Discharge Frequency Of Neurons Research Articles

Effects of lateral ventricle injection of 5,7-dihydroxytryptamine on neurons in the medial prefrontal cortex of rats: An electrophysiology study

The medial prefrontal cortex (mPFC) is closely associated with various psychopathologies in humans, and its dysfunction is invariably accompanied by abnormalities in the serotonin (5-hydroxytryptamine, 5-HT) system of the brain. In this study, in-vivo extracellular recording techniques were used to investigate changes in the excitability of pyramidal neurons and interneurons in the rat mPFC following injection of 5,7-dihydroxytryptamine (5,7-DHT) into the bilateral lateral ventricles to damage the serotoninergic neurons. The levels of 5-HT in the mPFC and dorsal raphe nucleus of rats were determined by high-performance liquid chromatography. The results showed that the levels of 5-HT were significantly reduced in the mPFC and dorsal raphe nucleus two weeks after injection of 5,7-DHT into the bilateral lateral ventricles, relative to the normal group. The discharge frequency of pyramidal neurons in the mPFC was markedly increased compared to the normal group, with a significant rise in burst discharge, while the average discharge frequency of interneurons was significantly reduced and tended towards irregular activity. The results of the study indicated that the brain’s 5-HT neurotransmitter system not only directly affects the activity of mPFC pyramidal neurons but also modulates the electrical activity of interneurons, thereby regulating the local microcircuitry within the mPFC and participating in its function

Functional Adaptation in the Brain Habenulo-Mesencephalic Pathway During Cannabinoid Withdrawal.

The mesolimbic reward system originating from dopamine neurons in the ventral tegmental area (VTA) of the midbrain shows a profound reduction in function during cannabinoid withdrawal. This condition may underlie aversive states that lead to compulsive drug seeking and relapse. The lateral habenula (LHb) exerts negative control over the VTA via the GABA rostromedial tegmental nucleus (RMTg), representing a potential convergence point for drug-induced opponent processes. We hypothesized that the LHb-RMTg pathway might be causally involved in the hypodopaminergic state during cannabinoid withdrawal. To induce Δ9-tetrahydrocannabinol (THC) dependence, adult male Sprague-Dawley rats were treated with THC (15 mg/kg, i.p.) twice daily for 6.5-7 days. Administration of the cannabinoid antagonist rimonabant (5 mg/kg, i.p.) precipitated a robust behavioral withdrawal syndrome, while abrupt THC suspension caused milder signs of abstinence. Extracellular single unit recordings confirmed a marked decrease in the discharge frequency and burst firing of VTA dopamine neurons during THC withdrawal. The duration of RMTg-evoked inhibition was longer in THC withdrawn rats. Additionally, the spontaneous activity of RMTg neurons and of LHb neurons was strongly depressed during cannabinoid withdrawal. These findings support the hypothesis that functional changes in the habenulo-mesencephalic circuit are implicated in the mechanisms underlying substance use disorders.

Changes in preBötzinger Complex neuron discharge associated with changes in PCO2 in decerebrate rabbits

Background: Maskrey and Nicol reported a strong increase in minute ventilation with increase in PCO2 (J Physiol 1980, 301: 49-58). We investigated a) whether there was a ceiling to this effect at high CO2 levels and b) whether the change in ventilation was associated with specific changes in respiratory neurons in the preBötzinger complex (preBC). Methods: The study was approved by the local Animal Care Committee and conformed to NIH standards. Adult New Zealand White rabbits (3-4 kg) were anesthetized, tracheotomized, ventilated, decerebrated and vagotomized. Phrenic nerve activity was recorded from the C5 rootlet, time averaged and used to calculate inspiratory (TI) and expiratory durations (TE) and peak phrenic activity (PPA). PPA was normalized to the value at PCO2 50mmHg. Individual neurons were recorded in the functionally identified preBC using multichannel electrodes at increasing CO2 levels. Statistical analysis used the Wilcoxon signed-rank test to determine changes in respiratory parameters between CO2 levels and Friedman RM-ANOVA to determine changes in neuronal discharge frequency (Fn). A generalized linear mixed model was used to determine associations between CO2-dependent changes in TI, TE, PPA, and changes in Fn for different neuron types. p<0.05 indicated a significant difference. Results: In 34 animals, the increase in minute ventilation with increasing PCO2 was due mostly to the change in PPA. The increase in respiratory rate was due mostly to a decrease in TE. There was little increase in respiratory output at PCO2 > 50 mmHg. In 209 neurons, increasing PCO2 increased Fn in inspiratory augmenting (I aug, n= 70, p<0.0001 for CO2 30 vs 40 and 40 vs 50mmHg), I parabolic (I para, n=43, p<0.0001 for CO2 40 vs 50 mmHg), pre-inspiratory (pre-I, n=35, p<0.01 for CO2 30 vs 40 mmHg), and expiratory decrementing (E dec, n=44, p<0.01 for CO2 40 vs 50 mmHg) neurons, but not in I dec (n=8) and non-respiratory modulated (NRM, n=9) neurons. The strongest correlation was found between the changes in phase timing and PPA and Fn in I aug and pre-I neurons. Conclusion: We found a ceiling effect to the increase in respiratory output at PCO2 levels > 50 mmHg. Inspiratory preBC neuron subtypes were more affected by the changes in PCO2. NIH R01HL159546. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

