Paired-pulse Inhibition Research Articles

Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis.

Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function. Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABA-ergic dysfunction in ALS, through recording focussed cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single pulse and novel inhibitory paired-pulse paradigms, TMS-EEG studies were undertaken on 21 ALS patients and results compared to healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30ms (P30), 60 ms (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 ms (N44), 100 ms (N100) and 280ms (N280) after T,MS stimulus. The single pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABA-ergic dysfunction. When compared to controls, the N100 component was significantly reduced (P<0.05) while the P190 component increased (P<0.05) in ALS patients. Additionally, the N44 component correlated with muscle weakness (r=-0.501, P<0.05). These finding were supported by reduced paired pulse inhibition of TEP components in ALS patients (P60, P<0.01; N100, P<0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Further, the reduction in SICI, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r=-0.698, P<0.001). In conclusion, intensive and focussed interrogation of the motor cortex utilising novel TMS-EEG combined technologies has established localised dysfunction of GABA-ergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABA-ergic circuits correlated with greater clinical disability and disease duration implying pathophysiological significance.

Thalamocortical mGlu8 Modulates Dorsal Thalamus Excitatory Transmission and Sensorimotor Activity.

Metabotropic glutamate receptor 8 (mGlu8) is a heterogeneously expressed and poorly understood glutamate receptor with potential pharmacological significance. The thalamic reticular nucleus (TRN) is a critical inhibitory modulator of the thalamocortical-corticothalamic (TC-CT) network and plays a crucial role in information processing throughout the brain, is implicated in a variety of psychiatric conditions, and is also a site of significant mGlu8 expression. Using both male and female mice, we determined via fluorescent in situ hybridization that parvalbumin-expressing cells in the TRN core and shell matrices (identified by spp1+ and ecel1+ expression, respectively), as well as the cortical layers involved in CT signaling, express grm8 mRNA. We then assayed the physiological and behavioral impacts of perturbing grm8 signaling in the TC circuit through conditional (adeno-associated virus-CRE mediated) and cell-type-specific constitutive deletion strategies. We show that constitutive parvalbumin grm8 knock-out (PV grm8 knock-out) mice exhibited (1) increased spontaneous excitatory drive onto dorsal thalamus relay cells and (2) impaired sensorimotor gating, measured via paired-pulse inhibition, but observed no differences in locomotion and thigmotaxis in repeated bouts of open field test (OFT). Conversely, we observed hyperlocomotive phenotypes and anxiolytic effects of AAV-mediated conditional knockdown of grm8 in the TRN (TRN grm8 knockdown) in repeated OFT. Our findings underscore a role for mGlu8 in regulating excitatory neurotransmission as well as anxiety-related locomotor behavior and sensorimotor gating, revealing potential therapeutic applications for various neuropsychiatric disorders and guiding future research endeavors into mGlu8 signaling and TRN function.

Evaluation of mechanomyogram efficacy as a tool for assessing paired-pulse inhibition of blink reflex early R1 component.

Paired-pulse stimulation provides clinically useful information regarding sensory inhibition. When supraorbital nerve stimulation is repeated within a short interval, the response to the second stimulation is reduced to varying degrees. This magnitude of change in stimulation response can be monitored by electromyogram (EMG) or by mechanomyogram (MMG) as in this report. MMG has some advantages such as being less time consuming and lacking stimulus artifact. We compared the use of MMG and EMG to validate MMG as an effective method of assessing blink reflex paired-pulse inhibition. Eight volunteers participated. Participants received electrical stimulation to the supraorbital nerve of each side. A paired-pulse paradigm was employed, varying the conditioning-test interval between 5 and 800 ms. The R1 component of the induced blink reflex was simultaneously recorded by EMG using a pair of electrodes placed on the lower eyelid and by MMG using an accelerometer placed between the electrodes. The correlation coefficient of the R1 amplitude between MMG and EMG of the grand-averaged waveforms was 0.99. The average participant r value was .91 (range .76-.99). Similar analyses were performed for the amplitude variation of the second response relative to the first response. Results correlated well, yielding r values of .97 and .86 for the grand-averaged waveform and the average for each subject. The present results demonstrate that MMG could be an alternative to EMG in assessing paired-pulse inhibition of the electrical blink reflex R1 component.

5-HT6 Receptors Control GABAergic Transmission and CA1 Pyramidal Cell Output of Dorsal Hippocampus.

