RESUMEN
Polygala tenuifolia Wild is an ancient traditional Chinese medicine. Its main component, tenuifolin (TEN), has been proven to improve cognitive impairment caused by neurodegenerative diseases and ovariectomy. However, there was hardly any pharmacological research about TEN and its potential gender differences. Considering the reduction of TEN on learning and memory dysfunction in ovariectomized animals, therefore, we focused on the impact of TEN in different mice genders in the current study. Spontaneous alternation behavior (SAB), light-dark discrimination, and Morris water maze (MWM) tests were used to evaluate the mice's learning and memory abilities. The field excitatory postsynaptic potential (fEPSP) of the hippocampal CA1 region was recorded using an electrophysiological method, and the morphology of the dendritic structure was examined using Golgi staining. In the behavioral experiments, TEN improved the correct rate in female mice in the SAB test, the correct rate in the light-dark discrimination test, and the number of crossing platforms in the MWM test. Additionally, TEN reduced the latency of female mice rather than male mice in light-dark discrimination and MWM tests. Moreover, TEN could significantly increase the slope of fEPSP in hippocampal Schaffer-CA1 and enhance the total length and the number of intersections of dendrites in the hippocampal CA1 area in female mice but not in male mice. Collectively, the results of the current study showed that TEN improved learning and memory by regulating long-term potentiation (LTP) and dendritic structure of hippocampal CA1 area in female mice but not in males. These findings would help to explore the improvement mechanism of TEN on cognition and expand the knowledge of the potential therapeutic value of TEN in the treatment of cognitive impairment.
Asunto(s)
Región CA1 Hipocampal , Dendritas , Diterpenos de Tipo Kaurano , Potenciación a Largo Plazo , Animales , Femenino , Masculino , Región CA1 Hipocampal/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Ratones , Dendritas/efectos de los fármacos , Memoria/efectos de los fármacos , Factores Sexuales , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiologíaRESUMEN
Learning and memory are thought to require hippocampal long-term potentiation (LTP), and one of the few central dogmas of molecular neuroscience that has stood undisputed for more than three decades is that LTP induction requires enzymatic activity of the Ca2+/calmodulin-dependent protein kinase II (CaMKII)1-3. However, as we delineate here, the experimental evidence is surprisingly far from conclusive. All previous interventions inhibiting enzymatic CaMKII activity and LTP4-8 also interfere with structural CaMKII roles, in particular binding to the NMDA-type glutamate receptor subunit GluN2B9-14. Thus, we here characterized and utilized complementary sets of new opto-/pharmaco-genetic tools to distinguish between enzymatic and structural CaMKII functions. Several independent lines of evidence demonstrated LTP induction by a structural function of CaMKII rather than by its enzymatic activity. The sole contribution of kinase activity was autoregulation of this structural role via T286 autophosphorylation, which explains why this distinction has been elusive for decades. Directly initiating the structural function in a manner that circumvented this T286 role was sufficient to elicit robust LTP, even when enzymatic CaMKII activity was blocked.
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Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Potenciación a Largo Plazo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/química , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Ácido Glutámico/metabolismo , Hipocampo/fisiología , Aprendizaje/fisiología , Potenciación a Largo Plazo/fisiología , Optogenética , Fosforilación , Unión ProteicaRESUMEN
Stress contributes to numerous psychopathologies, including memory impairment, and threatens one's well-being. It has been reported that creatine supplementation potentially influences cognitive processing. Hence, in this study, we examined the effects of creatine supplementation on memory, synaptic plasticity, and neuronal arborization in the CA1 region of the hippocampus in rats under chronic restraint stress (CRS). Thirty-two adult male Wistar rats (8 weeks old) weighing 200-250 g were randomly divided into four groups (nâ =â 8/per group): control, stress, creatine, and stress + creatine. CRS was induced for 6 h per day for 14 days, and creatine supplementation was carried out by dissolving creatine (2 g/kg body weight per day) in the animals' drinking water for 14 days. We used the Barnes maze and shuttle box for spatial and passive avoidance memory examination. The in-vivo field potential recording and Golgi-Cox staining were also used to investigate long-term potentiation (LTP) and dendrite arborization in the CA1 pyramidal neurons. Chronic stress impaired spatial memory, dysregulated LTP parameters, and decreased the number of dendrites in the CA1 pyramidal neurons of stressed rats, and creatine supplementation modified these effects in stressed rats. It seems that creatine supplementation can improve spatial memory deficits and synaptic plasticity loss induced by CRS in hippocampal CA1 neurons, possibly by reducing the dendrite arborization damages. However, understanding its mechanism needs further investigation.
