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Previous studies have established that the amygdala specifically the basolateral amygdala (BLA), has a fundamental role in decision-making. The present study aimed to investigate functional and neural synchronization between the BLA and anterior cingulate cortex (ACC) while making effort-choice decisions regarding pre-morphine dependence and morphine dependence times. A T-maze decision-making task with a differential outlay (great vs. small effort) and benefit (great vs. small reward) was done, and local field potentials from the BLA and ACC were assessed simultaneously. Results illustrated that in pre-morphine dependence time, when the animals made great reward/great effort decisions, there was a neural synchronization between both regions in beta and gamma frequency bands; and also, in delta, theta, beta, and gamma frequencies while expending effort and climbing the barrier. However, in morphine-dependent rats, during low reward/low effort choice and also during expending low effort, there was just a weak neural coherence in gamma frequency. Besides, there was neural synchronization in theta, beta, and gamma frequencies during reaching great reward in pre-morphine dependence time. Nevertheless, during reaching low reward in morphine dependence time, there was a weaker coherence in beta and gamma compared to pre-morphine dependence. These findings showed that functional and neural coherence between the BLA and ACC has a fundamental role in making the effort-based decision and expending effort. Preference for low reward/low effort, and decrease in expending effort in morphine-dependent rats is partly associated with the changes in the neural coherence between the BLA and ACC.
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AIMS: Drug addiction is an aberrant learning process that involves the recruitment of memory systems. We have previously demonstrated that morphine exposure causes maladaptive synaptic plasticity which involved hippocampal glial cells, especially astrocytes. Morphine addiction has been associated with astrocytic connexin 43 (Cx43), which plays a role in synaptic homeostasis. This study aimed to examine the role of hippocampal astrocytic Cx43 in morphine-induced maladaptive plasticity as a mechanism of addiction. MAIN METHODS: Male rats were injected with morphine (10 mg/kg) subcutaneously every 12 h for nine days to induce dependence. Cx43 was inhibited by TAT-Gap19 (1 µl/1 nmol) microinjection in the CA1 region of the hippocampus 30 min before each morning morphine injection. Field potential recordings were used to assess synaptic plasticity. fEPSP was recorded from the CA1 area following CA3 stimulation. KEY FINDINGS: Electrophysiological results showed that morphine treatment altered baseline synaptic responses. It also appears that morphine treatment augmented long-term potentiation (LTP) compared with the control group. Hippocampal astrocytic Cx43 inhibition, with the TAT-Gap19, undermines these effects of morphine on baseline synaptic responses and LTP. Despite this, long-term depression (LTD) did not differ significantly between the groups. Additionally, in the morphine-receiving group, inhibition of Cx43 significantly reduced the paired-pulse index at an 80-millisecond inter-pulse interval when assessing short-term plasticity. SIGNIFICANCE: The results of this study demonstrated that inhibiting Cx43 reduced synaptic plasticity induced by morphine. It can be concluded that hippocampal astrocytes through Cx43 are involved in morphine-induced metaplasticity.
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Conexina 43 , Morfina , Animales , Masculino , Ratas , Astrocitos , Región CA1 Hipocampal , Hipocampo , Potenciación a Largo Plazo , Morfina/farmacología , Plasticidad NeuronalRESUMEN
Understanding neuronal firing patterns and long-term potentiation (LTP) induction in studying learning, memory, and neurological diseases is critical. However, recently, despite the rapid advancement in neuroscience, we are still constrained by the experimental design, detection tools for exploring the mechanisms and pathways involved in LTP induction, and detection ability of neuronal action potentiation signals. This review will reiterate LTP-related electrophysiological recordings in the mammalian brain for nearly 50 years and explain how excitatory and inhibitory neural LTP results have been detected and described by field- and single-cell potentials, respectively. Furthermore, we focus on describing the classic model of LTP of inhibition and discuss the inhibitory neuron activity when excitatory neurons are activated to induce LTP. Finally, we propose recording excitatory and inhibitory neurons under the same experimental conditions by combining various electrophysiological technologies and novel design suggestions for future research. We discussed different types of synaptic plasticity, and the potential of astrocytes to induce LTP also deserves to be explored in the future.