The blockade of 5-HT6 receptors represents an experimental approach that might ameliorate the memory deficits associated with brain disorders, including Alzheimer's disease and schizophrenia. However, the synaptic mechanism by which 5-HT6 receptors control the GABAergic and glutamatergic synaptic transmission is barely understood. In this study, we demonstrate that pharmacological manipulation of 5-HT6 receptors with the specific agonist EMD 386088 (7.4nM) or the antagonist SB-399885 (300nM) modulates the field inhibitory postsynaptic potentials of the dorsal hippocampus and controls the strength of the population spike of pyramidal cells. Likewise, pharmacological modulation of 5-HT6 controls the magnitude of paired-pulse inhibition, a phenomenon mediated by GABAergic interneurons acting via GABAA receptors of pyramidal cells. The effects of pharmacological manipulation of the 5-HT6 receptor were limited to GABAergic transmission and did not affect the strength of field excitatory postsynaptic potentials mediated by the Schaffer collaterals axons. Lastly, in a modified version of the Pavlovian autoshaping task that requires the activation of the hippocampal formation, we demonstrated that the anti-amnesic effect induced by the blockade of the 5-HT6 receptor is prevented when the GAT1 transporter is blocked, suggesting that modulation of GABAergic transmission is required for the anti-amnesic properties of 5-HT6 receptor antagonists.

Reduced somatosensory evoked potentials and paired-pulse inhibition in the primary somatosensory cortex of athletes with chronic pain.

Chronic pain impedes athletic training and performance. However, it is challenging to identify the precise causes of chronic pain for effective treatment. To examine possible neuroplastic changes in sensory transmission and cortical processing, we compared somatosensory evoked potentials (SEPs) and paired-pulse inhibition (PPI) in primary sensory cortex (S1) between athletes with chronic pain and control athletes. Sixty-six intercollegiate athletes (39 males and 27 females) were recruited for this study, 45 control athletes and 21 reporting persistent pain for > 3months. Sensory-evoked potentials were induced in S1 by constant-current square-wave pulses (0.2-ms duration) delivered to the right median nerve, while PPI was induced by paired stimulation at interstimulus intervals of 30 and 100ms (PPI-30 and PPI-100ms, respectively). All participants were randomly presented with total 1,500 (each 500 stimuli) single stimuli and stimulus pairs at 2Hz. Both N20 amplitude and PPI-30ms were significantly lower in athletes with chronic pain compared to control athletes, while P25 amplitude and PPI-100ms did not differ significantly between groups. Chronic pain in athletes is associated with substantially altered excitatory-inhibitory balance within the primary somatosensory cortex, possibly due to reduced thalamocortical excitatory transmission and suppressed cortical inhibitory transmission.

Sex Differences in Excitatory and Inhibitory Function in the Primary Somatosensory Cortex during the Early Follicular Phase: A Preliminary Study.

We examined sex differences in the excitatory and inhibitory functions of the primary somatosensory cortex (S1) between males and females during the early follicular phase, when estradiol hormones are unaffected. Fifty participants (25 males and 25 females) underwent measurement of somatosensory evoked potentials (SEPs) and paired-pulse inhibition (PPI) in the S1; SEPs and PPI were elicited by constant current square-wave pulses (0.2 ms duration) delivered to the right median nerve by electrical stimulation. Paired-pulse stimulation occurred at 30- and 100-ms interstimulus intervals. Participants were randomly presented with 1500 (500 stimuli each) single- and paired-pulse stimuli at 2 Hz. The N20 amplitude was significantly larger in female subjects than in male subjects, and the PPI-30 ms was significantly potentiated in female subjects compared to that in male subjects. The excitatory and inhibitory functions in S1 differ between male and female subjects, at least during the early follicular phase.