Asunto(s)
Creatina , Potenciación a Largo Plazo , Ratas , Masculino , Animales , Potenciación a Largo Plazo/fisiología , Creatina/farmacología , Memoria Espacial , Ratas Wistar , Hipocampo , Plasticidad Neuronal , Trastornos de la Memoria/tratamiento farmacológico , Suplementos Dietéticos , Aprendizaje por LaberintoRESUMEN
Memory deterioration in Alzheimer's disease (AD) is thought to be underpinned by aberrant amyloid ß (Aß) accumulation, which contributes to synaptic plasticity impairment. Avenanthramide-C (Avn-C), a polyphenol compound found predominantly in oats, has a range of biological properties. Herein, we performed methanolic extraction of the Avns-rich fraction (Fr. 2) from germinated oats using column chromatography, and examined the effects of Avn-C on synaptic correlates of memory in a mouse model of AD. Avn-C was identified in Fr. 2 based on 1H-NMR analysis. Electrophysiological recordings were performed to examine the effects of Avn-C on the hippocampal long-term potentiation (LTP) in a Tg2576 mouse model of AD. Avn-C from germinated oats restored impaired LTP in Tg2576 mouse hippocampal slices. Furthermore, Avn-C-facilitated LTP was associated with changes in the protein levels of phospho-glycogen synthase kinase-3ß (p-GSK3ß-S9) and cleaved caspase 3, which are involved in Aß-induced synaptic impairment. Our findings suggest that the Avn-C extract from germinated oats may be beneficial for AD-related synaptic plasticity impairment and memory decline.
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Enfermedad de Alzheimer/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , ortoaminobenzoatos/farmacología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Avena/química , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipocampo/metabolismo , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Ratones Transgénicos , Plasticidad Neuronal , Extractos Vegetales/farmacologíaRESUMEN
High-fat diets (HFDs) and obesity can cause serious health problems, such as neurodegenerative diseases and cognitive impairments. Consumption of HFD is associated with reduction in hippocampal synaptic plasticity. Rosa damascena (R. damascena) is traditionally used as a dietary supplement for many disorders. This study was carried out to determine the beneficial effect of hydroalcoholic extract of R. damascena on in vivo hippocampal synaptic plasticity (long-term potentiation, LTP) in the perforant pathway (PP)-dentate gyrus (DG) pathway in rats fed with an HFD. Male Wistar rats were randomly assigned to four groups: Control, R. damascena extract (1 g/kg bw daily for 30 days), HFD (for 90 days) and HFD + extract. The population spike (PS) amplitude and slope of excitatory post-synaptic potentials (EPSP) were measured in DG area in response to stimulation applied to the PP. Serum oxidative stress biomarkers [total thiol group (TTG) and superoxide dismutase (SOD)] were measured. The results showed the HFD impaired LTP induction in the PP-DG synapses. This conclusion is supported by decreased EPSP slope and PS amplitude of LTP. R. damascena supplementation in HFD animals enhanced EPSP slope and PS amplitude of LTP in the granular cell of DG. Consumption of HFD decreased TTG and SOD. R. damascena extract consumption in the HFD animals enhanced TTG and SOD. These data indicate that R. damascena dietary supplementation can ameliorate HFD-induced alteration of synaptic plasticity, probably through its significant antioxidant effects and activate signalling pathways, which are critical in controlling synaptic plasticity.