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Potenciación a Largo Plazo , Plasticidad Neuronal , Ratas , Animales , Potenciación a Largo Plazo/fisiología , Ratas Sprague-Dawley , Plasticidad Neuronal/fisiología , Fenómenos Electrofisiológicos , Aprendizaje , Sinapsis/fisiología , MamíferosRESUMEN
Humans and animals frequently make an endeavor-based choice based on assessing reinforcement value and response costs. The cortical-limbic-striatal pathway mediates endeavor-based choice behavior, including the nucleus accumbens (NAc) and the anterior cingulate cortex (ACC). Furthermore, cannabinoid agonists demonstratively impairs decision-making processes. In this study, neural synchronization and functional connectivity between the NAc and ACC while endeavor-related decision-making and reaching reward were evaluated. The effect of exogenous cannabinoids on this synchronization was then assessed. A T-maze decision-making task with a differential expense (low vs. high endeavor) and remuneration (low vs. high remuneration) was performed and local field potentials (LFP) from the ACC and NAc were registered simultaneously. Results showed functional connectivity during endeavor-related decision-making while the animals chose the high endeavor/high remuneration in both regions' delta/beta (1-4 and 13-30 Hertz) frequency bands. Furthermore, functional connectivity existed between both areas in delta/theta (1-4 and 4-12) frequencies while reaching a remuneration. However, neural simultaneity was not observed while the animals received cannabinoid agonists, making a decision and reaching remuneration. The obtained results demonstrated that functional connectivity and neural simultaneity between the NAc and ACC in delta/beta and delta/theta frequencies have a role in endeavor-related decision-making and reaching remuneration, respectively. The effect of exogenous cannabinoids on decision-making impairment is relevant to changes in the ACC and NAC brain wave frequencies.
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Opioid exposure during adolescence, a crucial period of neurodevelopment, has lasting neurological and behavioral consequences and affects the cognitive functions in adulthood. This study investigated the effects of adolescent morphine exposure in spatial learning and memory and synaptic plasticity of the CA1 area of the dorsal hippocampus. Adolescent Wistar rats received increasing doses of morphine for 1, 5, and 10 days. Acute morphine group was injected 2.5 mg/kg morphine for 1 day, subchronic morphine group for 5 days, with an increasing dose of 2.5 mg/kg and reached to the dose of 12.5 mg/kg and chronic morphine group for 10 days that began with an increasing dose of 2.5 mg/kg and reached to the dose of 25 mg/kg. Then after 25 days and reaching adulthood, spatial learning and memory were evaluated via the Morris water maze (MWM) test. Moreover, we test the electrophysiological properties of dorsal hippocampal plasticity in adult rats by in vitro field potential recordings. Subchronic and chronic adolescent morphine exposure impaired spatial learning and memory in the MWM test. Baseline synaptic responses in the chronic morphine group were increased and long-term potentiation (LTP) impaired in the CA1 area in subchronic and chronic morphine groups. In adulthood, the slope of the field excitatory postsynaptic potential (fEPSP) required to elicit a half-maximal population spike (PS) amplitude was significantly larger in subchronic and chronic adolescent morphine exposure compared to the saline group. Therefore, subchronic and chronic adolescent morphine exposure altered synaptic transmission and plasticity in addition to learning and memory. Long-term morphine exposure during adolescence can interfere with neurodevelopment, making a persistent impression on plasticity and cognitive capability in adulthood.
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Morfina , Memoria Espacial , Animales , Hipocampo , Potenciación a Largo Plazo , Aprendizaje por Laberinto , Morfina/farmacología , Plasticidad Neuronal/fisiología , Ratas , Ratas WistarRESUMEN
Three-dimensional cell models represent the native in vivo situation more closely than two-dimensional cultures and are therefore preferred today for in vitro studies. In this context, there is a great demand for fast, non-invasive, real-time, and label-free methods that are capable for detailed analyses of three-dimensional cultures. To characterize heterogeneous cultures or to detect localized drug effects, a measurement method such as impedance spectroscopy in combination with microcavity arrays (MCAs) is desirable, which additionally offers spatial resolution. To overcome these limitations of the previously described MCA based on opaque silicon substrates and a square shape with four measurement electrodes imposed by the crystal structure, we used the selective laser etching (SLE) method to fabricate microcavities in fused silica and borosilicate glass without geometric constraints. We successfully developed MCAs with variable base including up to eight measurement electrodes in one cavity, which allows the increase in the number of electrode combinations to improve spatial resolution. In addition, we integrated a central cone electrode at the cavity bottom to extend the spatial resolution on the z-axis. To demonstrate the capability of the MCAs, we used MDA-HB-231 spheroids with an enclosed glass sphere to show that the heterogeneity of the model is evident in the relative impedance spectra. Analyses on various cell spheroids highlight the broad applicability of glass MCAs. In conclusion, our SLE-fabricated MCA clearly improve bioelectronic analyses of cellular changes in heterogeneous 3D models. Thus, bioelectronic analysis of electrophysiologically active cells and tumor biopsy samples could significantly benefit from our development.
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Técnicas Biosensibles , Técnicas Biosensibles/métodos , Espectroscopía Dieléctrica , Impedancia Eléctrica , Electrodos , Esferoides CelularesRESUMEN
OBJECTIVES: In the present study, we aimed to determine whether intraperitoneal injection of platelet-rich plasma (PRP) could have a neuroprotective effect on learning, memory, and synaptic plasticity impairment as well as hippocampal apoptosis in rats with hepatic encephalopathy induced by bile duct ligated (BDL). METHODS: The rats were divided into four groups: the control, sham, BDL+ V (vehicle), and BDL+ PRP. The BDL rats were treated with PRP immediately after the surgery, and the injection was done every 3 days for 30 days. The passive avoidance and Morris water maze tests were used for the evaluation of learning and memory. The long-term potentiation (LTP), basal-synaptic transmission, and paired-pulse ratio, as an index for measurement of neurotransmitter release probability, were evaluated by field-potential recording. After taking a blood sample for assessment of the liver enzymes, the animals were sacrificed and their hippocampus was removed for evaluation of cleaved caspase-3 by Western blot. RESULTS: Serological assessment of the liver function showed that BDL severely impaired the liver function. Also, PRP treatment could partially improve the liver dysfunction along with recovery in fear memory and spatial learning memory performance, LTP, basal-synaptic transmission, and neurotransmitter release probability. PRP-treated rats also showed a significant reduction in neuronal apoptosis in the CA1 area. CONCLUSIONS: The results of this study suggest that PRP improves cognitive performance and synaptic plasticity in BDL rats via direct neuroprotective property and/or indirectly by improvement of hepatic dysfunction.
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Encefalopatía Hepática , Plasma Rico en Plaquetas , Animales , Apoptosis , Modelos Animales de Enfermedad , Encefalopatía Hepática/terapia , Hipocampo , Potenciación a Largo Plazo , Aprendizaje por Laberinto , Plasticidad Neuronal , Ratas , Aprendizaje EspacialRESUMEN
Autism spectrum disorder (ASD) is a severe life-long neuropsychiatric disorder. Alterations and imbalance of several neurochemical systems may be involved in ASD pathophysiology, of them, serotonergic neurotransmission dysfunction and deficiency may underlie behavioral abnormalities associated with ASD. However, the functional importance of serotonergic receptors, particularly 5HT7 receptors in ASD pathology remains poorly defined. Serotonin receptor subtype 7 (5-HT7R) plays a direct regulatory role in the development and also for the mature function of the brain, therefore, further studies are necessary to elucidate the role of these receptors in the etiology of autism. To address this issue, we combined here behavioral, electrophysiological methods to further characterize the contribution of 5-HT7Rs in the prenatal valproic acid (VPA) exposure-induced impairment in synaptic plasticity and their impact on the associated behavioral changes. This may help to unravel the underlying cellular mechanisms involved in ASD and can lead to new treatment and/or prevention therapies based on the role of the serotonergic system for autism. Findings revealed that compared to control, autistic-like offspring showed increased anxiety-like behavior, reduced social interaction, decreased locomotor activity, and impaired identification of the novel object. However, administration of 5-HT7Rs agonist, LP-211, for 7 consecutive days before testing from postnatal day 21 to 27 reversed all behavioral deficits induced by prenatal exposure to VPA in offspring. Also, both short-term depression and long-term potentiation were impaired in the autistic-like pups, but activation of 5-HT7Rs rescued the LTP impairment in the autistic-like group so that there was no significant difference between the two groups. Blockade of 5-HT7Rs caused LTP impairment following HFS in the autistic-like group. Besides, there was a significant difference in LTD induction following SB-269970 application between the control and the autistic-like groups measured at first 10â¯min following TPS. Moreover, both the number and the size of retrograde fast blue-labelled neurons in the raphe nuclei were reduced. Overall, these results provide for the first time, as far as we know, functional evidence for the restorative role of 5-HT7Rs activation against prenatal VPA exposure induced behavioral deficits and hippocampal synaptic plasticity impairment. Therefore, these receptors could be a potential and promising pharmacotherapy target for the treatment of autism.