Increased Network Inhibition in the Dentate Gyrus of Adult Neuroligin-4 Knock-Out Mice

Loss-of-function mutations in neuroligin-4 (Nlgn4), a member of the neuroligin family of postsynaptic adhesion proteins, cause autism spectrum disorder in humans. Nlgn4 knockout (KO) in mice leads to social behavior deficits and complex alterations of synaptic inhibition or excitation, depending on the brain region. In the present work, we comprehensively analyzed synaptic function and plasticity at the cellular and network levels in hippocampal dentate gyrus of Nlgn4 KO mice. Compared with wild-type littermates, adult Nlgn4 KO mice exhibited increased paired-pulse inhibition of dentate granule cell population spikes, but no impairments in excitatory synaptic transmission or short-term and long-term plasticity in vivo In vitro patch-clamp recordings in neonatal organotypic entorhino-hippocampal slice cultures from Nlgn4 KO and wild-type littermates revealed no significant differences in excitatory or inhibitory synaptic transmission, homeostatic synaptic plasticity, and passive electrotonic properties in dentate granule cells, suggesting that the increased inhibition in vivo is the result of altered network activity in the adult Nlgn4 KO. A comparison with prior studies on Nlgn 1-3 knock-out mice reveals that each of the four neuroligins exerts a characteristic effect on both intrinsic cellular and network activity in the dentate gyrus in vivo.

Involvement of dopamine D2 -like receptors in the antiepileptogenic effects of deep brain stimulation during kindling in rats.

Deep brain electrical stimulation (DBS), as a potential therapy for drug resistive epileptic patients, has inhibitory action on epileptogenesis. In the present investigation, the role of dopamine D2 -like receptors in the antiepileptogenic action of DBS was studied. Seizures were induced in adult rats by stimulating the perforant path in a semi-rapid kindling method. Five minutes after the last kindling stimulation, daily DBS was applied to the perforant path at the pattern of low frequency stimulation (LFS; 1Hz; pulse duration: 0.1ms; intensity: 50-150 μA; 4 trains of 200 pulses at 5min intervals). Sulpiride (10μg/1μl, i.c.v.), a selective dopamine D2 -like receptor antagonist, was administered prior to the daily LFS application. Kindling stimulations increased cumulative daily behavioral seizure stages, daily afterdischarge duration (dADD), and population spike amplitude (PS) in dentate gyrus following perforant path stimulation, while applying LFS decreased the kindled seizures' parameters. In addition, kindling potentiated the early (at 10-50 ms inter-pulse interval) and late (at 150-1000 ms inter-pulse interval) paired-pulse inhibition and decreased the paired-pulse facilitation (at 70-100 ms inter-pulse interval). These effects were also inhibited by applying LFS. All inhibitory effects of LFS on kindling procedure were prevented by sulpiride administration. These data may suggest that LFS exerts its preventive effect on kindling development, at least partly, through the receptors on which sulpiride acts which are mainly dopamine D2 -like (including D2 , D3 , and D4 ) receptors.

A distinct impact of repeated morphine exposure on synaptic plasticity at Schaffer collateral-CA1, temporoammonic-CA1, and perforant pathway-dentate gyrus synapses along the longitudinal axis of the hippocampus.

We aimed to study how morphine affects synaptic transmission in the dentate gyrus and CA1 regions along the hippocampal long axis. For this, recording and measuring of field excitatory postsynaptic potentials (fEPSPs) were utilized to test the effects of repeated morphine exposure on paired-pulse evoked responses and long-term potentiation (LTP) at Schaffer collateral-CA1 (Sch-CA1), temporoammonic-CA1 (TA-CA1) and perforant pathway-dentate gyrus (PP-DG) synapses in transverse slices from the dorsal (DH), intermediate (IH), and ventral (VH) hippocampus in adult male rats. After repeated morphine exposure, the expression of opioid receptors and the α1 and α5 GABAA subunits were also examined. We found that repeated morphine exposure blunt the difference between the DH and the VH in their basal levels of synaptic transmission at Sch-CA1 synapses that were seen in the control groups. Significant paired-pulse facilitation of excitatory synaptic transmission was observed at Sch-CA1 synapses in slices taken from all three hippocampal segments as well as at PP-DG synapses in slices taken from the VH segment in the morphine-treated groups as compared to the control groups. Interestingly, significant paired-pulse inhibition of excitatory synaptic transmission was observed at TA-CA1 synapses in the DH slices from the morphine-treated group as compared to the control group. While primed-burst stimulation (a protocol reflecting normal neuronal firing) induced a robust LTP in hippocampal subfields in all control groups, resulting in a decaying LTP at TA-CA1 synapses in the VH slices and at PP-DG synapses in both the IH and VH slices taken from the morphine-treated rats. In the DH of morphine-treated rats, we found increased levels of the mRNAs encoding the α1 and α5 GABAA subunits as compared to the control group. Taken together, these findings suggest the potential mechanisms through which repeated morphine exposure causes differential changes in circuit excitability and synaptic plasticity in the dentate gyrus and CA1 regions along the hippocampal long axis.