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Dieta Alta en Grasa , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Extractos Vegetales/farmacología , Rosa/química , Animales , Dieta Alta en Grasa/efectos adversos , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Masculino , Vías Nerviosas/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
BACKGROUND: The plastic nature of the human brain lends itself to experience and training-based structural changes leading to functional recovery. Music, with its multimodal activation of the brain, serves as a useful model for neurorehabilitation through neuroplastic changes in dysfunctional or impaired networks. Neurologic Music Therapy (NMT) contributes to the field of neurorehabilitation using this rationale. OBJECTIVE: The purpose of this article is to present a discourse on the concept of neuroplasticity and music-based neuroplasticity through the techniques of NMT in the domain of neurological rehabilitation. METHODS: The article draws on observations and findings made by researchers in the areas of neuroplasticity, music-based neuroplastic changes, NMT in neurological disorders and the implication of further research in this field. RESULTS: A commentary on previous research reveal that interventions based on the NMT paradigm have been successfully used to train neural networks using music-based tasks and paradigms which have been explained to have cross-modal effects on sensorimotor, language and cognitive and affective functions. CONCLUSIONS: Multimodal gains using music-based interventions highlight the brain plasticity inducing function of music. Individual differences do play a predictive role in neurological gains associated with such interventions. This area deserves further exploration and application-based studies.
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Encéfalo/fisiología , Musicoterapia/métodos , Enfermedades del Sistema Nervioso/terapia , Rehabilitación Neurológica/métodos , Plasticidad Neuronal/fisiología , Encéfalo/diagnóstico por imagen , Humanos , Potenciación a Largo Plazo/fisiología , Música/psicología , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Enfermedades del Sistema Nervioso/psicología , Recuperación de la Función/fisiologíaRESUMEN
Drug addiction is a chronic and recurrent disease associated with learning and memory. Shaped by drug use and cues from the environment, drug memory serves a key role in drugseeking behaviour. Methamphetamine (MA), a globally abused drug, causes cognitive impairment, and endoplasmic reticulum (ER) stress is one of the mechanisms via which this occurs. In the current study, it was hypothesized that ER stress may serve a role in the disturbance of drug memory. The present study demonstrated that 5 mg/kg MA inhibited conditioned place preference behaviour via ER stress, which caused a disruption in longterm potentiation in the hippocampus. When mice were pretreated with the ER stress inhibitors 4phenyl butyric acid or tauroursodeoxycholic acid, drugevoked synaptic plasticity was induced. Western blotting results indicated that treatment with 5 mg/kg MA enhanced the expression of cyclindependent kinase5 and decreased the expression of Ca2+/calmodulindependent protein kinase II α via ER stress. Collectively, the present results suggested that a large dose of MA inhibited drugevoked synaptic plasticity and disrupted drug memory by inducing ER stress.
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Estrés del Retículo Endoplásmico/efectos de los fármacos , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Metanfetamina/farmacología , Plasticidad Neuronal/efectos de los fármacos , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Quinasa 5 Dependiente de la Ciclina/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiología , Potenciación a Largo Plazo/fisiología , Masculino , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Ácido Tauroquenodesoxicólico/farmacologíaRESUMEN
Neuroplasticity is essential to learning and memory in the brain; it has therefore also been implicated in numerous neurological and psychiatric disorders, making measuring the state of neuroplasticity of foremost importance to clinical neuroscience. Long-term potentiation (LTP) is a key mechanism of neuroplasticity and has been studied extensively, and invasively in non-human animals. Translation to human application largely relies on the validation of non-invasive measures of LTP. The current study presents a generative thalamocortical computational model of visual cortex for investigating and replicating interlaminar connectivity changes using non-invasive EEG recording of humans. The model is combined with a commonly used visual sensory LTP paradigm and fit to the empirical EEG data using dynamic causal modelling. The thalamocortical model demonstrated remarkable accuracy recapitulating post-tetanus changes seen in invasive research, including increased excitatory connectivity from thalamus to layer IV and from layer IV to II/III, established major sites of LTP in visual cortex. These findings provide justification for the implementation of the presented thalamocortical model for ERP research, including to provide increased detail on the nature of changes that underlie LTP induced in visual cortex. Future applications include translating rodent findings to non-invasive research in humans concerning deficits to LTP that may underlie neurological and psychiatric disease.