CABP4 mutation in mice shows alteration in protein expression level and neuron discharge frequency.

The calcium-binding protein 4 (CABP4) gene is a newly identified epilepsy-related gene that might be associated with a rare type of genetic focal epilepsy; that is, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In vitro, mutant CABP4 causes an increased inward flow voltage of calcium ions and a significant increase in the electrical signal discharge in hippocampus neurons; however, the role of CABP4 in epilepsy has not yet been specifically described, and there is not yet a CABP4 mutant animal model recapitulating the epilepsy phenotype. We introduced a human CABP4 missense mutation into the C57BL/6J mouse genome and generated a knock-in strain carrying a glycine-to-aspartic acid mutation in the gene. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to evaluate the CABP4 expression level. Slice patch-clamp recording was carried out on pyramidal cells of prefrontal cortex layers II and III. The CABP4G155D/+ mutant mice were viable and born at an expected Mendelian ratio. Surprisingly, the heterozygous (HE) mice did not display either an abnormal appearance or an overt seizure phenotype, and there was no statistically significant difference between the HE and wild-type (WT) mice in terms of overall messenger RNA (mRNA) and protein expression. However, the HE mutant mice showed an imbalance in the amount of protein expressed in the brain regions. Additionally, the patch-clamp recordings from the HE mouse layer II/III cortical pyramidal cells revealed an increase in the frequency of micro-excitatory post-synaptic currents (mEPSCs) but no change in the amplitude was observed. The findings of this study suggest that the CABP4 p.G155D mutation might be one of the mechanisms underlying seizure onset.

Inhibitory effect of acupoint electrostimulation with different layers and intensities on muscular inflammatory pain and spinal WDR neuron activity.

To observe the analgesic effects of different levels and intensities of electrical stimulation on the local acupoints in the pain source area and their impact on wide dynamic range (WDR) neurons in the spinal dorsal horn, in order to provide a basis for selecting appropriate parameters for electroacupuncture (EA) stimulation. Wistar rats were used in 3 parts of the experiment. Complete Freund's adjuvant was used to establish a model of inflammation-induced pain in the gastrocnemius muscle. After modeling, 6 rats were randomly selected for multi-channel extracellular electrophysiological recording of the electrical activity of WDR neurons, to determine the threshold for activating the A-component (Ta) and the C-component (Tc), which were used as the intervention intensities for skin transcutaneous electrical acupoint stimulation (TEAS) or EA. Thirty-six rats were randomly divided into normal , model , TEAS-Ta , TEAS-Tc, EA-Ta , and EA-Tc groups, with 6 rats in each group. In the pain source area , Ta or Tc intensity of TEAS or EA intervention at"Chengshan"(BL57) was performed for 30 min each time, once a day, for 3 consecutive days. A small animal pressure pain measurement instrument was used to measure the mechanical pressure pain threshold of the gastrocnemius muscle in rats, and the Von Frey filament was used to measure the mechanical pain threshold of the footpad. Thirteen rats were randomly selected to observe the immediate responsiveness of WDR neurons to Ta/Tc intensity of EA or TEAS in BL57. The thresholds of TEAS to activate WDR neuron A-component or C-component were (2.43±0.57) mA and (7.00±1.34) mA, respectively, while the thresholds for EA to activate muscle WDR neuron A-component or C-component were (0.72±0.34) mA and (1.58±0.35) mA, respectively. After injection of CFA into the gastrocnemius muscle, compared with the normal group both the mechanical pressure pain threshold of the gastrocnemius muscle and the mechanical pain threshold of the footpad of rats in the model group were significantly decreased (P<0.001). After TEAS-Ta, TEAS-Tc or EA-Ta intervention in the BL57, both the mechanical pressure pain threshold of the gastrocnemius muscle and the mechanical pain threshold of the footpad were significantly higher than those in the model group (P<0.05, P<0.001). Compared with the normal group, the electrical threshold for evoking WDR neuron C-component discharge was significantly decreased (P<0.001) in the model group, while increased after TEAS-Ta, TEAS-Tc, or EA-Ta intervention (P<0.01) compared with the model group. The evoked discharge frequency of muscle WDR neurons decreased significantly after immediate intervention with TEAS-Ta, TEAS-Tc, or EA-Ta (P<0.01, P<0.05). EA-Tc had no significant improvement on the evoked electrical activity of WDR neurons or pain behavior. TEAS-Ta, TEAS-Tc, or EA-Ta can all alleviate the local and footpad mechanical pain in rats with muscle inflammation and inhibit the responsiveness of WDR neurons, indicating that different intensities are required for analgesic effects at different levels of acupoints in the pain source area.

Local Administration of the Phytochemical, Quercetin, Attenuates the Hyperexcitability of Rat Nociceptive Primary Sensory Neurons Following Inflammation Comparable to lidocaine

Although in vivo local injection of quercetin into the peripheral receptive field suppresses the excitability of rat nociceptive trigeminal ganglion (TG) neurons, under inflammatory conditions, the acute effects of quercetin in vivo, particularly on nociceptive TG neurons, remain to be determined. The aim of this study was to examine whether acute local administration of quercetin into inflamed tissue attenuates the excitability of nociceptive TG neurons in response to mechanical stimulation. The mechanical escape threshold was significantly lower in complete Freund’s adjuvant (CFA)-inflamed rats compared to before CFA injection. Extracellular single-unit recordings were made from TG neurons of CFA-induced inflammation in anesthetized rats in response to orofacial mechanical stimulation. The mean firing frequency of TG neurons in response to both non-noxious and noxious mechanical stimuli was reversibly inhibited by quercetin in a dose-dependent manner (1–10 mM). The mean firing frequency of inflamed TG neurons in response to mechanical stimuli was reversibly inhibited by the local anesthetic, 1% lidocaine (37 mM). The mean magnitude of inhibition on TG neuronal discharge frequency with 1 mM quercetin was significantly greater than that of 1% lidocaine. These results suggest that local injection of quercetin into inflamed tissue suppresses the excitability of nociceptive primary sensory TG neurons. PerspectiveLocal administration of the phytochemical, quercetin, into inflamed tissues is a more potent local analgesic than voltage-gated sodium channel blockers as it inhibits the generation of both generator potentials and action potentials in nociceptive primary nerve terminals. As such, it contributes to the area of complementary and alternative medicines.

Electroacupuncture in the treatment of IBS in rats: Investigation of the mechanisms of CRH+ neurons in the paraventricular nucleus.

Electroacupuncture (EA) is well documented to treat irritable bowel syndrome (IBS). However, the mechanism of the central nervous system related to IBS and acupuncture stimulation is still not well known. In this study, a rat model of IBS was established by cold-restraint comprehensive stresses for 15 days, and it was found that the levels of corticotropin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH) in the peripheral serum were increased; the visceral sensitivity was enhanced; and the intestinal motility was accelerated, specifically, there was an enhancement in the discharge frequency of neurons in the paraventricular nucleus (PVN). EA treatment for 3 days, 20 min/day, alleviated the increase in the levels of CRH, CORT, and ACTH in the peripheral serum of rats, reduced the visceral sensitivity of IBS rats, and inhibited colon movement and discharge frequency of the neurons in the PVN. Additionally, EA could reduce the excitability of CRH neurons and the expression of CRHR1 and CRHR2 in PVN. At the same time, the expression of CRH, CRHR1, and CRHR2 in the peripheral colon was decreased. Taken together, EA appears to regulate intestinal functional activity through the central CRH nervous system, revealing the central regulation mechanism of EA in IBS rats, and providing a scientific research basis for the correlation among the meridians, viscera, and brain.

Lu AF35700 reverses the phencyclidine-induced disruption of thalamo-cortical activity by blocking dopamine D1 and D2 receptors

Antipsychotic drugs of different chemical/pharmacological families show preferential dopamine (DA) D2 receptor (D2-R) vs. D1 receptor (D1-R) affinity, with the exception of clozapine, the gold standard of schizophrenia treatment, which shows a comparable affinity for both DA receptors. Here, we examined the ability of Lu AF35700 (preferential D1-R>D2-R antagonist), to reverse the alterations in thalamo-cortical activity induced by phencyclidine (PCP), used as a pharmacological model of schizophrenia. Lu AF35700 reversed the PCP-induced alteration of neuronal discharge and low frequency oscillation (LFO, 0.15–4 Hz) in thalamo-cortical networks. Likewise, Lu AF35700 prevented the increased c-fos mRNA expression induced by PCP in thalamo-cortical regions of awake rats. We next examined the contribution of D1-R and D2-R to the antipsychotic reversal of PCP effects. The D2-R antagonist haloperidol reversed PCP effects on thalamic discharge rate and LFO. Remarkably, the combination of sub-effective doses of haloperidol and SCH-23390 (DA D1-R antagonist) fully reversed the PCP-induced fall in thalamo-cortical LFO. However, unlike with haloperidol, SCH-23390 elicited different degrees of potentiation of the effects of low clozapine and Lu AF35700 doses. Overall, the present data support a synergistic interaction between both DA receptors to reverse the PCP-induced alterations of oscillatory activity in thalamo-cortical networks, possibly due to their simultaneous blockade in direct and indirect pathways of basal ganglia. The mild potentiation induced by SCH-23390 in the case of clozapine and Lu AF35700 suggests that, at effective doses, these agents reverse PCP effects through the simultaneous blockade of both DA receptors.

Suppression of the excitability of rat nociceptive secondary sensory neurons following local administration of the Phytochemical, (-)-Epigallocatechin-3-gallate

The phytochemical, polyphenolic compound, (-)-epigallocatechin-3-gallate (EGCG), is the main catechin found in green tea. Although a modulatory effect of EGCG on voltage-gated sodium and potassium channels has been reported in excitable tissues, the in vivo effect of EGCG on the excitability of nociceptive sensory neurons remains to be determined. Our aim was to investigate whether local administration of EGCG to rats attenuates the excitability of nociceptive spinal trigeminal nucleus caudalis (SpVc) neurons in response to mechanical stimulation in vivo. Extracellular single unit recordings were made from SpVc neurons in response to orofacial mechanical stimulation of anesthetized rats. The mean firing frequency of SpVc wide-dynamic range neurons following both non-noxious and noxious mechanical stimuli was significantly inhibited by EGCG in a dose-dependent and reversible manner. The mean magnitude of inhibition by EGCG on SpVc neuronal discharge frequency was similar to that of the local anesthetic, 1% lidocaine. Local injection of half-dose of lidocaine replaced the half-dose of EGCG. These results suggest that local injection of EGCG suppresses the excitability of nociceptive SpVc neurons, possibly via the inhibition of voltage-gated sodium channels and opening of voltage-gated potassium channels in the trigeminal ganglion. Therefore, administration of EGCG as a local anesthetic may provide relief from trigeminal nociceptive pain without side effects.

Suppression of the Excitability of Rat Nociceptive Primary Sensory Neurons Following Local Administration of the Phytochemical, Quercetin

Although the modulatory effect of quercetin on voltage-gated Na, K, and Ca channels has been studied in vitro, the in vivo effect of quercetin on the excitability of nociceptive primary neurons remains to be determined. The aim of the present study was to examine whether acute local quercetin administration to rats attenuates the excitability of nociceptive trigeminal ganglion (TG) neurons in response to mechanical stimulation in vivo. Extracellular single unit recordings were made from TG neurons of anesthetized rats in response to orofacial non-noxious and noxious mechanical stimulation. The mean firing frequency of TG neurons in response to both non-noxious and noxious mechanical stimuli was dose-dependently inhibited by quercetin, and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. The inhibitory effect of quercetin lasted for 15 minutes and was reversible. The mean magnitude of inhibition on TG neuronal discharge frequency with 10 mM quercetin was almost equal to that of the local anesthetic, 2% lidocaine. These results suggest that local injection of quercetin into the peripheral receptive field suppresses the excitability of nociceptive primary sensory neurons in the TG, possibly via inhibition of voltage-gated Na channels and opening voltage-gated K channels. PerspectiveLocal administration of the phytochemical, quercetin, as a local anesthetic may provide relief from trigeminal nociceptive pain with smallest side effects, thus contributing to the area of complementary and alternative medicines.

A Comprehensive Quantitative and Biological Neural Network Optimization Model of Sports Industry Structure Based on Knowledge Mapping.

In this paper, a comprehensive quantitative and biological neural network optimization model of sports industry structure is thoroughly studied and analyzed using knowledge graphs. To address the problems of poor performance interpretability deficiency of knowledge graph-based recommendation methods in the face of relational sparse graphs, a pretraining-based implicit characterization algorithm strategy is proposed for the recall stage, which can solve the problems of difficulty in going online and high delay in the recall stage of the recommendation system while improving the accuracy, and not only this can be applied in the recall stage, but also the sorting and postsorting modules can be used as features. To study the relationship between signaling activity and energy metabolism of pyramidal neurons, an empirical model of the synaptic vesicle cycle is proposed to simulate the synaptic transmission process, the role played by energy metabolism in synaptic transmission is studied from the perspective of feedback control, and the quantitative relationship between neuronal pulse discharge frequency, energy consumption, and information quantity in dendritic integration is analyzed using the cable theory and atrial chamber model. It was found that, when 0 ≤ ε ≤ 0.6, the chaotic region shrinks and eventually disappears with the increase of the memory factor ε; however, when 0.6 ≤ ε ≤ 1 is used, chaos is recreated and the chaotic area gradually increases with the increase of the memory factor ε. This paper conducts comparative experiments on data sets in the recommendation domain and verifies that the proposed model and the feature intersection module can effectively perform feature interaction between items and entities, thus enhancing the recommendation effect.

Activation of δ-opioid Receptors in Anterior Cingulate Cortex Alleviates Affective Pain in Rats

The negative emotions caused by persistent pain, called affective pain, are known to seriously affect human physical and mental health. The anterior cingulate cortex (ACC), especially the rostral ACC (rACC) plays a key role in the development of this affective pain. N-methyl-d-aspartate (NMDA) receptors, which are widely distributed in the ACC, are involved in the regulation of emotional behavior. It is well known that activation of opioid receptors can relieve pain, but whether it can alleviate affective pain is not clear. In the present study, conditioned place avoidance (CPA) responses induced by complete Freund's adjuvant (CFA) were used to represent the affective pain of place aversion. The behavioral measurements were synchronously combined with multichannel electrophysiological recordings of the discharge frequency of rACC pyramidal neurons to explore whether affective pain could be alleviated by the synthetic opioid [D-Ala2, D-Leu5]-Enkefalin (DADLE), an agonist of δ-opioid receptors. To further investigate this treatment as a mechanism for the relief of affective pain in CFA-treated animals, we used whole-cell patch recordings in slice preparations of the rACC region to determine the dose-dependent effects of DADLE on NMDA receptor-mediated currents. Then, western blot was used to determine levels of phosphorylated NMDA receptor subunits GluN1, GluN2 and GluN3 as affected by the δ-opioid receptor activation. The results showed that activation of δ-opioid receptors down-regulates the phosphorylation of NMDA receptor subunits, thereby inhibiting NMDA currents, decreasing the discharge frequency of rACC pyramidal neurons, and reversing the CPA response. Thus, δ-opioid receptor activation in the rACC region can alleviate affective pain.

Theoretical Analysis of Coupled Modified Hindmarsh-rose Model Under Transcranial Magnetic-acoustic Electrical Stimulation

Transcranial magnetic-acoustic electrical stimulation (TMAES) is a new technology with ultrasonic waves and a static magnetic field to generate an electric current in nerve tissues to modulate neuronal firing activities. The existing neuron models only simulate a single neuron, and there are few studies on coupled neurons models about TMAES. Most of the neurons in the cerebral cortex are not isolated but are coupled to each other. It is necessary to study the information transmission of coupled neurons. The types of neuron coupled synapses include electrical synapse and chemical synapse. A neuron model without considering chemical synapses is not comprehensive. Here, we modified the Hindmarsh-Rose (HR) model to simulate the smallest nervous system—two neurons coupled electrical synapses and chemical synapses under TMAES. And the environmental variables describing the synaptic coupling between two neurons and the nonlinearity of the nervous system are also taken into account. The firing behavior of the nervous system can be modulated by changing the intensity or the modulation frequency. The results show that within a certain range of parameters, the discharge frequency of coupled neurons could be increased by altering the modulation frequency, and intensity of stimulation, modulating the excitability of neurons, reducing the response time of chemical postsynaptic neurons, and accelerating the information transferring. Moreover, the discharge frequency of neurons was selective to stimulus parameters. These results demonstrate the possible theoretical regulatory mechanism of the neurons' firing frequency characteristics by TMAES. The study establishes the foundation for large-scale neural network modeling and can be taken as the theoretical basis for TMAES experimental and clinical application.

Effect of electroacupuncture preconditioning on neuronal activities in lateral hypothalamus area of myocardial ischemia reperfusion injury rats

To observe the effect of electroacupuncture (EA) preconditioning of "Shenmen" (HT7)-"Tongli" (HT5) segment of the Heart Meridian on neuronal electrical activities of lateral hypothalamus area (LHA) in rats with myocardial ischemia reperfusion injury (MIRI), so as to investigate its possible mechanism underlying improvement of MIRI. Twenty-four SD rats were randomly divided into sham, model, EA and damage + EA (D+EA) groups, with 6 rats in each group. The MIRI model was established by occlusion of the anterior descending branch (ADB) of the left coronary artery for 30 min, followed by reperfusion for 2 h. In the sham operation group, the ADB was only threaded beneath the artery without ligation. EA (2 Hz, 1 V) was applied to bilateral HT7-HT5 for 20 min, once daily for 7 days. In the D+EA group, FN was injected with 0.4 μL of 1 g/L kainic acid solution. Electrocardiogram (ECG) of the neck-thoracic lead was recorded by using PowerLab. The electrical activities of the LHA region were recorded by the implanted microelectrode array (2×4) and Plexon multi-channel acquisition system. Cluster analysis of neuronal signals was carried out by Offline Sorter software. The discharge waveforms, autocorrelation and cross-correlation of neuronal activities were analyzed by using Neuro Explorer software. Compared with the sham group, the ECG-ST height was significantly increased (P<0.05), the discharge frequency of pyramidal neurons was significantly reduced (P<0.01), while the discharge frequency of interneurons was increased (P<0.01) in the model group. After EA treatment, the ECG-ST height was significantly decreased (P<0.05), the discharge frequency of pyramidal neurons was significantly increased (P<0.01) relevant to the model group. In comparison with the EA group, the ECG-ST height in the D+EA group was significantly elevated (P<0.05), whereas the discharge frequency of pyramidal neurons was significantly decreased (P<0.01). The discharge frequency of interneurons was kept increasing after MIRI. Real-time spectrum analysis showed that the local field potential spectrum energy of the EA group was significantly lower than that of the model group and the D+EA group. EA preconditioning of Heart Meridian can significantly increase the discharge frequency of LHA excitatory pyramidal neurons and reduce the energy of the local field potential spectrum, which maybe one of the important mechanisms of EA in anti -MIRI.

Local administration of genistein as a local anesthetic agent inhibits the trigeminal nociceptive neuronal activity in rats

A modulatory role has been reported for the isoflavone, genistein, on voltage-gated Na+ channels in the trigeminal ganglion in vitro. However, the acute effects of genistein in vivo, particularly on nociceptive transmission in the trigeminal system, remain to be determined. The aim of the present study was to examine whether acute local genistein administration to rats attenuates the excitability of wide-dynamic range (WDR) spinal trigeminal nucleus caudalis (SpVc) neurons in response to nociceptive and non-nociceptive mechanical stimulation in vivo.Extracellular single unit recordings were made from SpVc WDR neurons in response to orofacial non-noxious and noxious mechanical stimulation of pentobarbital-anesthetized rats. The effects of local administration of genistein, lidocaine, and lidocaine with genistein to the receptive field on the discharge frequency of SpVc neurons were evaluated. The mean firing frequency of SpVc WDR neurons in response to both non-noxious and noxious mechanical stimuli was significantly and dose-dependently (0.1−10 mM) inhibited by genistein, and maximum inhibition of the discharge frequency of both non-noxious and noxious mechanical stimuli was seen within 10 min. The inhibitory effect of genistein lasted for 20 min and was reversible. No significant difference was seen between the relative magnitude of inhibition by genistein on the SpVc WDR neuronal discharge frequency for noxious and non-noxious stimulation. The mean magnitude of inhibition by genistein (10 mM) on SpVc neuronal discharge frequency was almost equal to that of the local anesthetic, 1 % lidocaine (37 mM). Local injection of half-dose of lidocaine replaced the half-dose of genistein. These results suggest that local injection of genistein into the peripheral receptive field suppresses the excitability of SpVc neurons, possibly via inhibition of voltage-gated Na+ channels in the nociceptive nerve terminals of trigeminal ganglion. Therefore, administration of genistein as a local anesthetic may provide relief from trigeminal nociceptive pain without side effects, thus contributing to the area of complementary and alternative medicines.

Effect of etomidate on the reuniens neuronal activity.

To explore the effect of etomidate on the neuronal activity of ventral thalamic reuniens nucleus and the underlying mechanisms. Whole-cell patch clamp method was used to explore the effect of etomidate on the activity of ventral thalamic reuniens neurons in the acute brain slices obtained from 4-5 weeks old C57BL/6J mice. The electrophysiological characteristics of ventral thalamic reuniens neurons were recorded in the current clamp mode, and then the effects of etomidate (0.5, 2.0, 8.0 μmol/L etomidate groups) and intralipid (intralipid group) on the discharge frequency and membrane potential of ventral thalamic reuniens neurons were recorded. During the experiment, the ventral thalamic reuniens neuron firing rates (RNFRs) were recorded as FB, FD and Fw before, after administration, and after elution; and the membrane potential was recorded as MPB and MPD before, after administration. The chlorine channel of gamma-amino butyric acid Type A (GABAA) receptor was blocked with 100 μmol/L picrotoxin (PTX). The RNFRs were recorded as FBS, FETO and FETO+PTX before, after perfusing etomidate with sub-anesthesia concentration (0.5 μmol/L) and after perfusing both PTX and etomidate. In the intralipid group, there was no significant difference among the FB, FD and Fw (P>0.05). But in the etomidate groups (0.5, 2.0, 8.0 μmol/L), the FD was less than the FB, there was significant difference (all P<0.01); the Fw was higher than the FD, there was significant difference (all P<0.05). Moreover, there was significant difference in the inhibitory degree of the RNFRs between the 0.5 μmol/L etomidate group and the 8.0 μmol/L etomidate group (P<0.05). In the experiment to explore the mechanism of etomidate (0.5 μmol/L), the FETO was compared with the FBS, there was significant difference (P<0.01); but when the FETO+PTX was compared with the FBS, there was no significant difference (P>0.05). Etomidate can inhibit the activity of ventral thalamic reuniens neurons in concentration-dependent manner, and which is reversible. Etomidate with sub-anesthetic concentration inhibits the activity of ventral thalamic reuniens neurons via targeting the GABAA receptor.

Effect of resveratrol on the hyperexcitability of nociceptive neurons associated with ectopic hyperalgesia induced by experimental tooth movement.

The present study investigated whether, under in vivo conditions, systemic administration of resveratrol attenuates the experimental tooth movement-induced ectopic hyperalgesia associated with hyperexcitability of nociceptive trigeminal spinal nucleus caudalis (SpVc) neurons. The threshold of escape from mechanical stimulation applied to the ipsilateral whisker pad in rats exposed to experimental tooth movement was significantly lower than seen in control rats from day 1 to 3 following movement of the right maxillary first molar tooth. The lowered mechanical threshold in the rats exposed to experimental tooth movement had almost returned to the level of sham-treated naïve rats at day 3 following administration of resveratrol. The mean mechanical threshold of nociceptive SpVc neurons was significantly lower after experimental tooth movement but the lower threshold could be reversed by administration of resveratrol. The higher discharge frequency of nociceptive SpVc neurons for noxious mechanical stimuli observed in rats exposed to experimental tooth movement was statistically significantly lower following resveratrol administration. These results suggest that resveratrol attenuates experimental tooth movement-induced mechanical ectopic hyperalgesia via suppression of peripheral and/or central sensitization. These findings support the idea that resveratrol, a complementary alternative medicine, is a potential therapeutic agent for the prevention of experimental tooth movement-induced ectopic hyperalgesia.

Neural pathway between the nucleus accumbens and the rostral ventrolateral medulla in a rat model of anorexia nervosa

To investigate the potential neural pathway connecting the nucleus accumbens (NAc) and the rostral ventrolateral medulla (RVLM), and whether the pathway participates in the regulation of cardiovascular function in a model rat of anorexia nervosa (AN). Rat models of AN were established by allowing voluntary activity in a running wheel with restricted feeding, with the rats having free access to normal chow without exercise as the control group. FluoroGold (FG) retrograde tracing method and multi-channel simultaneous recording technique were used to explore the possible pathway between the NAc and the RVLM. The rats in AN group exhibited significantly reduced systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) with significantly increased discharge frequency of RVLM neurons in comparison with the control rats. After the injection of FG into the RVLM, retrograde labeled neurons were observed in the NAc of the rats in both the normal control and AN groups. In both groups, SBP and HR were significantly decreased in response to 400 μA electrical stimulation of the NAc accompanied by an obvious increase in the discharge frequency of the RVLM neurons; the diastolic blood pressure (DBP) and MAP were significantly lower in AN model rats than in the normal rats in response to the stimulation. We successfully established a rat model of AN via hyperactivity and restricted feeding and confirm the presence of a neural pathway connecting the NAc and the RVLM. This pathway might participate in the regulation of cardiovascular function in AN model rats.

Resolvin D1 suppresses inflammation-induced hyperexcitability of nociceptive trigeminal neurons associated with mechanical hyperalgesia

7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid (resolvin D1 [RvD1]) is biosynthesized from docosahexaenoic acid (DHA), and belongs to a novel family of lipid mediators showing remarkable anti-inflammatory effects; however, the effect of RvD1 on inflammation-induced hyperexcitability of nociceptive neurons under in vivo conditions remains to be determined. The present study, therefore, investigated whether under in vivo conditions, systemic administration of RvD1 could attenuate the inflammation-induced hyperexcitability of spinal trigeminal nucleus caudalis (SpVc) wide-dynamic range (WDR) neurons associated with hyperalgesia in rats.The threshold of escape from mechanical stimulation applied to the orofacial area in rats with complete Freund’s adjuvant-induced inflammation was significantly lower than in naïve rats. The lowered mechanical threshold in rats with inflammation was returned to control levels following administration of RvD1 (3 ng/kg, i.p.) for 3 days. The mean discharge frequency of SpVc WDR neurons in rats with inflammation was significantly decreased after RvD1 administration for both non-noxious and noxious mechanical stimuli. Increased spontaneous discharge of SpVc WDR neurons in rats with inflammation was also significantly decreased after RvD1 administration. Noxious pinch-evoked afterdischarge frequency and occurrence in rats with inflammation was significantly diminished after RvD1 administration. Expansion of the receptive field in rats with inflammation also returned to control levels after RvD1 administration.These results suggest that administration of RvD1 attenuates inflammation-induced hyperexcitability of SpVc WDR neurons associated with inflammatory hyperalgesia. These findings support the idea that RvD1, derived from DHA, as well as DHA itself, are potential complementary or alternative therapeutic agents for the alleviation of inflammatory hyperalgesia.

Lesions of mediodorsal thalamic nucleus reverse abnormal firing of the medial prefrontal cortex neurons in parkinsonian rats.

The dysfunction of the medial prefrontal cortex is associated with affective disorders and non-motor features in Parkinson's disease. However, the exact role of the mediodorsal thalamic nucleus in the function of the prefrontal cortex remains unclear. To study the possible effects of the mediodorsal thalamic nucleus on the neurological function of the medial prefrontal cortex, a model of Parkinson's disease was established by injecting 8 µg 6-hydroxydopamine into the substantia nigra compacta of rats. After 1 or 3 weeks, 0.3 µg ibotenic acid was injected into the mediodorsal thalamic nucleus of the midbrain. At 3 or 5 weeks after the initial injury, neuronal discharge in medial prefrontal cortex of rat brain was determined electrophysiologically. The numbers of dopamine-positive neurons and tyrosine hydroxylase immunoreactivity in substantia nigra compacta and ventral tegmental area were detected by immunohistochemical staining. Results demonstrated that after injury, the immunoreactivity of dopamine neurons and tyrosine hydroxylase decreased in the substantia nigra compacta and ventral tegmental areas of rats. Compared with normal medial prefrontal cortical neurons, at 3 and 5 weeks after substantia nigra compacta injury, the discharge frequency of pyramidal neurons increased and the discharge pattern of these neurons tended to be a burst-discharge, with an increased discharge interval. The discharge frequency of interneurons decreased and the discharge pattern also tended to be a burst-discharge, but the discharge interval was only higher at 3 weeks. At 3 weeks after the combined lesions, the discharge frequency, discharge pattern and discharge interval were restored to a normal level in pyramidal neurons and interneurons in medial prefrontal cortex. These findings have confirmed that mediodorsal thalamic nucleus is involved in regulating neuronal activities of the medial prefrontal cortex. The changes in the function of the mediodorsal thalamic nucleus may be associated with the abnormal discharge activity of the medial prefrontal cortex neurons after substantia nigra compacta injury. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Xi'an Jiaotong University, China (approval No. XJTULAC2017-067) on August 26, 2017.