Effect of whole-hand water flow stimulation on the neural balance between excitation and inhibition in the primary somatosensory cortex.

Sustained peripheral somatosensory stimulations, such as high-frequency repetitive somatosensory stimulation (HF-RSS) and vibrated stimulation, are effective in altering the balance between excitation and inhibition in the somatosensory cortex (S1) and motor cortex (M1). A recent study reported that whole-hand water flow (WF) stimulation induced neural disinhibition in the M1. Based on previous results, we hypothesized that whole-hand WF stimulation would lead to neural disinhibition in the S1 because there is a strong neural connection between M1 and S1 and aimed to examine whether whole-hand WF stimulation would change the neural balance between excitation and inhibition in the S1. Nineteen healthy volunteers were studied by measuring excitation and inhibition in the S1 before and after each of the four 15-min interventions. The excitation and inhibition in the S1 were assessed using somatosensory evoked potentials (SEPs) and paired-pulse inhibition (PPI) induced by single- and paired-pulse stimulations, respectively. The four interventions were as follows: control, whole-hand water immersion, whole-hand WF, and HF-RSS. The results showed no significant changes in SEPs and PPI following any intervention. However, changes in PPI with an interstimulus interval (ISI) of 30 ms were significantly correlated with the baseline value before whole-hand WF. Thus, the present findings indicated that the whole-hand WF stimulation had a greater decreased neural inhibition in participants with higher neural inhibition in the S1 at baseline. Considering previous results on M1, the present results possibly show that S1 has lower plasticity than M1 and that the duration (15 min) of each intervention may not have been enough to alter the balance of excitation and inhibition in the S1.

Therapeutic benefits of noninvasive somatosensory cortex stimulation on cortical plasticity and somatosensory function: A systematic review.

Optimal limb coordination requires efficient transmission of somatosensory information to the sensorimotor cortex. The primary somatosensory cortex (S1) is frequently damaged by stroke, resulting in both somatosensory and motor impairments. Noninvasive brain stimulation (NIBS) to the primary motor cortex is thought to induce neural plasticity that facilitates neurorehabilitation. Several studies have also examined if NIBS to the S1 can enhance somatosensory processing as assessed by somatosensory-evoked potentials (SEPs) and improve behavioural task performance, but it remains uncertain if NIBS can reliably modulate S1 plasticity or even whether SEPs can reflect this plasticity. This systematic review revealed that NIBS has relatively minor effects on SEPs or somatosensory task performance, but larger early SEP changes after NIBS can still predict improved performance. Similarly, decreased paired-pulse inhibition in S1 post-NIBS is associated with improved somatosensory performance. However, several studies still debate the role of inhibitory function in somatosensory performance after NIBS in terms of the direction of the change (i.e., disinhibition or inhibition). Altogether, early SEP and paired-pulse inhibition (particularly inter-stimulus intervals of 30-100 ms) may become useful biomarkers for somatosensory deficits, but improved NIBS protocols are required for therapeutic applications.

Chronic stimulation of the serotonergic 5-HT4 receptor modulates amyloid-beta-related impairments in synaptic plasticity and memory deficits in male rats

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory decline and impaired hippocampal synaptic plasticity. The serotonin 5-HT4 receptor is involved in learning and memory processes. This study explored the effects of chronic stimulation of 5-HT4R on cognition, memory, long-term potentiation (LTP), paired-pulse ratio (PPR), and neuronal apoptosis in a rat model of amyloid-beta (Aβ)-induced AD.Thirty-five male Wistar rats were randomly divided into three groups as follows: the sham, Aβ, and Aβ + BIMU8 groups. Aβ (6 µg/µl) was administrated by intracerebroventricular (icv) injection. The animals were treated with BIMU8 (1 μg/μL, ICV) as a 5-HT4R agonist for 30 days. Memory and behavioral changes were assessed by the passive avoidance learning, novel object recognition, open field, and elevated plus maze tests. Hippocampal synaptic plasticity was evaluated in the dentate gyrus (DG) in response to the stimulation applied to the perforant pathway. Furthermore, neuronal apoptosis was measured in the hippocampus. Data were analyzed by SPSS version 19 using one-way ANOVA, followed by Tukey’s post hoc test.Aβ induced memory deficits and neuronal loss and inhibited LTP induction. Aβ also increased the normalized PPR. BIMU8 enhanced the slope of the field excitatory postsynaptic potential in LTP and improved cognition behavior. Paired-pulse inhibition or facilitation was not affected by LTP induction in Aβ animals receiving the BIMU8.It can be concluded that the stimulation of the 5-HT4 receptor modulated the Aβ-induced cognition and memory deficits, probably via a decrease in the hippocampal apoptotic neurons and an improvement in the hippocampal synaptic functions without involving its inhibitory interneurons.