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Potenciación a Largo Plazo/fisiología , Modelos Neurológicos , Tálamo/fisiología , Corteza Visual/fisiología , Adulto , Animales , Biología Computacional , Electroencefalografía , Femenino , Humanos , Masculino , Red Nerviosa/fisiología , Adulto JovenRESUMEN
Introduction: Phytoestrogens are non-steroidal estrogen analogues and are found primarily in soy products. They have received increasing attention as dietary supplements for estrogen deficiency and as modulators of endogenous estrogen functions, including cognition and emotion. In addition to modifying the levels of circulating sex hormones, phytoestrogens also exert direct effects on estrogen and androgen receptors in the brain and thus effectively modulate the neural circuit functions.Objective: The aim of this study was to investigate the long-term effects of low phytoestrogen intake (â¼6 weeks) on the hippocampal plasticity and hippocampus-dependent memory formation in the adult C57BL/6 male mice.Methods and Results: In comparison to mice on a diet with normal phytoestrogen content, mice on low phytoestrogen diet showed a significant reduction in the phosphorylation of NR2B subunit, a molecular correlate of plasticity in the Schaffer collateral-CA1 synapse. We observed a profound decrease in long-term potentiation (LTP) in the ventral hippocampus, whereas no effect on plasticity was evident in its dorsal portion. Furthermore, we demonstrated that acute perfusion of slices with an estrogen analogue equol, an isoflovane metabolized from daidzein produced by the bacterial flora in the gut, was able to rescue the observed LTP deficit. Examining potential behavioral correlates of the plasticity attenuation, we found that mice on phytoestrogen-free diet display decreased contextual fear memory at remote but not at recent time points after training.Conclusions: Our data suggests that nutritional phytoestrogens have profound effects on the plasticity in the ventral hippocampus and ventral hippocampus-dependent memory.
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Dieta , Hipocampo/fisiología , Memoria/fisiología , Plasticidad Neuronal/fisiología , Fitoestrógenos/administración & dosificación , Animales , Conducta Animal , Equol/farmacología , Miedo/fisiología , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Fosforilación/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Sinapsis/fisiologíaRESUMEN
OBJECTIVE: To observe the impacts of electroacupuncture (EA) stimulation at "Zusanli and Kunlun Points" on spinal dorsal horn microglia activation in L5 spinal nerve ligation (SNL) rats and BNDF, P2 × 4 and GABAAγ2, and the changes in spinal dorsal horn synaptic plasticity in model rats. METHODS: Adult male SD rats (180-220 g) were selected and randomly divided into 6 groups, including the sham group, the SNL group, the SNL + EA group, the SNL+5-BDBD group, the SNL + EA + 5-BDBD group and the SNL + FEA group. The changes in the Iba-1, BDNF, P2 × 4 and GABAAγ2 in the spinal cord of rats were observed by Western blotting, immunofluorescence, RT-PCR and other techniques; the long-term changes in the potential after the excitatory synapse of the spinal dorsal horn in rats were observed by in vivo electrophysiological technique. RESULTS: After 7 days of intervention, the fluorescence intensity (FI) of P2 × 4 and Iba-1 in the SNL + EA group was lower than that in the SNL group and higher than that in the sham group(P < 0.01), but the FI of GABAAγ2 was higher than that in the SNL group(P < 0.01); the expression of Iba-1, BDNF and P2 × 4 proteins in the SNL + EA group, the SNL+5-BDBD group and the SNL + EA + 5-BDBD group was significantly lower than that in the SNL + FEA group(P < 0.05), but the expression of GABAAγ2 protein was higher (P < 0.05); after treatment with EA, the expression levels of Iba-1 mRNA and P2 × 4 mRNA in the SNL + EA group were lower than those in the SNL group(P < 0.01), but the expression levels of GABAAγ2 mRNA were higher (P < 0.01). Meanwhile, long-term potentiation changes could not be induced in the SNL + EA group. CONCLUSION: The EA stimulation at "Zusanli" and "Kunlun" points can improve the pain threshold of rats with neuropathic pain (NP), inhibit the excitatory postsynaptic potential (EPSP), and weaken the excitatory transmission efficiency between synapses during NP.
