of peripheral nerves, and sensitization of damage-sensing (nociceptive) nerves. However, the precise mechanism for GM-CSF-dependent pain is unclear. In this study, we found that GM-CSF is highly expressed in human malignant osteosarcoma. Female Sprague Dawley rats implanted with bone cancer cells develop mechanical and thermal hyperalgesia, but antagonizing GM-CSF in these animals significantly reduced such hypersensitivity. The voltage-gated Na+ channels Nav1.7, Nav1.8, and Nav1.9 were found to be selectively upregulated in rat DRG neurons treated with GM-CSF, which resulted in enhanced excitability. GM-CSF activated the Janus kinase 2 (Jak2)-signal transducer and activator of transcription protein 3 (Stat3) signaling pathway, which promoted the transcription of Nav1.7-1.9 in DRG neurons. Accordingly, targeted knocking down of either Nav1.7-1.9 or Jak2/Stat3 in DRG neurons in vivo alleviated the hyperalgesia in male Sprague Dawley rats. Our findings describe a novel bone cancer pain mechanism and provide a new insight into the physiological and pathological functions of GM-CSF.SIGNIFICANCE STATEMENT It has been reported that granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a key role in bone cancer pain, yet the underlying mechanisms involved in the GM-CSF-mediated signaling pathway in nociceptors is not fully understood. Here, we showed that GM-CSF promotes bone cancer-associated pain by enhancing the excitability of DRG neurons via the Janus kinase 2 (Jak2)-signal transducer and activator of transcription protein 3 (Stat3)-mediated upregulation of expression of nociceptor-specific voltage-gated sodium channels. Our study provides a detailed understanding of the roles that sodium channels and the Jak2/Stat3 pathway play in the GM-CSF-mediated bone cancer pain; our data also highlight the therapeutic potential of targeting GM-CSF.

Loss of homeoprotein Msx1 and Msx2 leading to athletic and kinematic impairment related to the increasing neural excitability of neurons in aberrant neocortex in mice.

Although homeoproteins Msx1 and Msx2, the cell-specific transcription regulators, have been proven to play multiple roles in the embryogenesis of bone, muscle and tooth, the functions and mechanisms of Msx1 and Msx2 in the development of the central nervous system of mice after birth are not clear because of the death of Msx1 and Msx1/2 germline-deleted embryo at late gestation of mouse. In current research, Nestin-Cre mice was introduced to generate the central nervous system-specific knockout mice (Nestin-Cre;Msx1,Msx2fl/fl). We found that besides the falling of the body mass and the brain volume, the cortical tissue sections and staining showed the decreasing thickness of layer II-IV and declining number of vertebral cells in layer V resulting from Msx1/2 deletion. In addition, electrophysiological tests revealed the aberrant action potential parameters of deep pyramidal neurons in Nestin-Cre;Msx1,2 fl/fl mice, which may be related with the ethology impairment displayed in further experiments. We discovered Nestin-Cre;Msx1,2 fl/fl mice had severe impairment in their athletic ability and kinematic learning ability in rotate test, and exhibited hyperactivity in open-field test. Above all, our results revealed that deletion of homeoproteins Msx1 and Msx2 could lead to behavioral disorders and suggested that Msx1 and Msx2 played a crucial role in regulating the development and function of the neocortex. In addition, our current research provided a new mouse model for understanding the pathogenesis of human central nervous system disease.

Maternal mobile phone exposure alters intrinsic electrophysiological properties of CA1 pyramidal neurons in rat offspring.

Some studies have shown that exposure to electromagnetic field (EMF) may result in structural damage to neurons. In this study, we have elucidated the alteration in the hippocampal function of offspring Wistar rats (n = 8 rats in each group) that were chronically exposed to mobile phones during their gestational period by applying behavioral, histological, and electrophysiological tests. Rats in the EMF group were exposed to 900 MHz pulsed-EMF irradiation for 6 h/day. Whole cell recordings in hippocampal pyramidal cells in the mobile phone groups did show a decrease in neuronal excitability. Mobile phone exposure was mostly associated with a decrease in the number of action potentials fired in spontaneous activity and in response to current injection in both male and female groups. There was an increase in the amplitude of the afterhyperpolarization (AHP) in mobile phone rats compared with the control. The results of the passive avoidance and Morris water maze assessment of learning and memory performance showed that phone exposure significantly altered learning acquisition and memory retention in male and female rats compared with the control rats. Light microscopy study of brain sections of the control and mobile phone-exposed rats showed normal morphology.Our results suggest that exposure to mobile phones adversely affects the cognitive performance of both female and male offspring rats using behavioral and electrophysiological techniques.

The Relationship between Muscarinic and Cannabinoid Receptors in Neuronal Excitability and Epilepsy: A Review.

Background: Of the seventy million people who suffer from epilepsy, 40 percent of them become resistant to more than one antiepileptic medication and have a higher chance of death. While the classical definition of epilepsy was due to the imbalance between excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA)-ergic signalling, substantial evidence implicates muscarinic receptors in the regulation of neural excitability. Summary: Cannabinoids have shown to reduce seizure activity and neuronal excitability in several epileptic models through the activation of muscarinic receptors with drugs which modulate their activity. Cannabinoids also have been effective in reducing antiepileptic activity in pharmaco-resistant individuals; however, the mechanism of its effects in temporal lobe epilepsy is not clear. Key Messages: This review seeks to elucidate the relationship between muscarinic and cannabinoid receptors in epilepsy and neural excitability.

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 maximal H-reflex (Hmax) and maximal motor response (Mmax) from the soleus, fibularis longus, and tibialis anterior muscles. The primary outcome measure was the Hmax/Mmax 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 Hmax/Mmax ratios following ALAS (0.38 ± 0.20) compared to healthy controls (0.53 ± 0.16). Furthermore, lower Hmax/Mmax 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.

Nrf-2 modulates excitability of hippocampal neurons by regulating ferroptosis and neuroinflammation after subarachnoid hemorrhage in rats.

Excitability of hippocampal neurons in subarachnoid hemorrhage (SAH) rats has not been well studied. The rat SAH model was applied in this study to explore the role of nuclear factor E2-related factor (Nrf-2) in the early brain injury of SAH. The neural excitability of CA1 pyramidal cells (PCs) in SAH rats was evaluated by using electrophysiology experiments. Ferroptosis and neuroinflammation were measured by ELISA, transmission electron microscopy and western blotting. Our results indicated that SAH induced neurological deficits, brain edema, ferroptosis, neuroinflammation and neural excitability in rats. Ferrostatin-1 treatment significantly decreased the expression and distribution of IL-1ß, IL-6, IL-10, TGF-ß and TNF-α. Inhibiting ferroptosis by ferrostatin-1 can attenuate neural excitability, neurological deficits, brain edema and neuroinflammation in SAH rats. Inhibiting the expression of Nrf-2 significantly increased the neural excitability and the levels of IL-1ß, IL-6, IL-10, TGF-ß and TNF-α in Fer-1-treated SAH rats. Taken together, inhibiting the Nrf-2 induces early brain injury, brain edema and the inflammatory response with increasing of neural excitability in Fer-1-treated SAH rats. These results have indicated that inhibiting ferroptosis, neuroinflammation and neural excitability attenuates early brain injury after SAH by regulating the Nrf-2.

Effects of sleep deprivation on perceived and performance fatigability in females: An exploratory study.

Sleep deprivation (SD) is prevalent and impairs motor function; however, little is known about its effect on perceived and performance fatigability, especially in females. To examine the effects of 24 h of SD on these attributes of fatigue, nine females completed a 20-min isometric, sustained elbow flexion contraction, followed by 10 min of recovery. The superimposed twitch (SIT) elicited via transcranial magnetic stimulation (TMS) assessed supraspinal drive. Biceps brachii electromyographic data indicated neural excitability in response to stimulation over the motor cortex (motor evoked potential; MEP), corticospinal tract (cervicomedullary motor evoked potential; CMEP), and brachial plexus (maximal M-wave; Mmax). MEPs and CMEPs were recorded during a TMS-induced silent period. At baseline, ratings of perceived effort (RPE; 2.9 vs. 1.6) and fatigue (RPF; 6.9 vs. 2.9), were higher for SD than control. Across the 20-min contraction, RPE increased from 2.2 to 7.6, SIT and MEP/CMEP increased by 284 and 474%, respectively, whereas maximal voluntary isometric contraction (MVC) torque and CMEP/Mmax decreased by 26 and 57%, respectively. No differences were found across conditions for MVC, SIT, Mmax, CMEP/Mmax, or MEP/CMEP prior to, during, and after the fatiguing task. During recovery, RPE (4.9 vs. 3.4), RPF (7.6 vs. 2.8), and perception of task difficulty (5.5 vs. 4.5) were greater for SD than control. Acute SD does not appear to alter performance fatigability development and subsequent recovery; however, it increases perceptions of fatigue, effort, and task difficulty. Thus, the disconnect between perceived and actual neuromuscular capacity following a sustained, submaximal isometric task is exacerbated by SD.HighlightsSleep deprivation did not alter supraspinal drive or neural excitability during and after a 20-min submaximal elbow flexion contractionSleep deprivation increased perceived fatigue and perception of task difficultyThe disconnect between perceived and performance fatigability is exacerbated in a sleep-deprived state.

Diabetes-induced electrophysiological alterations on neurosomes in ganglia of peripheral nervous system.

Diabetes mellitus (DM) leads to medical complications, the epidemiologically most important of which is diabetic peripheral neuropathy (DPN). Electrophysiology is a major component of neural functioning and several studies have been undertaken to elucidate the neural electrophysiological alterations caused by DM and their mechanisms of action. Due to the importance of electrophysiology for neuronal function, the review of the studies dealing predominantly with electrophysiological parameters and mechanisms in the neuronal somata of peripheral neural ganglia of diabetic animals during the last 45 years is here undertaken. These studies, using predominantly techniques of electrophysiology, most frequently patch clamp for voltage clamp studies of transmembrane currents through ionic channels, have investigated the experimental DPN. They also have demonstrated that various cellular and molecular mechanisms of action of diabetic physiopathology at the level of biophysical electrical parameters are affected in DPN. Thus, they have demonstrated that several passive and active transmembrane voltage parameters, related to neuronal excitability and neuronal functions, are altered in diabetes. The majority of the studies agreed that DM produces depolarization of the resting membrane potential; alters excitability, increasing and decreasing it in dorsal root ganglia (DRG) and in nodose ganglion, respectively. They have tried to relate these changes to sensorial alterations of DPN. Concerning ionic currents, predominantly studied in DRG, the most frequent finding was increases in Na+, Ca2+, and TRPV1 cation current, and decreases in K+ current. This review concluded that additional studies are needed before an understanding of the hierarchized, time-dependent, and integrated picture of the contribution of neural electrophysiological alterations to the DPN could be reached. DM-induced electrophysiological neuronal alterations that so far have been demonstrated, most of them likely important, are either consistent with the DPN symptomatology or suggest important directions for improvement of the elucidation of DPN physiopathology, which the continuation seems to us very relevant.

The effects of 72 h of dynamic ankle immobilization on neural excitability and lower extremity kinematics.

BACKGROUND: Ankle injuries can foster maladaptive changes in nervous system function that predisposes patients to subsequent injury. Patients are often placed in a dynamic boot immobilizer (BI) following injury; however, little is known about the effects of this treatment on neuromechanical function. RESEARCH QUESTION: We aimed to determine the effect of 72 h of BI-use on neural excitability and lower extremity joint motion in a healthy cohort. METHODS: Twelve uninjured individuals (20.8 ± 1.4 yrs, 1.7 ± 0.1 m, 75.2 ± 9.9 kg) participated in this crossover study. Neural excitability and lower extremity kinematics were assessed before and after 72 h of BI or compression sock (CS) use. Neural excitability was assessed via the Hoffmann (H) reflex and transcranial magnetic stimulation of the motor cortex by measuring muscle activation at the tibialis anterior, peroneus longus, and soleus of the immobilized extremity. Three-dimensional lower extremity joint angles were assessed while participants walked on a treadmill. Repeated-measures analyses of variance detected changes in neural excitability and peak joint angles across time-points and testing conditions, while statistical parametric mapping (SPM) was implemented to determine continuous joint angle changes (α = 0.05). RESULTS: Pre-BI to post-BI, HMax:MMax ratio (F = 6.496; p = 0.031) significantly decreased. The BI did not alter resting motor threshold (F = 0.601; p = 0.468), or motor evoked potential amplitudes (F > 2.82; p > 0.608). Significant changes in peak knee and hip angles in the frontal and transverse planes were observed (p < 0.05), with no changes at the ankle. SPM analyses revealed significant hip and knee changes in range of motion (p < 0.05). SIGNIFICANCE: Decreased measures of reflex but not corticospinal excitability suggest that BI-use for 72 h unloaded the joint enough to generate peripheral changes, but not the CNS, as has been described in casting models. Further, kinematic changes were observed in proximal lower extremity joints, likely due to swing-phase adaptations while wearing the BI.

Inhibition of intracellular proton-sensitive Ca2+-permeable TRPV3 channels protects against ischemic brain injury.

Ischemic brain stroke is pathologically characterized by tissue acidosis, sustained calcium entry and progressive cell death. Previous studies focusing on antagonizing N-methyl-d-aspartate (NMDA) receptors have failed to translate any clinical benefits, suggesting a non-NMDA mechanism involved in the sustained injury after stroke. Here, we report that inhibition of intracellular proton-sensitive Ca2+-permeable transient receptor potential vanilloid 3 (TRPV3) channel protects against cerebral ischemia/reperfusion (I/R) injury. TRPV3 expression is upregulated in mice subjected to cerebral I/R injury. Silencing of TRPV3 reduces intrinsic neuronal excitability, excitatory synaptic transmissions, and also attenuates cerebral I/R injury in mouse model of transient middle cerebral artery occlusion (tMCAO). Conversely, overexpressing or re-expressing TRPV3 increases neuronal excitability, excitatory synaptic transmissions and aggravates cerebral I/R injury. Furthermore, specific inhibition of TRPV3 by natural forsythoside B decreases neural excitability and attenuates cerebral I/R injury. Taken together, our findings for the first time reveal a causative role of neuronal TRPV3 channel in progressive cell death after stroke, and blocking overactive TRPV3 channel may provide therapeutic potential for ischemic brain injury.

Respiration aligns perception with neural excitability.

Recent studies from the field of interoception have highlighted the link between bodily and neural rhythms during action, perception, and cognition. The mechanisms underlying functional body-brain coupling, however, are poorly understood, as are the ways in which they modulate behavior. We acquired respiration and human magnetoencephalography data from a near-threshold spatial detection task to investigate the trivariate relationship between respiration, neural excitability, and performance. Respiration was found to significantly modulate perceptual sensitivity as well as posterior alpha power (8-13 Hz), a well-established proxy of cortical excitability. In turn, alpha suppression prior to detected versus undetected targets underscored the behavioral benefits of heightened excitability. Notably, respiration-locked excitability changes were maximized at a respiration phase lag of around -30° and thus temporally preceded performance changes. In line with interoceptive inference accounts, these results suggest that respiration actively aligns sampling of sensory information with transient cycles of heightened excitability to facilitate performance.

Neural excitability of lower extremity musculature in individuals with and without chronic ankle instability: A systematic review and meta-analysis.

This systematic review and meta-analysis examined differences in lower extremity neural excitability between ankles with and without chronic ankle instability (CAI). We searched the literature for studies that compared corticomotor or spinal reflexive excitability between a CAI group and controls or copers, or between limbs of a CAI group. Random effects meta-analyses calculated pooled effect sizes for each outcome. Nineteen studies were included. Meta-analyses of motor thresholds of the fibularis longus (Z = 1.17, P = 0.24) and soleus (Z = 0.47, P = 0.64) exhibited no differences between ankles with and without CAI. Pooled data indicate that ankles with CAI had reduced soleus spinal reflexive excitability (Z = 2.18, P = 0.03) and significantly less modulation of the soleus (Z = 6.96, P < 0.01) and fibularis longus (Z = 4.75, P < 0.01) spinal reflexive excitability when transitioning to more challenging stances. Pre-synaptic inhibition was facilitated in ankles with CAI (Z = 4.05, P < 0.01), but no difference in recurrent inhibition existed (Z = 1.50, P = 0.13). Soleus spinal reflexive activity is reduced in those with CAI. Reduced ability of ankles with CAI to modulate soleus and fibularis longus reflexive activity may contribute to impaired balance.

Late fMRI Response Components Are Altered in Autism Spectrum Disorder.

Disrupted cortical neural inhibition has been hypothesized to be a primary contributor to the pathophysiology of autism spectrum disorder (ASD). This hypothesis predicts that ASD will be associated with an increase in neural responses. We tested this prediction by comparing fMRI response magnitudes to simultaneous visual, auditory, and motor stimulation in ASD and neurotypical (NT) individuals. No increases in the initial transient response in any brain region were observed in ASD, suggesting that there is no increase in overall cortical neural excitability. Most notably, there were widespread fMRI magnitude increases in the ASD response following stimulation offset, approximately 6-8 s after the termination of sensory and motor stimulation. In some regions, the higher fMRI offset response in ASD could be attributed to a lack of an "undershoot"-an often observed feature of fMRI responses believed to reflect inhibitory processing. Offset response magnitude was associated with reaction times (RT) in the NT group and may explain an overall reduced RT in the ASD group. Overall, our results suggest that increases in neural responsiveness are present in ASD but are confined to specific components of the neural response, are particularly strong following stimulation offset, and are linked to differences in RT.

The absence of NIPA2 enhances neural excitability through BK (big potassium) channels.

AIM: To reveal the pathogenesis and find the precision treatment for the childhood absence epilepsy (CAE) patients with NIPA2 mutations. METHODS: We performed whole-cell patch-clamp recordings to measure the electrophysiological properties of layer V neocortical somatosensory pyramidal neurons in wild-type (WT) and NIPA2-knockout mice. RESULTS: We identified that layer V neocortical somatosensory pyramidal neurons isolated from the NIPA2-knockout mice displayed higher frequency of spontaneous and evoked action potential, broader half-width of evoked action potential, and smaller currents of BK channels than those from the WT mice. NS11021, a specific BK channel opener, reduced neuronal excitability in the NIPA2-knockout mice. Paxilline, a selective BK channel blocker, treated WT neurons and could simulate the situation of NIPA2-knockout group, thereby suggesting that the absence of NIPA2 enhanced the excitability of neocortical somatosensory pyramidal neurons by decreasing the currents of BK channels. Zonisamide, an anti-epilepsy drug, reduced action potential firing in NIPA2-knockout mice through increasing BK channel currents. CONCLUSION: The results indicate that the absence of NIPA2 enhances neural excitability through BK channels. Zonisamide is probably a potential treatment for NIPA2 mutation-induced epilepsy, which may provide a basis for the development of new treatment strategies for epilepsy.

Role of spinal glial cells in excitability of wide dynamic range neurons and the development of neuropathic pain with the L5 spinal nerve transection in the rats: Behavioral and electrophysiological study.

The activation of glial cells affects the neuronal excitability in the spinal cord. Therefore, in this study, we tried to find out the modulatory role of spinal glial cells in the excitability of wide dynamic range (WDR) neurons, induction of the long-term potentiation (LTP) and development of neuropathic pain by L5 spinal nerve transection model in the rats. Forty-eight adult male Wistar rats were used to measure the paw withdrawal threshold to mechanical stimuli and also, to carry out the spinal extracellular single unit recording experiments. In these experiments, spinal nerve ligation (SNL) and a daily injection of propentofylline (1 mg/kg, ip) as a glial cell inhibitor agent, 1 h following nerve ligation during 7-day post-SNL period, were performed. Our findings showed that the mechanical allodynia, and synaptically-evoked firing were caused LTP in the Aδ-fiber, C-fiber and lesser in the Aß-fiber after high frequency stimulation. Daily injection of propentofylline considerably decreased LTP induction in the Aδ- and C-fibers (P < .001). It was concluded that glial cell activation mediates LTP induction in the spinal cord following peripheral nerve injury. It seems that pain modulatory role of glial cells is partly parallel to changes in neural excitability of the WDR neurons in the dorsal horn of spinal cord.

Humans strategically shift decision bias by flexibly adjusting sensory evidence accumulation.

Decision bias is traditionally conceptualized as an internal reference against which sensory evidence is compared. Instead, we show that individuals implement decision bias by shifting the rate of sensory evidence accumulation toward a decision bound. Participants performed a target detection task while we recorded EEG. We experimentally manipulated participants' decision criterion for reporting targets using different stimulus-response reward contingencies, inducing either a liberal or a conservative bias. Drift diffusion modeling revealed that a liberal strategy biased sensory evidence accumulation toward target-present choices. Moreover, a liberal bias resulted in stronger midfrontal pre-stimulus 2-6 Hz (theta) power and suppression of pre-stimulus 8-12 Hz (alpha) power in posterior cortex. Alpha suppression in turn was linked to the output activity in visual cortex, as expressed through 59-100 Hz (gamma) power. These findings show that observers can intentionally control cortical excitability to strategically bias evidence accumulation toward the decision bound that maximizes reward.