Fluoroethylnormemantine, A Novel Derivative of Memantine, Facilitates Extinction Learning Without Sensorimotor Deficits.

BackgroundMemantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, has been approved for use in Alzheimer’s disease, but an increasing number of studies have investigated its utility for neuropsychiatric disorders. Here, we characterized a novel compound, fluoroethylnormemtantine (FENM), which was derived from memantine with an extra Fluor in an optimized position for in vivo biomarker labeling. We sought to determine if FENM produced similar behavioral effects as memantine and/or if FENM has beneficial effects against fear, avoidance, and behavioral despair.MethodsWe administered saline, FENM, or memantine prior to a number of behavioral assays, including paired-pulse inhibition, open field, light dark test, forced swim test, and cued fear conditioning in male Wistar rats.ResultsUnlike memantine, FENM did not produce nonspecific side effects and did not alter sensorimotor gating or locomotion. FENM decreased immobility in the forced swim test. Moreover, FENM robustly facilitated fear extinction learning when administered prior to either cued fear conditioning training or tone reexposure.ConclusionsThese results suggest that FENM is a promising, novel compound that robustly reduces fear behavior and may be useful for further preclinical testing.

Behavioral profiling reveals an enhancement of dentate gyrus paired pulse inhibition in a rat model of PTSD

We recently introduced behavioral profiling as a translational approach to increase the validity of animal models of posttraumatic stress disorder (PTSD). Behavioral profiling utilizes the response of a ‘normal population’ of control animals and compares the performance of animals with a history of traumatic stress in different behavioral tests that can capture PTSD-like symptoms. Thus, affected, PTSD-like individuals can be subdivided from resilient trauma-exposed animals.While in our recent study we focused mainly on tests for activity and anxiety, we now expand the behavioral tests battery and include also fear memory and extinction tasks as well as a spatial object recognition test in our behavioral profiling approach. Utilizing underwater trauma as the traumatic event, we found that only a small subset of animals exposed to underwater trauma showed lasting increases in anxiety-like behavior and heightened emotional memory formation. Adding juvenile stress as a model for childhood adversity increased the prevalence of such affected animals and furthermore and induced additional cognitive deficits in a subgroup of such emotionally affected individuals. In addition, multiple affected individual rats displayed increased local circuit activity in the dorsal dentate gyrus, as measured in vivo with paired pulse protocols in anesthetized animals.Together, our findings highlight behavioral profiling, refined by including multiple behavioral tests, as a valid tool to identify PTSD-like vs. resilient individual animals and further suggest that enhanced local inhibition in specific circuits of the dorsal dentate gyrus may be associated with the observed symptoms.

Paired-pulse Inhibition and Disinhibition of the Dentate Gyrus Following Orexin Receptors Inactivation in the Basolateral Amygdala.