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Electroacupuntura/métodos , Potenciación a Largo Plazo/fisiología , Neuralgia/metabolismo , Receptores de GABA-A/biosíntesis , Receptores Purinérgicos P2X4/biosíntesis , Médula Espinal/metabolismo , Animales , Expresión Génica , Masculino , Neuralgia/genética , Neuralgia/terapia , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/genética , Receptores Purinérgicos P2X4/genética , Resultado del TratamientoRESUMEN
The acquisition of fear memories involves plasticity of the thalamic and cortical pathways to the lateral amygdala (LA). In turn, the maintenance of synaptic plasticity requires the interplay between input-specific synaptic tags and the allocation of plasticity-related proteins. Based on this interplay, weakly activated synapses can express long-lasting forms of synaptic plasticity by cooperating with strongly activated synapses. Increasing the number of activated synapses can shift cooperation to competition. Synaptic cooperation and competition can determine whether two events, separated in time, are associated or whether a particular event is selected for storage. The rules that determine whether synapses cooperate or compete are unknown. We found that synaptic cooperation and competition, in the LA, are determined by the temporal sequence of cortical and thalamic stimulation and that the strength of the synaptic tag is modulated by the endocannabinoid signaling. This modulation is particularly effective in thalamic synapses, supporting a critical role of endocannabinoids in restricting thalamic plasticity. Also, we found that the availability of synaptic proteins is activity-dependent, shifting competition to cooperation. Our data present the first evidence that presynaptic modulation of synaptic activation, by the cannabinoid signaling, functions as a temporal gating mechanism limiting synaptic cooperation and competition.
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Amígdala del Cerebelo/metabolismo , Corteza Auditiva/metabolismo , Endocannabinoides/metabolismo , Potenciación a Largo Plazo/fisiología , Células Piramidales/metabolismo , Receptores de Cannabinoides/metabolismo , Tálamo/metabolismo , Animales , Potenciales Postsinápticos Excitadores , Miedo , Memoria/fisiología , Plasticidad Neuronal , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-DawleyRESUMEN
RATIONALE AND OBJECTIVE: Paeoniflorin has been reported to exhibit antidepressant-like effects in several animal model depression; and it also exerts a neuroprotective effect. In the present study, we investigated the effects of paeoniflorin administration on depression-like behaviors and cognitive abilities in mice subjected to chronic unpredictable mild stress (CUMS), an animal model associated with depressive disorders and cognitive deficits. METHODS: We administered paeoniflorin (20 mg/kg), which is the main active constituent extracted from Paeonia lactiflora Pall. and exerts multiple pharmacological actions, to CUMS mice. Subsequently, animals were subjected to tests of depression-like behavior including the sucrose preference test, the forced swimming test and the tail suspension test. The Morris water maze (MWM) task was applied to evaluate learning and memory capacity. Hippocampal CA1 long-term potentiation (LTP) was recorded. Dendritic spine density and the expression levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95) in the hippocampus were also investigated. RESULTS: The administration of paeoniflorin protected against CUMS-induced depression-like behavior. Paeoniflorin also improved the performance of CUMS mice in the MWM. The impairment of hippocampal CA1 LTP caused by CUMS was also reversed. Furthermore, paeoniflorin administration prevented decreases in dendritic spine density and in the expression of BDNF and PSD95 in the hippocampus of CUMS mice. CONCLUSION: Our observations suggest that paeoniflorin is a potential antidepressant that protects against cognitive impairment in depression.
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Glucósidos/uso terapéutico , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Monoterpenos/uso terapéutico , Aprendizaje Espacial/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/psicología , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/fisiopatología , Trastorno Depresivo Mayor/psicología , Glucósidos/farmacología , Hipocampo/fisiopatología , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Monoterpenos/farmacología , Técnicas de Cultivo de Órganos , Distribución Aleatoria , Aprendizaje Espacial/fisiología , Estrés Psicológico/fisiopatologíaRESUMEN
The aim of this study was to investigate the time-dependent effects of acupuncture on the excitability and long-term potentiation- (LTP-) like plasticity induced by paired-associative stimulation (PAS) over the primary motor cortex (M1). The present examination is the first to report the influence of acupuncture on the motor-evoked potential (MEP) throughout the treatment process, including baseline (before acupuncture), the needle in situ, and the needle removal. Subsequently, the LTP-like plasticity induced by paired-associative stimulation (PAS) was explored, which consisted of 200 pairs of electrical stimulation of the ulnar nerve at the first dorsal interosseous (FDI), followed by transcranial magnetic stimulation (TMS) over the bilateral M1. TMS-MEP amplitudes over the bilateral M1 in resting conditions were measured throughout the whole treatment process. Finally, we confirmed the behavioral measurements. Significant changes were found in both the contralateral and ipsilateral acupuncture sizes as compared to the baseline values. Our results indicated that acupuncture modulated the excitability of M1, and the synaptic plasticity was time-dependent. We concluded that acupuncture should be combined with rehabilitation techniques to improve the motor function in stroke patients. Therefore, we put forward the combined application of the acupuncture timing and rehabilitation for higher therapeutic effectiveness. This trial was registered in the Chinese Clinical Trial Registry (registration no. ChiCTR-IPR-1900020515).
