Spontaneous Neuronal Discharge Research Articles

Tinnitus pitch does not always fall within the frequency range of hearing loss – a cross-sectional study on the mechanism of tinnitus production

Background Clinically, we find that tinnitus patients often have hearing loss. According to the most accepted mechanism of tinnitus, that is, the spontaneous discharge and abnormal synchronization of neurons after afferent reduction, tinnitus frequency is closely related to the frequency of hearing loss. Objective The purpose of this study was to investigate the correlation of tinnitus pitch with the frequency of hearing loss. Materials and Methods A total of 500 patients with unilateral or bilateral chronic tinnitus were enrolled in this study. All patients underwent pure tone audiometry (PTA) and tinnitus acoustic examination. Hearing loss levels and frequencies were recorded. The relationship between tinnitus pitch and hearing loss level and frequency was statistically analyzed. Results Our results showed that 96.6% of the 500 tinnitus patients had hearing loss. Statistical analysis showed that low frequency (LF) tinnitus was correlated with LF hearing loss, but moderate frequency & high frequency (MF&HF) tinnitus was not significantly associated with MF&HF hearing loss. The coincidence of tinnitus pitch with the highest hearing threshold correlated with the degree of hearing loss. Conclusion and significance The vast majority of patients with chronic subjective tinnitus had hearing loss, and the frequency of tinnitus correlated with the degree and frequency of hearing loss but not exactly fall within the frequency range of hearing loss.

Effect of theanine on the hyperexcitability of trigeminal secondary nociceptive neurons following orofacial inflammation in rats.

The present in vivo study investigated whether systemic administration of theanine attenuates the inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis (SpVc) neurons associated with hyperalgesia. Complete Freund's adjuvant (CFA) was injected into the whisker pads of 24 rats to induce inflammation, and then mechanical stimulation was applied to the orofacial area to assess the threshold of escape. The mechanical threshold was statistically significantly lower in CFA-inflamed rats compared to uninjected naïve rats, and this lowered threshold returned to control levels after 2 days of theanine administration. The mean discharge frequency of SpVc wide-dynamic range (WDR) neurons to mechanical stimuli in anesthetized CFA-inflamed rats was statistically significantly lower after two days of theanine administration. In addition, the increased mean spontaneous discharge of SpVc WDR neurons in CFA-inflamed rats statistically significantly decreased after theanine administration. Similarly, theanine restored the expanded mean receptive field size in CFA-inflamed rats to control levels. Taken together, these results suggest that administration of theanine attenuates inflammatory hyperalgesia associated with hyperexcitability of nociceptive SpVc WDR neurons. These findings support the potential of theanine as a therapeutic agent in complementary alternative medicine strategies to prevent inflammatory hyperalgesia.

Abnormal Spontaneous Discharges of Primary Sensory Neurons and Pain Behavior in a Rat Model of Vascular Dementia.

Patients with vascular dementia experience more pain than healthy elders, potentially due to the presence of central neuropathic pain. However, the mechanisms underlying neuropathic pain in vascular dementia remain poorly understood, and there is currently a lack of effective treatment available. In this study, a rat model of vascular dementia was induced by permanently occluding the common carotid arteries bilaterally (2-VO). The cognitive impairments in the 2-VO rats were evaluated using the Morris Water Maze test, while HE and LBF staining were employed to assess brain tissue lesions in the hippocampal, cerebral cortex, and white matter regions known to be associated with severe memory and learning deficits. Furthermore, pain-related behavioral tests, including mechanical and thermal stimuli assessments, were conducted, and in vivo electrophysiological recordings of primary sensory neurons were performed. Compared to sham-operated and pre-operative rats, rats with vascular dementia exhibited mechanical allodynia and thermal hyperalgesia 30 days after surgery. Furthermore, in vivo electrophysiology revealed a significant increase in the occurrence of spontaneous activity of Aβ- and C-fiber sensory neurons in the rat model of vascular dementia. These results indicate that neuropathic pain behaviors developed in the rat model of vascular dementia, and abnormal spontaneous discharges of primary sensory neurons may play a crucial role in the development of pain after vascular dementia.

Phytochemical quercetin alleviates hyperexcitability of trigeminal nociceptive neurons associated with inflammatory hyperalgesia comparable to NSAIDs.

Quercetin is a flavonoid that is widely found in fruits and vegetables. Quercetin inhibits cyclooxygenase-2 and modulates voltage-gated ion channels, however, its effect on nociceptive neuron-associated inflammatory hyperalgesia remains unknown. The present study investigated under in vivo conditions whether systemic administration of quercetin attenuates the inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis (SpVc) neurons associated with mechanical hyperalgesia and compared its effect to the non-steroidal anti-inflammatory drug, diclofenac. Complete Freund’s adjuvant was injected into the whisker pads of rats to induce inflammation, and then mechanical stimulation was applied to the orofacial area to assess the threshold of escape. The mechanical threshold was significantly lower in inflamed rats compared to uninjected naïve rats, and this lowered threshold returned to control levels 2 days after administration of quercetin or diclofenac. The mean discharge frequency of SpVc wide-dynamic range (WDR) neurons to both non-noxious and noxious mechanical stimuli in inflamed rats was significantly decreased after quercetin or diclofenac administration under combination of three anesthetic agents (medetomidine, midazolam and butorphanol). In addition, the increased mean spontaneous discharge of SpVc WDR neurons in inflamed rats significantly decreased after quercetin or diclofenac administration. Similarly, quercetin or diclofenac restored the expanded mean receptive field size in inflamed rats to control levels. In this study, the combination of three anesthetic agents did not result in any obvious “noxious pinch-evoked after discharges” in CFA inflamed day 2 rat as described previously in pentobarbital-anesthetized rats. Together, these results suggest that administration of quercetin attenuates inflammatory hyperalgesia associated with hyperexcitability of nociceptive SpVc WDR neurons via inhibition of the peripheral cyclooxygenase-2 signaling cascade and voltage-gated ion channels. These findings support the proposed potential of quercetin as a therapeutic agent in complementary alternative medicine strategies for preventing trigeminal inflammatory mechanical hyperalgesia.

Microglia-derived TNF-α inhibiting GABAergic neurons in the anterior lateral bed nucleus of the stria terminalis precipitates visceral hypersensitivity induced by colorectal distension in rats

Irritable bowel syndrome (IBS) is a common and debilitating gastrointestinal disorder that is exacerbated by stress and characterized by abdominal pain. Although microglia in the CNS have been implicated as an important mediator of the stress response, the role of microglia and microglia-GABAergic neuron interactions in the limbic area, most notably BNST, in the development of colorectal hypersensitivity has not been determined. We established a neonatal colorectal distension-induced chronic visceral hyperalgesia model in rats. The results showed that the frequency of spontaneous discharges of alBNST GABAergic neurons and the expression of GAD65/67 were significantly decreased in rats with chronic visceral pain. Moreover, ablation of BNST GABAergic neurons significantly reduced the visceral pain threshold in normal rats. Meanwhile, the number of M1 proinflammatory microglia and the expression of the M1 proinflammatory microglia-derived cytokines IL-6 and TNF-α were increased in the alBNST of rats with chronic visceral pain. Furthermore, alBNST infusion of the microglial inhibitor minocycline or IL-6 and TNF-α neutralizing antibodies significantly increased the visceral pain threshold. The decreased frequency of spontaneous discharges of alBNST GABAergic neurons in rats with chronic visceral pain was mimicked by a bath perfusion of TNF-α, but not IL-6, and was abolished by a perfusion of the microglial inhibitor minocycline. In addition, the alBNST infusion of the microglial inhibitor minocycline upregulated the expression of GAD65/67. Moreover, ablation of BNST GABAergic neurons significantly decreased the visceral pain threshold in normal rats, which was not reversed by a subsequent infusion of the microglial inhibitor minocycline. Our findings revealed this microglia-GABAergic neuron circuit in the alBNST, and this microglia-driven disinhibitory mechanism is essential for brain and gut dysfunction in stressful condition, providing a novel potential target for treating patients with IBS presenting visceral pain that is worsened during episodes of stress.

New monoamine antidepressant, hypidone hydrochloride (YL-0919), enhances the excitability of medial prefrontal cortex in mice via a neural disinhibition mechanism.

Hypidone hydrochloride (YL-0919) is a novel antidepressant in clinical phase II trial. Previous studies show that YL-0919 is a selective 5-HT (serotonin) reuptake inhibitor, 5-HT1A receptor partial agonist, and 5-HT6 receptor agonist, which exerts antidepressant effects in various animal models, but its effects on neural function remain unclear. Medial prefrontal cortex (mPFC), a highly evolved brain region, controls highest order cognitive functions and emotion regulation. In this study we investigated the effects of YL-0919 on the mPFC function, including the changes in neuronal activities using electrophysiological recordings. Extracellular recording (in vivo) showed that chronic administration of YL-0919 significantly increased the spontaneous discharges of mPFC neurons. In mouse mPFC slices, whole-cell recording revealed that perfusion of YL-0919 significantly increased the frequency of sEPSCs, but decreased the frequency of sIPSCs. Then we conducted whole-cell recording in mPFC slices of GAD67-GFP transgenic mice, and demonstrated that YL-0919 significantly inhibited the excitability of GABAergic neurons. In contrast, it did not alter the excitability of pyramidal neurons in mPFC slices of normal mice. Moreover, the inhibition of GABAergic neurons by YL-0919 was prevented by pre-treatment with 5-HT1A receptor antagonist WAY 100635. Finally, chronic administration of YL-0919 significantly increased the phosphorylation levels of mTOR and GSK-3β in the mPFC as compared with vehicle. Taken together, our results demonstrate that YL-0919 enhances the excitability of mPFC via a disinhibition mechanism to fulfill its rapid antidepressant neural mechanism, which was accomplished by 5-HT1A receptor-mediated inhibition of inhibitory GABAergic interneurons.

Microglia secrete miR-146a-5p-containing exosomes to regulate neurogenesis in depression

Enhancing neurogenesis within the hippocampal dentate gyrus (DG) is critical for maintaining brain development and function in many neurological diseases. However, the neural mechanisms underlying neurogenesis in depression remain unclear. Here, we show that microglia transfer a microglia-enriched microRNA, miR-146a-5p, via secreting exosomes to inhibit neurogenesis in depression. Overexpression of miR-146a-5p in hippocampal DG suppresses neurogenesis and spontaneous discharge of excitatory neurons by directly targeting Krüppel-like factor 4 (KLF4). Downregulation of miR-146a-5p expression ameliorates adult neurogenesis deficits in DG regions and depression-like behaviors in rats. Intriguingly, circular RNA ANKS1B acts as a miRNA sequester for miR-146a-5p to mediate post-transcriptional regulation of KLF4 expression. Collectively, these results indicate that miR-146a-5p can function as a critical factor regulating neurogenesis under conditions of pathological processes resulting from depression and suggest that microglial exosomes generate new crosstalk channels between glial cells and neurons.

Microglia Secrete miR-146a-5p-Containing Exosomes to Regulate Neurogenesis in Depression

Enhancing neurogenesis within the hippocampal dentate gyrus (DG) is critical for maintaining brain development and function in many neurological diseases. However, the neural mechanisms underlying neurogenesis in depression remain unclear. Here, we show that microglia transfer a microglia-enriched microRNA, miR-146a-5p, which then inhibits neurogenesis in depression via its capacity to secrete exosomes to DG regions. Overexpression of miR-146a-5p in DG regions suppresses neurogenesis and spontaneous discharge of excitatory neurons by directly targeting Kruppel-like factor 4 (KLF4). Down-regulation of miR-146a-5p expression, ameliorates adult neurogenesis deficits in DG regions and depression-like behaviors in rats. Intriguingly, circular-RNA ANKS1B acts as a miRNA sponge for miR-146a-5p to mediate posttranscriptional regulation of KLF4 expression. Collectively, these results indicate that miR-146a-5p can function as a critical factor regulating neurogenesis under conditions of pathological processes resulting from depression and suggest that microglial exosomes generate new cross-talk channels between glial cells and neurons.

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.

Dietary constituent genistein inhibits the hyperexcitability of trigeminal nociceptive neurons associated with mechanical hyperalgesia following orofacial inflammation

ObjectivesGenistein, a dietary constituent, modulates voltage-dependent and ligand-gated ionic channels, suggesting that it could also attenuate inflammatory hyperalgesia. However, the mechanism underlying how genistein affects inflammation-induced hyperexcitability of nociceptive neurons in vivo remains to be determined. The present study therefore investigated whether administration of genistein could attenuate the inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis (SpVc) neurons associated with mechanical hyperalgesia in vivo. MethodsInflammation was induced by injection of complete Freund's adjuvant into the whisker pad. The mechanical thresholds for escape behavior and electrophysiological single-unit recording of SpVc neurons responding to mechanical stimulation were then conducted in naïve rats, inflamed rats, and inflamed rats with genistein administered intraperitoneally. ResultsThe lowered mechanical threshold in the inflamed rats was returned to control level following administration of genistein for 2 days. The mean number of discharge frequencies of SpVc neurons in inflamed rats was significantly decreased after genistein administration with both non-noxious and noxious mechanical stimuli. The increased spontaneous discharges of SpVc neurons in inflamed rats were significantly decreased after genistein administration. Noxious pinch-evoked after-discharge frequency and occurrence in inflamed rats was also significantly diminished after genistein administration, and expansion of the receptive field was significantly returned to control levels in inflamed rats. ConclusionHerein, we present the first evidence that genistein attenuates hyperexcitability of SpVc neurons associated with inflammatory mechanical hyperalgesia. These findings suggest that genistein could be a potential therapeutic agent in complementary alternative medicine for the prevention of trigeminal inflammatory hyperalgesia.

Docosahexaenoic acid attenuates inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis neurons associated with hyperalgesia in rats.

The present study investigated whether daily systemic administration of docosahexaenoic acid (DHA) in rats could attenuate the hyperexcitability of trigeminal spinal nucleus caudalis (SpVc) neurons associated with hyperalgesia. Inflammation was induced in rats by injecting complete Freund's adjuvant into the whisker pads. The threshold of escape from mechanical stimulation applied to the whisker pads in inflamed rats was significantly lower than that in naïve rats. The lowered mechanical threshold in the inflamed rats was returned to that in naïve rats by 3 d intraperitoneal administration of DHA. The mean discharge frequency of SpVc neurons in inflamed rats was significantly decreased after DHA administration for 3 d with both non-noxious and noxious mechanical stimuli. DHA administration also significantly decreased the increased spontaneous discharges of SpVc neurons in the inflamed rats, while DHA significantly diminished noxious pinch evoked after the discharge frequency and the expanded receptive field in the inflamed rats was returned to control levels. These results suggested that chronic administration of DHA attenuates inflammation-induced mechanical hyperalgesia associated with the suppression of the hyperexcitability of SpVc neurons. These findings support the potential use of DHA as a therapeutic agent in complementary alternative medicine for mitigating trigeminal inflammatory hyperalgesia.

Abnormal Spontaneous Neuronal Discharge and Local Field Potential both in Cortex and Striatum of a Non- human Primate of Parkinson's Disease using Implantable Microelectrode Arrays.

Parkinson's disease (PD) is a neurodegenerative disease with the loss of dopaminergic neurons in substantia nigra. This study described abnormal spontaneous neuronal information both in cortex and striatum of a non-human primate of PD using implantable microelectrode arrays. In cortex of PD monkey, Neurons discharged from single-spike mode to burst-firing mode compared to normal monkey; Mean amplitude was $197 \mu \mathrm{V}$ that was twice of mean amplitude of normal monkey, and mean firing rate was 82Hz; burst-firing activity showed distinctive, stereotypic periods of oscillatory lasted for $20 \pm 5\mathrm{s}$ occurring ever 30-40 seconds, which was consistent with local field potential (LFP) oscillating at 4.79Hz related to PD tremor; neuronal discharge were approximately synchronous from four channels, that were consistent with local field potential fluctuating greatly with a correlation coefficient of 0.99997, and the main frequency of local field potential had a good respond to firing rate of spike with a correlation coefficient of 0.9891. In striatum of PD monkey, two types of neurons were detected with mean amplitude of $102 \mu \mathrm{V}$ and $296 \mu \mathrm{V}$ respectively; the mean firing rate was 62 Hz significantly higher than that in normal monkey; as for one representative type of neurons, with respect to local field potential oscillating at a period in cortex, local field potential continuously oscillated in striatum at low frequency at the range of 4-7Hz which was constituent with neuronal burst firing rate, while single neuron discharged at the range of 10-32Hz, almost at beta frequencies. Abnormal neural information detection by microelectrode arrays with ifferent signals in different position will play an important role in target location in brain of PD patients, especially for treatment.

Effect of acupuncture at three different acupoints on electrical activity of gastric distention-affected neurons in rat medial vestibular nucleus

OBJECTIVETo observe the effect of gastric distention (GD) and acupuncture at three different acupoints on the spontaneous discharge of neurons in the medial vestibular nucleus (MVN), and to clarify the specific function of the MVN in the central integration mechanism underlying acupuncture regulation. METHODSGD was conducted using a balloon inserted in the stomach cavity, and acupuncture was performed separately at each of three acupoints: Zusanli (ST 36), Quchi (LI 11), and Weishu (BL 21). The effect of acupuncture and GD on the spontaneous discharge of MVN neurons was assessed using a glass microelectrode filled with a sodium acetate electrolyte solution containing 1% pontamine sky blue; the discharge signals from the neurons were amplified by the microelectrode amplifier and recorded in the Spike2 system. RESULTSGD and acupuncture significantly affected the spontaneous discharge of MVN neurons. Furthermore, acupuncture at Zusanli (ST 36) and Weishu (BL 21) was significantly more effective at altering the discharge of GD-responsive MVN neurons compared with GD-nonresponsive neurons. CONCLUSIONGD and acupuncture at three different acupoints affected the electrical activity of MVN neurons. The MVN is involved in the central integration mechanism underlying acupuncture regulation of gastric functions. The effects of acupuncture on gastric function may therefore be mediated via these particular MVN neurons.

Segmentation of quasiperiodic patterns in EEG recordings for analysis of post-traumatic paroxysmal activity in rat brains

The study of the consequences of traumatic brain injury represents an important problem in modern medicine. Brain trauma leads to the manifestation of neurological and psychiatric disturbances in most patients; severe traumatic brain injuries are accompanied by paroxysms and neurologic impairment, which in the long term lead to post-traumatic epilepsy. The mechanisms of post-traumatic epilepsy, in view of cellular and molecular plasticity, include rearrangement of neuronal networks. These processes induce spontaneous and synchronous discharges of numerous neurons, clinically manifested in the form of paroxysms. The posttraumatic period before the first unprovoked seizures is known as the latent phase of post-traumatic epileptogenesis, which can last for years in humans. Unfortunately, approaches to its detection and to the prediction of post-traumatic epilepsy have not been sufficiently developed yet; though they are of exceptional importance for clinical practice. Moreover, it is still poorly understood how the damage of the brain tissue leads to the brain structural rearrangement connected with epileptogenesis. In other words, the question is why and when the epileptogenesis occurs. The current paper considers the first results of the approach that we have suggested to quantitative assessment of the epileptogenesis development on the basis of EEG analysis as an alternative to the regular activity of the brain. This approach is based on the analysis of highly nonstationary signals that contain quasiperiodic fragments. In particular, the pipeline of procedures for the analysis includes detection of local quasiperiodic (rhythmic) behavior with further assessment of its dynamic characteristics and segmentation of fragments with “rhythmic” behavior. The first results of this approach application are connected with the analysis of experimental data obtained in the modeling of traumatic brain injury in rats. The characteristics of the EEG rhythm and their dynamics are analyzed in the background (before traumatic brain injury) and one, two, three and six days after the injury on the basis of ten-hour EEG recordings. The results demonstrate a significant difference in the degree of periodicity of the characteristics (total duration of the corresponding EEG fragments) before and after traumatic brain injury (a week after the trauma some restoration of the periodicity is observed). At the end of the paper we offer some interpretation of these results and express a hope that such studies could provide new ways for development and assessment of methods of the paroxysmal activity in the post-traumatic period.

On a unified point process approach for the characterization of bioelectric discrete phenomena.

This paper discusses a unified method based on the theory of point processes to characterize various types of bioelectric discrete signals such as heart beat timing, myoelectric activity, discharge of primary sensory neurons or neurons in the central nervous systems. The doubly stochastic point processes, in which the discrete event occurring intensity is stochastic, forms the most general class to characterize the discrete phenomena. In this paper the self-exciting process has been shown to be useful to characterize wide range of discrete biosignals. The modeling of conditional intensity function is the essential part of the characterization. When the intensity has a parametric model, the maximum likelihood parameter estimation will be the useful way to characterize the phenomena. The effectiveness of the method is demonstrated by a specific modeling of the spontaneous neuronal burst discharges recorded from the brain thalamus during the neuro surgery. The first approximation model has four parameters obtained by the instantaneous nonlinearly transformed sinusoidal function. An extended model allows arbitrary periodic intensity with refractory period. Predicted interval histograms show good agreement with the observed ones indicating the validity of the proposed method.

Peripheral and central administration of T3 improved the histological changes, memory and the dentate gyrus electrophysiological activity in an animal model of Alzheimer's disease.

The amyloid beta (Aβ) induced Alzheimer's disease (AD) is associated with formation the amyloid plaques, cognitive impairments and decline in spontaneous discharge of neurons. In the current study, we evaluated the effect of subcutaneous (S. C) and intrahippocampal (I. H) administrations of triiodothyronine (T3) on the histological changes, memory and the dentate gyrus (DG) electrophysiological activity in an animal model of AD. Eighty adult male Wistar rats (250-300g) were divided randomly into five groups: Sham-Operated (Sh-O), AD+Vehicle (S. C), AD+Vehicle (I. H), AD+ T3 (S. C) and AD+T3 (I. H). In order to induce animal model of AD, Aβ (10ng/μl, bilaterally) were injected intrahippocampally. Rats were treated with T3 and/or normal saline for 10days. Passive avoidance and spatial memory were evaluated in shuttle box apparatus and Morris water maze, respectively. Neuronal single unit recording was assessed from hippocampal DG. The percent of total time that animals spent in target quarter, the mean latency time (sec), the step through latency and the average number of spikes/bin were decreased significantly in AD rats compared with the Sh-O group (p<0.001) and were increased significantly in AD groups that have received T3 (S. C and I. H) in compared with AD group (p<0.01, p<0.001). Also, formation of amyloid plaques was decreased in AD rats treated with T3.The results showed that T3 injection (S. C and I. H), by reduction of neural damage and increment of neuronal spontaneous activity improved the memory deficits in Aβ-induced AD rats.

Central and peripheral administrations of levothyroxine improved memory performance and amplified brain electrical activity in the rat model of Alzheimer's disease

Alzheimer's disease (AD) is associated with cognitive impairments and a decline in the spontaneous neuronal discharge. In the current study, we evaluated the effect of subcutaneous (S.C.) and intrahippocampal (I.H.) administrations of levothyroxine (LT-4) on the passive avoidance and spatial memory, as well as electrophysiological activity in an animal model of AD. One hundred-sixty male Wistar rats were divided into two main groups. The S.C. group included two Sham and four AD (vehicle or L-T4 25, 50 & 100μg/kg); and the I.H. had consisted of two Sham and two AD (vehicle or L-T4 10μg/kg) subgroups. To make an animal model of AD, amyloid beta (Aβ) plus ibotenic acid (Ibo) were injected I.H. Rats were treated with L-T4 and/or normal saline for ten days. Passive avoidance and spatial memory were evaluated in shuttle box and Morris water maze, respectively. Neuronal single unit recording was assessed from hippocampal dentate gyrus (DG). Results showed that the mean latency time (s) increased significantly (p<0.001) in AD animals and decreased significantly in both S.C. and I.H. L-T4 injected AD animals, compared with the AD group (p<0.001). The percentage of total time that animals spent in goal quarter and the step through latency decreased significantly in AD rats (p<0.001) and increased significantly in both S.C. and I.H. L-T4 injected AD animals in comparison with the AD group (p<0.01, p<0.001). Data showed that the average number of spikes/bin significantly decreased in the AD group (p<0.001). The S.C. and I.H. L-T4 injections in AD rats significantly increased the spike rate in comparison to the AD group (p<0.001).In conclusion, both S.C. and I.H. injections of L-T4 alleviated memory deficits and spontaneous neuronal activity in Aβ-induced AD rats. Also, I.H. microinjection of L-T4 had more beneficial effects on memory and neuronal electrophysiological activity in comparison to S.C. administration.

Effects of acupuncture at "Zusanli" (ST 36) on sensitive neurons of gastric distention in LHA-FN circuit in rats

To observe the regulation effects of acupuncture at "Zusanli" (ST 36) on sensitive neurons of gastric distention (GD) in lateral hypothalamus area (LHA) and fastigial nuclear (FN) circuit, and to explore the central mechanism of acupuncture for gastric function. A total of 101 rats were randomly assigned into a LHA group (50 rats) and a FN group (51 rats). Gastric distension surgery was performed in all the rats. According to the stereotaxic atlas of rat brain, the LHA and FN were located, followed by craniotomy. The endocranium was removed to exposure brain tissue, and warm paraffin oil was used to prevent desiccation. The electrical activities of neurons were probed by glass microelectrode to perform extracellular recording. The electrical activities of GD sensitive neurons in LHA were observed in LHA group, while those in FN were observed in FN group. One min after the electrical signal of neurons was recorded, acupuncture was given at left "Zusanli" (ST 36) with mild reinforcing and attenuating technique, 120~180 times/min for 1 min. The effects of acupuncture at "Zusanli" (ST 36) on spontaneous discharge of GD sensitive neurons in LHA and FN were observed. (1) Totally 54 LHA neurons of spontaneous discharge in LHA group and 85 FN neurons in FN group were recorded. GD-excitatory (GD-E) neurons were mainly in the LHA group (46.3%) and GD-non-response (GD-N) neurons were mainly in the FN group (54.12%). The average discharge frequency of GD-N neurons was (39.03±14.91) spikes/s, that of GD-E neurons was (19.67±12.08) spikes/s, and that of GD-inhibitory (GD-I) neurons was (28.76±7.26) spikes/s, which were statistically different from those before GD (all P<0.01). (2) In LHA group, acupuncture excited the activity of GD-E neurons, and inhibited the activity of GD-I neurons (P<0.05); in FN group, acupuncture excited the activity of GD-I neurons, but showed no effect on GD-E neurons (P<0.01). The signal of GD and acupuncture could converge in LHA and FN; acupuncture presented different regulation effects on identical type of GD-sensitive neurons in different nuclear groups; LHA-FN circuit might participate in central integration mechanism of acupuncture on gastric function.

Activity-Dependent Inhibitory Synaptogenesis in Cerebellar Cultures.

Inhibitory synapses on Purkinje cell somata in organotypic cerebellar cultures derived from newborn mice were increased after chronic exposure post explantation to agents that enhance neuronal activity. Inhibitory synaptogenesis was reduced in similar cultures after continuous blockade of spontaneous neuronal discharges. By contrast, excitatory synapses developed fully in the absence of neuronal activity. The reduction of inhibitory synaptogenesis was prevented by the simultaneous application of activity blocking agents and neurotrophins BDNF or NT-4, which are TrkB receptor ligands, but not with NT-3, a TrkC receptor ligand. The effect of endogenous neurotrophins was evaluated by continuously exposing cerebellar cultures to antibodies to BDNF and NT-4, which caused a significant reduction in the development of inhibitory Purkinje cell axosomatic synapses. These combined results indicated a role for TrkB receptors in activity-dependent inhibitory synaptogenesis. This concept was supported by the promotion of inhibitory synaptogenesis by specific antibody activation of TrkB receptors.

Resveratrol attenuates inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis neurons associated with hyperalgesia in rats.

BackgroundResveratrol, a component of red wine, has been reported to decrease prostaglandin E2 production by inhibiting the cyclooxygenase-2 cascade and to modulate various voltage-dependent ion channels, suggesting that resveratrol could attenuate inflammatory hyperalgesia. However, the effects of resveratrol on inflammation-induced hyperexcitability of nociceptive neurons in vivo remain to be determined. Thus, the aim of the present study was to determine whether daily systemic administration of resveratrol to rats attenuates the inflammation-induced hyperexcitability of spinal trigeminal nucleus caudalis wide-dynamic range neurons associated with hyperalgesia.ResultsInflammation was induced by injection of complete Freund’s adjuvant into the whisker pad. The threshold of escape from mechanical stimulation applied to whisker pad in inflamed rats was significantly lower than in control rats. The decreased mechanical threshold in inflamed rats was restored to control levels by daily systemic administration of resveratrol (2 mg/kg, i.p.). The mean discharge frequency of spinal trigeminal nucleus caudalis wide-dynamic range neurons to both nonnoxious and noxious mechanical stimuli in inflamed rats was significantly decreased after resveratrol administration. In addition, the increased mean spontaneous discharge of spinal trigeminal nucleus caudalis wide-dynamic range neurons in inflamed rats was significantly decreased after resveratrol administration. Similarly, resveratrol significantly diminished noxious pinch-evoked mean after discharge frequency and occurrence in inflamed rats. Finally, resveratrol restored the expanded mean size of the receptive field in inflamed rats to control levels.ConclusionThese results suggest that chronic administration of resveratrol attenuates inflammation-induced mechanical inflammatory hyperalgesia and that this effect is due primarily to the suppression of spinal trigeminal nucleus caudalis wide dynamic range neuron hyperexcitability via inhibition of both peripheral and central cyclooxygenase-2 cascade signaling pathways. These findings support the idea of resveratrol as a potential complementary and alternative medicine for the treatment of trigeminal inflammatory hyperalgesia without side effects.