Introduction:The Basolateral Amygdala (BLA) substantially affects neuronal transmission and synaptic plasticity processes through the dentate gyrus. Orexin neuropeptides play different roles in the sleep/wakefulness cycle, feeding, learning, and memory. The present study aimed to investigate the function of the orexin receptors of the BLA in the hippocampal local interneuron circuits.Methods:For this, the region’s paired-pulse responses from the Dentate Gyrus (DG) were recorded. Within the procedure, SB-334867-A (12μg/0.5μL) and TCS-OX2-29 (10μg/0.5μL (orexin 1 & 2 receptors antagonists, respectively), were administered into both sides of the BLA areas of the rat brain. Dimethyl Sulfoxide (DMSO) was used as the solvent in the control animals with a volume of 0.5μL.Results:Our data indicated that the Paired-pulse (PP) responses were not affected by the inactivation of the orexin receptors of the BLA.Conclusion:Due to not observing any significant changes in the short form of synaptic plasticity, after inactivation of the orexin system of the BLA, we hypothesize that the orexinergic fibers to the basolateral part of the amygdala influence the long-term synaptic efficacy; however, the primary processing of information in short-term plasticity model is not affected by the same system. The elementary processing of the data by the amygdala might happen through the action of other neurotransmitter systems.HighlightsThe neuronal transmission of DG following orexin receptors antagonism of the BLA.Paired-pulse responses were not affected by the orexin 1 receptors antagonism.Paired-pulse responses were not affected by the orexin 2 receptors antagonism.Plain Language SummaryThe orexinergic system has modulatory effects by sending projection fibers to several parts of the brain, such as the hippocampus and amygdala. Orexin neuropeptides activate basolateral amygdala neural circuits during different arousal states. Although, this system plays a vital role in creating appropriate behavioral reactions, the primary processing of the information in short-term plasticity model is not affected by it.

Influence of Menstrual Cycle Phases on Neural Excitability in the Primary Somatosensory Cortex and Ankle Joint Position Sense.

Introduction: Ankle sprain (AS) is one of the most common injuries among women engaged in competitive sports and recreational activities. Many studies have shown that several factors contributing to AS are influenced by the menstrual cycle. Despite the finding that abnormal joint position sense (JPS) is one of the major risk factors of AS, the alteration of the JPS throughout the menstrual cycle and its associated neural mechanisms remain unclear.Objective: This study aimed to examine whether the menstrual cycle phases affect neural excitability in the primary somatosensory cortex (S1) and JPS.Methods: Fourteen right-footed women participated in this study. Somatosensory-evoked potential and paired-pulse inhibition (PPI) were measured to assess S1 excitatory and inhibitory functions. Ankle JPS was measured using an active joint position matching method. Menstrual syndrome was evaluated using the menstrual distress questionnaire. All assessments were conducted in the follicular, ovulatory, and luteal phases.Results: The two main findings of this study were as follows: First, PPI decreased in the ovulatory phase than in the follicular phase. This may have been the reason for estrogen altering the neural inhibition and facilitation balance throughout the menstrual cycle. Second, JPS was not changed during the menstrual cycle.Conclusion: In conclusion, phases of the menstrual cycle affect the neural excitability in S1 as shown by the decreased PPI in the ovulatory phase, and the ankle JPS was unchanged throughout the menstrual cycle.

Implementation of PPI with Nano Amorphous Oxide Semiconductor Devices for Medical Applications.

BackgroundElectronic devices which mimic the functionality of biological synapses are a large step to replicate the human brain for neuromorphic computing and for numerous medical research investigations. One of the representative synaptic behaviors is paired-pulse facilitation (PPF). It has been widely investigated because it is regarded to be related to biological memory. However, plasticity behavior is only part of the human brain memory behavior.MethodsHere, we present a phenomenon which is opposite to PPF, i.e., paired-pulse inhibition (PPI), in nano oxide devices for the first time. The research here suggests that rather than being enhanced, the phenomena of memory loss would also be possessed by such electronic devices. The device physics mechanism behind memory loss behavior was investigated. This mechanism is sustained by historical memory and degradation manufactured by device trauma to regulate characteristically stimulated origins of artificial transmission behaviors.ResultsUnder the trauma of a memory device, both the signal amplitude and signal time stimulated by a pulse are lower than the first signal stimulated by a previous pulse in the PPF, representing a new scenario in the struggle for memory. In this way, more typical human brain behaviors could be simulated, including the effect of age on latency and error generation, cerebellar infarct, trauma and memory loss pharmacological actions (such as those caused by hyoscines and nitrazepam).ConclusionThus, this study developed a new approach for implementing the manner in which the brain works in semiconductor devices for improving medical research.

Impairments in sensory-motor gating and information processing in a mouse model of Ehmt1 haploinsufficiency.

Regulators of chromatin dynamics and transcription are increasingly implicated in the aetiology of neurodevelopmental disorders. Haploinsufficiency of EHMT1, encoding a histone methyltransferase, is associated with several neurodevelopmental disorders, including Kleefstra syndrome, developmental delay and autism spectrum disorder. Using a mouse model of Ehmt1 haploinsufficiency (Ehmt1D6Cre/+), we examined a number of brain and behavioural endophenotypes of relevance to neurodevelopmental disorders. Specifically, we show that Ehmt1D6Cre/+ mice have deficits in information processing, evidenced by abnormal sensory-motor gating, a complete absence of object recognition memory, and a reduced magnitude of auditory evoked potentials in both paired-pulse inhibition and mismatch negativity. The electrophysiological experiments show that differences in magnitude response to auditory stimulus were associated with marked reductions in total and evoked beta- and gamma-band oscillatory activity, as well as significant reductions in phase synchronisation. The pattern of electrophysiological deficits in Ehmt1D6Cre/+ matches those seen in control mice following administration of the selective NMDA-R antagonist, ketamine. This, coupled with reduction of Grin1 mRNA expression in Ehmt1D6Cre/+ hippocampus, suggests that Ehmt1 haploinsufficiency may lead to disruption in NMDA-R. Taken together, these data indicate that reduced Ehmt1 dosage during forebrain development leads to abnormal circuitry formation, which in turn results in profound information processing deficits. Such information processing deficits are likely paramount to our understanding of the cognitive and neurological dysfunctions shared across the neurodevelopmental disorders associated with EHMT1 haploinsufficiency.

Modulation of inhibitory function in the primary somatosensory cortex and temporal discrimination threshold induced by acute aerobic exercise

Acute aerobic exercise beneficially affects brain function. The effect of acute aerobic exercise on the inhibitory mechanism of the primary somatosensory cortex (S1) and somatosensory function remains unclear. We investigated whether acute aerobic exercise modulates S1 inhibitory function and somatosensory function. In Experiment 1, we measured somatosensory evoked potentials (SEP) and paired-pulse inhibition (PPI) in 15 healthy right-handed participants. The right median nerve underwent electrical stimulation (ES). Interstimulus intervals were 5 ms, 30 ms, and 100 ms. In Experiment 2, we assessed the somatosensory function by using a somatosensory temporal discrimination task. Single or paired ES was applied to the distal phalanx of the right index finger. Both the experiments involved three sessions: 20 min of moderate-intensity exercise, 30 min of low-intensity exercise, and 30 min of seated rest. Before and after each session, PPI and somatosensory temporal discrimination task performance were measured. The N20 latency was significantly shortened immediately after moderate exercise. The SEP amplitude was not modulated in any session. The PPI at 30 ms (PPI_30ms) significantly decreased 20 min after moderate exercise, whereas the PPI at 5 ms (PPI_5ms) and PPI at 100 ms (PPI_100ms) did not change. The 50% and 75% thresholds and reaction time did not improve in any session. We found negative relationships between the change in PPI_5ms and the change in the 75% threshold under low-intensity exercise condition. Thus, acute aerobic exercise modulated S1 inhibitory function depending on exercise intensity. The exercise-induced change in PPI was associated with the change in temporal discrimination.

Repeated toluene exposure alters the synaptic transmission of layer 5 medial prefrontal cortex

Toluene is an organic solvent commonly misused by inhalation among adolescents to experience psychoactive effects. Repeated toluene exposure produces several cognitive deficits, including working memory impairment in which the medial prefrontal cortex (mPFC) plays a central role. Among other effects, toluene antagonizes NMDA receptors, enhance GABAA receptor-mediated responses and increases dopamine release. We have recently reported that animals repeatedly exposed to toluene show increased mPFC excitability; however, alterations in synaptic transmission, including long-term synaptic plasticity of glutamatergic responses have not been studied thus far. Here we used extracellular recordings to determine the effects of repeated toluene exposure (8000 ppm for 30 min, twice a day, for ten days) on the synaptic transmission converging on prelimbic layer 5 pyramidal neurons of the mPFC in adolescent male Wistar rats. Repeated toluene exposure increased mPFC's synaptic strength and reduced the inhibitory transmission assessed by input-output curves and paired-pulse inhibition protocols, respectively. Both toluene and a selective D1 receptor antagonist blocked the ability of exogenous dopamine to induce synaptic potentiation. Repeated toluene exposure also altered the ability of NMDA to induce synaptic depression of excitatory transmission. Taken together, the changes in synaptic strength and impairment of the NMDA-mediated plasticity of the mPFC demonstrate a series of synaptic modifications of the glutamatergic transmission that may underlie the cognitive impairment resulting from repeated toluene exposure.