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Terapia por Acupuntura/métodos , Potenciación a Largo Plazo/fisiología , Factores de Tiempo , Adolescente , Adulto , Pueblo Asiatico/genética , China , Estimulación Eléctrica/métodos , Electromiografía/métodos , Potenciales Evocados Motores/fisiología , Femenino , Lateralidad Funcional , Mano , Humanos , Masculino , Corteza Motora/fisiología , Plasticidad Neuronal/fisiología , Estimulación Magnética Transcraneal/métodosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Liuwei Dihuang decoction (LW), a classic formula in Traditional Chinese medicine (TCM), has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency. LW consists of 6 herbs including Dihuang (prepared root of Rehmannia glutinosa (Gaertn.) DC.), Shanyao (rhizome of Dioscorea polystachya Turcz.), Shanzhuyu (fruit of Cornus officinalis Siebold & Zucc.), Mudanpi (root bark of Paeonia × suffruticosa Andrews), Zexie (rhizome of Alisma plantago-aquatica L.) and Fuling (scleorotia of Wolfiporia extensa (Peck) Ginns). LW-active fraction combination (LW-AFC) is extracted from LW, it is effective for the treatment of kidney yin deficiency in many animal models. Recent researches indicate that the "kidney deficiency" is related to a disturbance in the neuroendocrine immunomodulation (NIM) network, and glucocorticoids play an important role in kidney deficiency. AIM OF THE STUDY: This study evaluated the effects of LW-AFC and the active fractions (polysaccharide, LWB-B; glycoside, LWD-b; oligosaccharide, CA-30) on corticosterone (Cort)-induced long-term potentiation (LTP) impairment in vivo. MATERIALS AND METHODS: In this study, LTP was used to evaluate the synaptic plasticity. LW-AFC was orally administered for seven days. The active fractions were given by either chronic administration (i.g., i.p., 7 days) or single administration (i.c.v., i.g., i.p.). Cort was injected subcutaneously 1â¯h before the high-frequency stimulation (HFS) to induce LTP impairment. Moreover, in order to research on the possible effective pathways, an antibiotic cocktail and an immunosuppressant were also used. RESULTS: Chronic administration (i.g.) of LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Single administration (i.c.v., i.g., i.p.) of any of the active fractions had no effect on Cort-induced LTP impairment, while chronic administration (i.g., i.p.) of LWB-B or LWD-b showed positive effects against Cort. Interestingly, CA-30 only showed protective effects via i.g. administration, and there was little effect when CA-30 was administered i.p. In addition, when the intestinal microbiota was disrupted by application of the antibiotic cocktail, CA-30 showed little protective effects against Cort. The effects of LW-AFC were also abolished when the immune function was inhibited. In the hippocampal tissue, Cort treatment increased corticosterone and glutamate, and LW-AFC could inhibit the Cort-induced elevation of corticosterone and glutamate; there was little change in D-serine in Cort-treated animals, but LW-AFC could increase the D-serine levels. CONCLUSION: LW-AFC and its three active fractions could ameliorate Cort-induced LTP impairment. Their protective effects are unlikely by a direct way, and immune modulation might be the common pathway. CA-30 could protect LTP from impairment via modulating the intestinal microbiota. Decreasing corticosterone and glutamate and increasing D-serine in the Cort-treated animals' hippocampal tissue might be one of the mechanisms for the neural protective effects of LW-AFC. Further study is needed to understand the underlying mechanisms.