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Trastorno del Espectro Autista/metabolismo , Región CA1 Hipocampal/metabolismo , Potenciación a Largo Plazo/fisiología , Receptores de Serotonina/metabolismo , Animales , Trastorno del Espectro Autista/fisiopatología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Región CA1 Hipocampal/fisiopatología , Modelos Animales de Enfermedad , Prueba de Laberinto Elevado , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , GABAérgicos/toxicidad , Locomoción/efectos de los fármacos , Locomoción/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Prueba de Campo Abierto , Fenoles/farmacología , Piperazinas/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Núcleos del Rafe/metabolismo , Núcleos del Rafe/patología , Ratas , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Conducta Social , Sulfonamidas/farmacología , Ácido Valproico/toxicidadRESUMEN
Optimal decision making reflects the ability to choose the most advantageous option for various alternatives so that the anterior cingulate cortex is an important area involved in effort-based decision making. The current study aimed to investigate the functional connectivity between the ACC (anterior cingulate cortex) and the orbitofrontal cortex (OFC) during effort-based decision-making. A T-maze decision-making task with different rewards (large vs. small reward) and costs (high vs. low effort) was used, and simultaneously, local field potentials (LFP) from the ACC and OFC were also recorded in male Wistar rats. During the effort-based decision making, when the animals preferred the higher over, the lower reward, neural synchronization was observed in theta/low beta (4-20 Hz) frequency bands between both of the areas. Also, neural synchronization was not significant when the animals chose a lower reward. High gamma (80-100 Hz) synchrony between the areas was also observed; however, it was not dependent on the animal's decision. In this regard, the present findings revealed that neural synchronization and functional connectivity between the ACC and OFC in the low-frequency range (theta/low beta) is essential during the effort-based decision making.
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Sincronización Cortical/fisiología , Toma de Decisiones/fisiología , Giro del Cíngulo/fisiología , Corteza Prefrontal/fisiología , Animales , Ritmo beta/fisiología , Ritmo Gamma/fisiología , Masculino , Aprendizaje por Laberinto , Vías Nerviosas/fisiología , Ratas , Recompensa , Ritmo Teta/fisiologíaRESUMEN
OBJECTIVE: To investigate the effects of acid-sensing ion channels (ASICs) on electrophysiological epileptic activities of mouse hippocampal pyramidal neurons in the extracellular acidotic condition. METHODS: We investigated effects of extracellular acidosis on epileptic activities induced by elevated extracellular K + concentration or the application of an antagonist of GABAA receptors in perfusate of mouse hippocampal slices under field potential recordings. We also tested the effects of extracellular acidosis on neuronal excitability under field potential recording and evaluated the changes in epileptic activities of the neurons in response to pharmacological inhibition of ASICs using a specific inhibitor of ASICs. RESULTS: Extracellular acidosis significantly suppressed epileptic activities of the hippocampal neurons by converting ictal-like epileptic activities to non-ictal-like epileptic activities in both high [K +]o and disinhibition models, and also suppressed the intrinsic excitability of the neurons. ASICs inhibitor did not antagonize the inhibitory effect of extracellular acidosis on ictal epileptic activities and intrinsic neuronal excitability, but exacerbated non-ictal epileptic activities of the neurons in extracellular acidotic condition in both high [K+]o and disinhibition models. CONCLUSIONS: ASICs can differentially modulate ictal-like and non-ictallike epileptic activities via its direct actions on excitatory neurons.
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Acidosis , Canales Iónicos Sensibles al Ácido , Animales , Hipocampo , Concentración de Iones de Hidrógeno , Ratones , Células PiramidalesRESUMEN
Although many studies have shown that the prelimbic (PL) cortex of the mPFC is involved in the formation of conditioned freezing behavior, few have considered the acoustic response characteristics of PL cortex. Importantly, the change in auditory response characteristics of the PL cortex after conditional fear learning is largely unknown. Here we used in vivo cell-attached recordings targeting the mPFC during the waking state. We confirmed that the mPFC of adult C57 mice have neurons that respond to noise and tone in the waking state, especially in the PL cortex. Interestingly, the data also confirmed that these neurons responded well to the intensity of sound but did not have frequency topological distribution characteristics. Furthermore, we found that the number of c-fos positive neurons in the PL cortex increased significantly after auditory fear conditioning. The auditory-induced local field potential recordings and in vivo cell-attached recordings demonstrated that the PL cortex was more sensitive to the auditory conditioned stimulus after the acquisition of conditioned fear. The proportion of neurons responding to noise was significantly increased, and the signal to noise ratio of the spikes were also increased. These data reveal that PL neurons themselves responded to the main information (sound intensity), while the secondary information (frequency) response was almost negligible after auditory fear conditioning. This phenomenon may be the functional basis for handling this type of emotional memory, and this response characteristic is thought to be emotional sensitization but does not change the nature of this response.
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Miedo , Corteza Prefrontal , Animales , Condicionamiento Clásico , Memoria , Ratones , NeuronasRESUMEN
PURPOSE: Epilepsy therapy is currently based on anti-seizure drugs that do not modify the course of the disease, i.e., they are not anti-epileptogenic in nature. Previously, we observed that in vivo casein kinase 2 (CK2) inhibition with 4,5,6,7-tetrabromotriazole (TBB) had anti-epileptogenic effects in the acute epilepsy slice model. METHODS: Here, we pretreated rats with TBB in vivo prior to the establishment of a pilocarpine-induced status epilepticus (SE) in order to analyze the long-term sequelae of such a preventive TBB administration. RESULTS: We found that TBB pretreatment delayed onset of seizures after pilocarpine and slowed down disease progression during epileptogenesis. This was accompanied with a reduced proportion of burst firing neurons in the CA1 area. Western blot analyses demonstrated that CA1 tissue from TBB-pretreated epileptic animals contained significantly less CK2 than TBB-pretreated controls. On the transcriptional level, TBB pretreatment led to differential gene expression changes of KCa2.2, but also of HCN1 and HCN3 channels. Thus, in the presence of the HCN channel blocker ZD7288, pretreatment with TBB rescued the afterhyperpolarizing potential (AHP) as well as spike frequency adaptation in epileptic animals, both of which are prominent functions of KCa2 channels. CONCLUSION: These data indicate that TBB pretreatment prior to SE slows down disease progression during epileptogenesis involving increased KCa2 function, probably due to a persistently decreased CK2 protein expression.
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Background: The conversion of glutamic acid into γ-aminobutyric acid (GABA) is catalyzed by the glutamic acid decarboxylase (GAD). Antibodies against this enzyme have been described in neurological disorders, but the pathophysiological role of these antibodies is still poorly understood. We hypothesized that anti-GAD autoantibodies could diminish the GABA content in the slice and facilitate epileptic activity. Methods: Cerebrospinal fluids (CSF) from two patients containing anti-GAD (A and B) were injected into the rat hippocampus in vivo. Hippocampal slices were prepared for electrophysiological field potential recordings in order to record recurrent epileptic discharges (REDs) in the CA1 region induced by the removal of Mg2+ and/or by adding gabazine. As control groups, we injected an anti-GAD-negative human CSF or saline solution, and we used non-operated naive animals. Results: RED frequencies were significantly higher in the Mg2+-free solution than in the gabazine-containing solution. The average frequency of REDs in the last 10 min and the average duration of REDs in the last 5 min did not show significant differences between the anti-GAD-B-treated and the control slices, but in the Mg2+-free solution, anti-GAD-A had significantly higher epileptic activity than anti-GAD-B. Conclusions: These results indicate that anti-GAD has distinct effects on the development of spontaneous epileptic activity.
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OBJECTIVE@#To investigate the effects of acid-sensing ion channels (ASICs) on electrophysiological epileptic activities of mouse hippocampal pyramidal neurons in the extracellular acidotic condition.@*METHODS@#We investigated effects of extracellular acidosis on epileptic activities induced by elevated extracellular K concentration or the application of an antagonist of GABA receptors in perfusate of mouse hippocampal slices under field potential recordings. We also tested the effects of extracellular acidosis on neuronal excitability under field potential recording and evaluated the changes in epileptic activities of the neurons in response to pharmacological inhibition of ASICs using a specific inhibitor of ASICs.@*RESULTS@#Extracellular acidosis significantly suppressed epileptic activities of the hippocampal neurons by converting ictal-like epileptic activities to non-ictal-like epileptic activities in both high [K ]o and disinhibition models, and also suppressed the intrinsic excitability of the neurons. ASICs inhibitor did not antagonize the inhibitory effect of extracellular acidosis on ictal epileptic activities and intrinsic neuronal excitability, but exacerbated non-ictal epileptic activities of the neurons in extracellular acidotic condition in both high [K]o and disinhibition models.@*CONCLUSIONS@#ASICs can differentially modulate ictal-like and non-ictallike epileptic activities via its direct actions on excitatory neurons.
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Animales , Ratones , Canales Iónicos Sensibles al Ácido , Acidosis , Hipocampo , Concentración de Iones de Hidrógeno , Células PiramidalesRESUMEN
In the immature brain the neurotransmitter γ-amino butyric acid (GABA) mediates a membrane depolarization and can contribute to both, inhibition and excitation. Therefore the consequences of a positive modulation of GABA(A) receptors by neurosteroids on epileptiform activity are hard to predict. In order to analyze whether neurosteroids attenuate or exaggerate epileptiform activity in the immature brain, we investigated the effect of the neurosteroid allopregnanolone on epileptiform activity in an in-toto hippocampus preparation of early postnatal mice (postnatal days 4-7) using field potential recordings. These in-vitro experiments revealed that 0.5⯵mol/L allopregnanolone had no effect on ictal-like epileptiform activity, but increased the occurrence of interictal epileptiform events. The allopregnanolone-induced enhancement of interictal epileptiform activity could be blocked by a selective inhibition of synaptic GABAA receptors. In contrast, allopregnanolone had no effect on interictal epileptiform activity upon enhanced extrasynaptic GABAergic activity. Patch-clamp experiments demonstrated that allopregnanolone prolonged the decay of GABAergic postsynaptic currents, but had no effect on tonic GABAergic currents. We conclude from these results that allopregnanolone can enhance excitability in the immature hippocampus viaprolonged synaptic GABAergic currents. This potential effect of neurosteroids on brain excitability should be considered if they are applied as anticonvulsants to premature or early postnatal babies.
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Hipocampo/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Pregnanolona/farmacología , Animales , Antagonistas de Receptores de GABA-A/farmacología , Ratones , Técnicas de Placa-Clamp , Picrotoxina/farmacologíaRESUMEN
OBJECTIVE: The high incidence of epileptic seizures in neonates and their frequent refractoriness to pharmacologic therapies require identification of new therapeutical options. Therefore, we investigated whether the modulatory effect of taurine on γ-aminobutyric acid (GABA)A receptors can enhance the anticonvulsive potential of the GABAA receptor agonist muscimol and of the barbiturate pentobarbital. METHODS: We performed field potential recordings in in toto hippocampus preparations of immature (postnatal days 4-7) C57Bl/6 mouse pups. Spontaneous epileptiform activity was induced by the continuous presence of the potassium channel blocker 4-aminopyridine and the glycinergic antagonist strychnine in Mg2+ -free solutions. RESULTS: Bath application of 0.1 µmol/L muscimol increases the occurrence of recurrent epileptiform discharges, whereas they are significantly attenuated in a dose-dependent manner by muscimol in concentrations between 0.5 and 5 µmol/L. Taurine at concentrations between 0.1 and 0.5 mmol/L induces a proconvulsive effect, but upon coapplication, it significantly augments the anticonvulsive effect of moderate muscimol doses (0.5-1 µmol/L). In addition, the anticonvulsive effect of 100 and 200 µmol/L pentobarbital is increased significantly in the presence of 0.5 µmol/L taurine. SIGNIFICANCE: These observations demonstrate that taurine can indeed enhance the anticonvulsive effects of muscimol and pentobarbital, suggesting that taurine may act as a positive modulator on GABAA receptors. Thus, interfering with the modulatory taurine binding site of GABAA receptors or the interstitial taurine concentration may provide new therapeutical options for anticonvulsive therapies in neonates.
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Anticonvulsivantes/farmacología , Agonistas de Receptores de GABA-A/farmacología , Hipocampo/efectos de los fármacos , Muscimol/farmacología , Pentobarbital/farmacología , Taurina/farmacología , Animales , Animales Recién Nacidos , Anticonvulsivantes/administración & dosificación , Sinergismo Farmacológico , Agonistas de Receptores de GABA-A/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Muscimol/administración & dosificación , Pentobarbital/administración & dosificación , Convulsiones/tratamiento farmacológico , Convulsiones/prevención & control , Taurina/administración & dosificaciónRESUMEN
Nicotinic acetylcholine receptors are cationic channels that mediate fast excitatory transmission in the central nervous system. Several nicotinic acetylcholine receptor subunits have been detected within cerebellar granule cell layer (GCL), and activation of these receptors may have a significant influence on neuronal synaptic transmission of the cerebellum. The aim of present study was to better understand the roles of nicotinic acetylcholine receptors during the sensory stimulation-evoked synaptic transmission in the cerebellar GCL. Our results showed that cerebellar surface perfusion of nicotine significantly facilitated the cerebellar GCL field potential responses evoked by air-puff stimulation of ipsilateral whisker pad, which exhibited increases in amplitude and area under the curve (AUC) of both stimulus onset responses (N1) and stimulus offset responses (N2). The nicotine-induced increase in AUC of facial stimulation-evoked N1 was dose-dependent with a 50% effective concentration (EC50) of 32.6⯵M. Application of either a selective α4ß2 nicotinic acetylcholine receptors antagonist, DHßE (1⯵M) or a selective α7 nicotinic acetylcholine receptors antagonist, MLA (1⯵M) alone attenuated, but not completely abolished the nicotine-induced increases in the amplitude and AUC of the facial stimulation-evoked N1. However, simultaneous blockade of α7 and α4ß2 nicotinic acetylcholine receptor subunits abolished the nicotine-induced increase in the amplitude of N1. These results indicate that nicotine activates α7 and α4ß2 nicotinic acetylcholine receptor subunits, resulting in an enhancement of facial stimulation-evoked responses in mouse cerebellar GCL. Our results suggest that nicotine modulates the sensory information processing in the cerebellar GCL through α7 and α4ß2 subunits nicotinic acetylcholine receptors.
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Cerebelo/citología , Cerebelo/fisiología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/fisiología , Animales , Cara , Femenino , Masculino , Ratones Endogámicos ICR , Estimulación Física , Transmisión SinápticaRESUMEN
Hydroxysafflor yellow A (HSYA) is the major active chemical component of the safflower plant flower, which is widely used in Chinese medicine for cerebrovascular and cardiovascular disease treatment. Recent studies have demonstrated that HSYA exerts neuroprotective effect on cerebral ischemia, such as neuronal anti-apoptosis, antioxidant activity and oxygen free radical-scavenging. However, whether and how HSYA has a protective effect on cognitive impairment induced by cerebral ischemia reperfusion remains elusive. In the present study, by using the middle cerebral artery occlusion (MCAO) model, we found that 8 mg/kg and 16 mg/kg HSYA administration by common carotid artery (CCA) injection improved impaired cognitive function in Morris water maze (MWM) and passive avoidance tasks, but not 4 mg/kg HSYA treatment, suggesting that HSYA treatment in a certain concentration can improve cognitive impairment in MCAO rats. Furthermore, we found that 8 mg/kg HSYA treatment rescued the impaired long-term potentiation (LTP) in hippocampus of MCAO rats. Taken together, these results for the first time demonstrate that HSYA has the capacity to protect cognitive function and synaptic plasticity against cerebral ischemia-reperfusion injury, and provide a new insight that HSYA may be a promising alternative for recovery of cognitive dysfunction after brain ischemic injury.
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BACKGROUND: Aluminum (Al) causes neurodegeneration and its toxic effects on cholinergic system in the brain is well documented. However, it is unknown whether and how Al changes oscillation patterns, driven by the cholinergic system, in the hippocampus. OBJECTIVE: We studied acute effects of Al on nicotinic acetylcholine receptors (nAChRs)-mediated modulation of persistent gamma oscillations in the hippocampus. METHOD: The field potential recording was done in CA3 area of acute hippocampal slices. RESULTS: Carbachol-induced gamma oscillation peak power increased (1.32±0.09mV2/Hz, P<0.01) in control conditions (without Al) by application of 10µM nicotine as compared to baseline value normalized to 1. This nicotine-induced facilitation of gamma oscillation peak power was found to depend on non-α7 nAChRs. In slices with Al pre-incubation for three to four hours, gamma oscillation peak power was reduced (5.4±1.8mV2/Hz, P<0.05) and facilitatory effect of nicotine on gamma oscillation peak power was blocked as compared to the control (18.06±2.1mV2/Hz) or one hour Al pre-incubated slices (11.3±2.5mV2/Hz). Intriguingly wash-out, after three to four hours of Al incubation, failed to restore baseline oscillation power and its facilitation by nicotine as no difference was observed in gamma oscillation peak power between Al wash-out slices (3.4±1.1mV2/Hz) and slices without washout (3.6±0.9mV2/Hz). CONCLUSION: This study shows that at cellular level, exposure of hippocampal tissue to Al compromised nAChR-mediated facilitation of cholinergic hippocampal gamma oscillations. Longer in vitro Al exposure caused permanent changes in hippocampal oscillogenic circuitry and changed its sensitivity to nAChR-modulation. This study will help to understand the possible mechanism of cognitive decline induced by Al.
Asunto(s)
Aluminio/farmacología , Ritmo Gamma/efectos de los fármacos , Hipocampo/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Animales , Colinérgicos/farmacología , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Técnicas de Placa-Clamp , Factores de TiempoRESUMEN
BACKGROUND: Refractory olfactory dysfunction is a common finding in head trauma due to olfactory nerve injury. Anti-inflammatory treatment using steroids is known to contribute to functional recovery of the central and peripheral nervous systems in injury models, while there is a concern that steroids can induce side effects. The present study examines if the inhibition of proinflammatory cytokine, high mobility group box 1 (HMGB1), can facilitate olfactory functional recovery following injury. METHODS: Olfactory nerve transection (NTx) was performed in OMP-tau-lacZ mice to establish injury models. We measured HMGB1 gene expression in the olfactory bulb using semi-quantitative polymerase chain reaction (PCR) assays and examined HMGB1 protein localization in the olfactory bulb using immunohistochemical staining. Anti-HMGB1 antibody was intraperitoneally injected immediately after the NTx and histological assessment of recovery within the olfactory bulb was performed at 5, 14, 42, and 100 days after the drug injection. X-gal staining labeled OMP in the degenerating and regenerating olfactory nerve fibers, and immunohistochemical staining detected the presence of reactive astrocytes and macrophages/microglia. Olfactory function was assessed using both an olfactory avoidance behavioral test and evoked potential recording. RESULTS: HMGB1 gene and protein were significantly expressed in the olfactory bulb 12 h after NTx. Anti-HMGB1 antibody-injected mice showed significantly smaller areas of injury-associated tissue, fewer astrocytes and macrophages/microglia and an increase in regenerating nerve fibers. Both an olfactory avoidance behavioral test and evoked potential recordings showed improved functional recovery in the anti-HMGB1 antibody-injected mice. CONCLUSIONS: These findings suggest that inhibition of HMGB1 could provide a new therapeutic strategy for the treatment of olfactory dysfunction following head injuries.