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Medicamentos Herbarios Chinos/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Sistemas Neurosecretores/efectos de los fármacos , Animales , Corticosterona/toxicidad , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Potenciación a Largo Plazo/fisiología , Masculino , Medicina Tradicional China , Ratones Endogámicos BALB C , Sistemas Neurosecretores/fisiopatología , Deficiencia YinRESUMEN
Throughout life, individuals learn to predict a punishment via its association with sensory stimuli. This process ultimately prompts goal-directed actions to prevent the danger, a behavior defined as avoidance. Neurons in the lateral habenula (LHb) respond to aversive events as well as to environmental cues predicting them, supporting LHb contribution to cue-punishment association. However, whether synaptic adaptations at discrete habenular circuits underlie such associative learning to instruct avoidance remains elusive. Here, we find that, in mice, contingent association of an auditory cue (tone) with a punishment (foot shock) progressively causes cue-driven LHb neuronal excitation during avoidance learning. This process is concomitant with the strengthening of LHb AMPA receptor-mediated neurotransmission. Such a phenomenon occludes long-term potentiation and occurs specifically at hypothalamus-to-habenula synapses. Silencing hypothalamic-to-habenulainputs or optically inactivating postsynaptic AMPA receptors within the LHb disrupts avoidance learning. Altogether, synaptic strengthening at a discrete habenular circuit transforms neutral stimuli into salient punishment-predictive cues to guide avoidance.
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Reacción de Prevención/fisiología , Señales (Psicología) , Habénula/fisiología , Hipotálamo/fisiología , Potenciación a Largo Plazo/fisiología , Castigo , Sinapsis/fisiología , Animales , Aprendizaje por Asociación/fisiología , Masculino , Ratones , Técnicas de Placa-Clamp , Receptores AMPA/antagonistas & inhibidores , Receptores AMPA/fisiologíaRESUMEN
Sensory experience and perceptual learning changes receptive field properties of cortical pyramidal neurons (PNs), largely mediated by synaptic long-term potentiation (LTP). The circuit mechanisms underlying cortical LTP remain unclear. In the mouse somatosensory cortex, LTP can be elicited in layer 2/3 PNs by rhythmic whisker stimulation. We dissected the synaptic circuitry underlying this type of plasticity in thalamocortical slices. We found that projections from higher-order, posterior medial thalamic complex (POm) are key to eliciting N-methyl-D-aspartate receptor (NMDAR)-dependent LTP of intracortical synapses. Paired activation of cortical and higher-order thalamocortical inputs increased vasoactive intestinal peptide (VIP) and parvalbumin (PV) interneuron (IN) activity and decreased somatostatin (SST) IN activity, which together disinhibited the PNs. VIP IN-mediated disinhibition was critical for inducing LTP. This study reveals a circuit motif in which higher-order thalamic inputs gate synaptic plasticity via disinhibition. This motif may allow contextual feedback to shape synaptic circuits that process first-order sensory information.
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Potenciación a Largo Plazo/fisiología , Plasticidad Neuronal/fisiología , Filtrado Sensorial/fisiología , Corteza Somatosensorial/fisiología , Sinapsis/fisiología , Tálamo/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibición Neural/fisiología , Técnicas de Cultivo de ÓrganosRESUMEN
AIMS: Acupuncture has been reported to affect vascular dementia through a variety of molecular mechanisms. An isobaric tag for relative and absolute quantification (iTRAQ) with high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses makes it possible to attain a global profile of proteins. Hence, we used an iTRAQ-LC-MS/MS strategy to unravel the underlying mechanism of acupuncture. METHODS: Wistar rats were subjected to vascular dementia with bilateral common carotid occlusion. Acupuncture was intervened for 2 weeks at 3 days after surgery. The Morris water maze was used to assess the cognitive function. Proteins were screened by quantitative proteomics and analyzed by bioinformatic analysis. Four differentially expressed proteins (DEPs) were validated by western blot. The reactive oxygen species (ROS) production, neuron cell loss, and long-term potentiation (LTP) were determined after western blot. RESULTS: Acupuncture at proper acupoints significantly improved cognitive function. A total of 31 proteins were considered DEPs. Gene ontology (GO) analysis showed that most of the DEPs were related to oxidative stress, apoptosis, and synaptic function, which were regarded as the major cellular processes related to acupuncture effect. Western blot results confirm the credibility of iTRAQ results. Acupuncture could decrease ROS production, increase neural cell survival, and improve LTP, which verified the three major cellular processes. CONCLUSION: Acupuncture may serve as a promising clinical candidate for the treatment of vascular dementia via regulating oxidative stress, apoptosis, or synaptic functions.
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Acupuntura/métodos , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/terapia , Demencia Vascular/complicaciones , Regulación de la Expresión Génica/fisiología , Puntos de Acupuntura , Animales , Enfermedades de las Arterias Carótidas/complicaciones , Cromatografía por Intercambio Iónico , Biología Computacional , Demencia Vascular/etiología , Modelos Animales de Enfermedad , Estimulación Eléctrica , Potenciación a Largo Plazo/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Microinyecciones , Proteómica/métodos , ARN Interferente Pequeño/administración & dosificación , Ratas , Ratas Wistar , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Espectrometría de Masas en TándemRESUMEN
Synaptic refinement improves synaptic efficiency, which provides a possibility to improve memory in Alzheimer's disease (AD). In the current study, we aimed to investigate the role of L-theanine, a natural constituent in green tea, in hippocampal synaptic transmission and to assess its potential to improve memory in transgenic AD mice. Initially, we found that L-theanine bath application facilitated hippocampal synaptic transmission and reduced paired-pulse facilitation (PPF). These effects were blocked by antagonists of N-methyl-D-aspartic acid receptors and the dopamine D1/5 receptor, and a selective protein kinase A (PKA) inhibitor. Moreover, L-theanine enhanced PKA phosphorylation via dopamine D1/5 receptor activation. L-theanine did not influence hippocampal long-term potentiation (LTP) in the slices obtained from wild-type mice, but rescued the impairment of hippocampal LTP in AD mice. Importantly, systemic application of L-theanine also improved memory and hippocampal LTP in AD mice. Our results demonstrate that L-theanine administration promotes hippocampal dopamine and noradrenaline release, and stimulates PKA phosphorylation. Moreover, the rescued hippocampal LTP in AD mice could be impaired by a PKA inhibitor. Our data reveal that L-theanine ameliorates the impairment of memory and hippocampal LTP in AD mice, likely through dopamine D1/5 receptor-PKA pathway activation. These data warrant the consideration of L-theanine as a candidate for the treatment of AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Glutamatos/farmacología , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Nootrópicos/farmacología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Hipocampo/patología , Hipocampo/fisiopatología , Potenciación a Largo Plazo/fisiología , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Trastornos de la Memoria/fisiopatología , Ratones Transgénicos , Neurotransmisores/farmacología , Norepinefrina/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Té , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: We have previously demonstrated, in mice, that antidepressant treatment can prevent relapse of PTSD-like behaviors (avoidance, hyperarousal, and anxiety) through increased activation in the infralimbic cortex (IL) of the medial prefrontal cortex. OBJECTIVE: Here, we examined whether direct high-frequency stimulation (HFS) of the IL, provoking its heightened activation (i.e., long-term potentiation, LTP), would also prevent the return of PTSD-like symptoms. METHODS: A 1.5-mA foot-shock was used to generate PTSD-like symptoms in Swiss mice. In Experiment 1, local field potentials were recorded in the IL to test whether normal IL LTP can be induced after the suppression of PTSD-like symptoms. In Experiment 2, IL HFS was applied after symptom suppression, but prior to the provocation of relapse, to test HFS effect on symptom return. RESULTS: We observed that PTSD-like state was associated with impairment in IL HFS-induced IL LTP. However, IL LTP induction was near normal when PTSD-like symptoms were suppressed. We then found that IL HFS, applied after symptom suppression, prevented symptom return. CONCLUSIONS: Increased activation of the IL may be a key mechanism preventing PTSD relapse. Prefrontal cortex deep brain stimulation may, therefore, be relevant for preventing PTSD symptom return in remitted high-risk patients.
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Corteza Cerebral/fisiopatología , Terapia por Estimulación Eléctrica/métodos , Potenciación a Largo Plazo/fisiología , Trastornos por Estrés Postraumático/fisiopatología , Trastornos por Estrés Postraumático/terapia , Animales , Masculino , Ratones , Corteza Prefrontal/fisiopatología , Recurrencia , Trastornos por Estrés Postraumático/psicologíaRESUMEN
Soluble amyloid-ß (Aß) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). Aß oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aß oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aß peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aß oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aß oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aß oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD.