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1.
Science ; 372(6537)2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33795429

RESUMO

Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat medial (MEC) and lateral (LEC) entorhinal cortices and found impairments in spatial and object learning tasks, respectively. MEC and LEC were synchronized with the hippocampal dentate gyrus through high- and low-gamma-frequency rhythms, respectively, and engaged either granule cells or mossy cells and CA3 pyramidal cells in a task-dependent manner. Gamma perturbation disrupted the learning-induced assembly organization of target neurons. Our findings imply that pathway-specific gamma oscillations route task-relevant information between distinct neuronal subpopulations in the entorhinal-hippocampal circuit. We hypothesize that interregional gamma-time-scale spike coordination is a mechanism of neuronal communication.


Assuntos
Giro Denteado/fisiologia , Córtex Entorrinal/fisiologia , Ritmo Gama , Aprendizagem , Neurônios/fisiologia , Aprendizagem Espacial , Potenciais de Ação , Animais , Masculino , Aprendizagem em Labirinto , Rememoração Mental , Vias Neurais/fisiologia , Optogenética , Células Piramidais/fisiologia , Ratos , Ratos Long-Evans , Navegação Espacial
2.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(2): 207-215, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33829693

RESUMO

Objective: To investigate whether long-term exposure to inhaled sevoflurane, a volatile anesthetic, causes abnormal activities and memory impairment related to attention-deficit/hyperactivity disorder (ADHD) in neonatal rats. Methods: On postnatal day 5 (P5), Sprague-Dawley rats were randomly assigned to two sevoflurane subgroups and two control subgroups and underwent experimental intervention. The two sevoflurane (SEVO) subgroups were exposed to 3% sevoflurane for 2 h and 4 h respectively, while the two control subgroups were given pure oxygen for the same amount and duration. Behavioral tests, including open-field test (OFT), five-choice serial reaction time task (5-CSRTT), fear-conditioning (FC) and Morris water maze (MWM), were applied to evaluate changes in cognition, memory, anxiety and ADHD-related behavioral changes in the rats in adolescence (-P25) and in adulthood (-P65). Results: In OFT, the SEVO 2 h and SEVO 4 h subgroups displayed activity level and exploratory behaviors similar to those of the control subgroups on P21 and P61, with no statistically significant difference identified in the data. 5-CSRTT results on P25 and P65 indicated no statistically significant difference between the SEVO subgroups and the control subgroups in regard to ADHD-related abnormal behaviors, including number of immature reaction, rate of correct response and omission rate. In the FC experiment, SEVO 4 h group had a shorter freezing period and longer period of freezing latency ( P=0.029) in comparison to the control groups. The results of the MWM test showed that the escape latency period of rats in the SEVO 4 h group was significantly prolonged on the second day and the third day, compared to the control groups ( P<0.05). The average swimming speed of SEVO groups did no exhibit any statistically significant difference on P69 or P76. The time the SEVO 4 h group spent in the target quadrant was significantly shorter than that of the control group ( P=0.039) and percentage of distance traveled in the target quadrant was significantly reduced compared to that the control group ( P=0.048). Conclusion: The findings suggest that four hours of inhaled sevoflurane exposure in neonate rats may cause memory impairment, but does no increase risks for ADHD-related abnormal activities.


Assuntos
Anestésicos Inalatórios , Transtorno do Deficit de Atenção com Hiperatividade , Anestésicos Inalatórios/toxicidade , Animais , Animais Recém-Nascidos , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Aprendizagem em Labirinto , Ratos , Ratos Sprague-Dawley , Sevoflurano
3.
Zhen Ci Yan Jiu ; 46(3): 226-30, 2021 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-33798296

RESUMO

OBJECTIVE: To observe the effect of moxibustion on the expression of phosphorylated calcium/calmodulin-dependent protein kinase Ⅱα(pCaMKⅡα) and neuronal nuclei (NeuN) and the ability of learning and memory in the neonatal mice model of hypoxic-ischemia encephalopathy(HIE), so as to explore its mechanism underlying improvement of learning and memory. METHODS: ICR mice (aged 7 days) were randomly divided into sham operation, model and moxibustion groups. HIE model was induced by ligation of the right common carotid artery combined with hypoxia in a closed transparent chamber. Mice in the moxibustion group were treated with gentle moxibustion at "Dazhui"(GV14) for 35 min,once daily for 3 consecutive days. The pathological changes of brain tissues were observed with the naked eyes and under microscope after H.E. staining, respectively. The expressions of pCaMKⅡα and NeuN in the ischemic penumbra were examined by immunofluorescent staining, and the learning and memory ablility was tested with Morris maze. RESULTS: No infarcts were found in the brain tissue of the mice in the sham operation group. Compared with the sham operation group, mice in the model group had infarcts and the expression of pCaMKⅡα and NeuN in the ischemic penumbra was significantly reduced (P<0.01), and the latency to find a platform was significantly prolonged in Morris maze test (P<0.01). After moxibustion, in comparison with the model group showed that, small areas of infarction were seen in the right hemisphere of the moxibustion group, and the expressions of pCaMKⅡα, NeuN increased significantly (P<0.01), and the latency to find a platform was significantly shortened (P<0.01). CONCLUSION: Moxibustion can improve the ability of learning and memory in the neonatal mice with HIE, which might be related to alleviating brain injury and increasing the expression of pCaMKⅡα in neurons of ischemic brain tissues.


Assuntos
Hipóxia-Isquemia Encefálica , Moxibustão , Animais , Hipocampo , Hipóxia-Isquemia Encefálica/genética , Hipóxia-Isquemia Encefálica/terapia , Isquemia , Aprendizagem em Labirinto , Memória , Camundongos , Camundongos Endogâmicos ICR
4.
Ars pharm ; 62(1): 6-14, ene.-mar. 2021. graf
Artigo em Inglês | IBECS | ID: ibc-199697

RESUMO

INTRODUCTION: Khamira Gawzaban Ambari Jadwar Ood Saleeb Wala (KGAJOS) is a polyherbal compound Unani Pharmacopoeial formulation described in traditional Unani texts as Muqawwi-e-Aza-e-Raeesa (tonic for brain, heart, liver and stomach). KGAJOS is reported to possess anxiolytic and antidepressant activity in mice. Though it is used clinically for various neurological conditions, preclinical efficacy of this formulation in learning and memory enhancement / improvement is not established. METHOD: KGAJOS was evaluated for cognitive function improvement activity using Morris water maze test in C57BL/6 mice. Piracetam was used as positive control for comparison. Anymaze video tracking software was used for tracking the path of mice in pool as per standard protocol. RESULTS: During probe trial in Morris water maze test, a significant increase in time spent in platform quadrant was observed at 1000 and 1500 mg/kg bw of KGAJOS (p < 0.01 and 0.001, respectively) as well as in piracetam group (p < 0.01) compared to vehicle control. Latency to reach the platform quadrant (escape latency) was significantly reduced (p < 0.001) in piracetam and KGAJOS group at 1000 and 1500 mg/kg bw compared to vehicle control. No change in time spent in platform quadrant and escape latency was observed at 500 mg/kg bw of KGAJOS. CONCLUSIONS: Morris water maze experiment conducted in mice revealed improved learning and memory function of KGAJOS at the dose levels of 1000 and 1500 mg/kg bw whereas 500 mg/kg bw was not found to be effective. Observed efficacy of KGAJOS confirmed the traditional claims and usage of this formulation in conditions associated with cognition and memory


INTRODUCCIÓN: Khamira Gawzaban Ambari Jadwar Ood Saleeb Wala (KGAJOS) es una formulación de Unani compuesto de poliherbal descrito como tónico para el cerebro, corazón, hígado y estómago. Este estudio se realizó para evaluar la eficacia preclínica de KGAJOS en el aprendizaje y la memoria. MÉTODO: Se evaluó la actividad de mejora de la función cognitiva de KGAJOS utilizando la prueba de laberinto de agua de Morris en ratones C57BL / 6. Se utilizó piracetam como control positivo. Se utilizó el software de seguimiento de video Anymaze para rastrear la ruta. RESULTADOS: Durante la prueba de la sonda, se observó un aumento significativo en el tiempo empleado en el cuadrante de la plataforma a 1000 y 1500 mg / kg de peso corporal de KGAJOS (p < 0,01 y 0,001, respectivamente) y en el grupo de piracetam (p < 0,01) en comparación con el control. La latencia para alcanzar el cuadrante de la plataforma (latencia de escape) se redujo significativamente (p < 0,001) en el grupo de piracetam y KGAJOS a 1000 y 1500 mg / kg de peso corporal en comparación con el control. CONCLUSIONES: El experimento del laberinto de agua de Morris reveló una mejora en la función de aprendizaje y memoria con 1000 y 1500 mg / kg de peso corporal de KGAJOS, mientras que 500 mg / kg de peso corporal no fue efectivo. La eficacia observada de KGAJOS confirmó las afirmaciones tradicionales y el uso de esta formulación en condiciones asociadas con la cognición y la memoria


Assuntos
Animais , Masculino , Camundongos , Cognição/efeitos dos fármacos , Extratos Vegetais/farmacologia , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Aprendizagem em Labirinto , Piracetam/farmacologia , Fármacos Neuroprotetores/farmacologia , Fatores de Tempo , Resultado do Tratamento
5.
Nat Commun ; 12(1): 1903, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771994

RESUMO

Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer's disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD.


Assuntos
Doença de Alzheimer/genética , Proteínas do Citoesqueleto/genética , Transtornos da Memória/genética , MicroRNAs/genética , Sinapses/metabolismo , Quinases Associadas a rho/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Hipocampo/citologia , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/fisiologia , Fosforilação , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sinapses/fisiologia , Quinases Associadas a rho/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
6.
Nat Commun ; 12(1): 1778, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741954

RESUMO

Memory reconsolidation, the process by which memories are again stabilized after being reactivated, has strengthened the idea that memory stabilization is a highly plastic process. To date, the molecular and cellular bases of reconsolidation have been extensively investigated particularly within the hippocampus. However, the role of adult neurogenesis in memory reconsolidation is unclear. Here, we combined functional imaging, retroviral and chemogenetic approaches in rats to tag and manipulate different populations of rat adult-born neurons. We find that both mature and immature adult-born neurons are activated by remote memory retrieval. However, only specific silencing of the adult-born neurons immature during learning impairs remote memory retrieval-induced reconsolidation. Hence, our findings show that adult-born neurons immature during learning are required for the maintenance and update of remote memory reconsolidation.


Assuntos
Aprendizagem/fisiologia , Consolidação da Memória/fisiologia , Memória de Longo Prazo/fisiologia , Neurônios/fisiologia , Animais , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/citologia , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Microscopia Confocal , Neurônios/metabolismo , Biossíntese de Proteínas/genética , Biossíntese de Proteínas/fisiologia , Ratos Sprague-Dawley , Fatores de Tempo
7.
Ecol Lett ; 24(4): 751-760, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33616308

RESUMO

Cognitive biases for encoding spatial information (orientation strategies) in relation to self (egocentric) or landmarks (allocentric) differ between species or populations according to the habitats they occupy. Whether biases in orientation strategy determine early habitat selection or if individuals adapt their biases following experience is unknown. We determined orientation strategies of pheasants, Phasianus colchicus, using a dual-strategy maze with an allocentric probe trial, before releasing them (n = 20) into a novel landscape, where we monitored their movement and habitat selection. In general, pheasants selected for woodland over non-woodland habitat, but allocentric-biased individuals exhibited weaker avoidance of non-woodland habitat, where we expected allocentric navigation to be more effective. Sex did not influence selection but was associated with speed and directional persistence in non-woodland habitat. Our results suggest that an individual's habitat selection is associated with inherent cognitive bias in early life, but it is not yet clear what advantages this may offer.


Assuntos
Navegação Espacial , Viés , Cognição , Ecossistema , Humanos , Aprendizagem em Labirinto
8.
Bratisl Lek Listy ; 122(1): 78-84, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33393325

RESUMO

AIMS: The aim was to investigate the improvement properties of apocynin and its potential mechanism on diabetes-associated cognitive decline. METHODS: In this study, the model of diabetic rat was established by STZ (50 mg/kg) and treated with apocynin (16 mg/kg/d for 12 weeks). The cognitive ability was evaluated by Morris water maze test. The indicators of oxidative stress (SOD and MDA) were analyzed by spectrophotometer. The inflammatory cytokines were measured by real time-PCR and ELISA. The protein expressions of Nrf-2, HO-1, Bcl-2 and Bax were determined by Western blot. RESULTS: Treatment with apocynin ameliorated diabetes-related learning and memory injury, as represented by decreasing escape latency and enhancement of the number of times of crossing platform, in the Morris water maze test. In hippocampus, apocynin markedly augmented SOD activity and inhibited MDA level to alleviate oxidative stress. Moreover, apocynin obviously relieved inflammatory reaction by suppressing TNF-α, IL-1ß and IL-6 concentrations. Concomitantly, apocynin also statistically enhanced Nrf-2 and HO-1 protein expression to improve DACD. Lastly, apocynin notably ameliorated Bax/Bcl-2 ratio by regulating Bax and Bcl-2 protein expression to mitigate apoptosis. CONCLUSION: Our results have shown that apocynin may be a valid therapeutic agent against DACD via modulation of antioxidant, anti-inflammatory, and anti-apoptosis (Tab. 1, Fig. 18, Ref. 35).


Assuntos
Disfunção Cognitiva , Diabetes Mellitus Experimental , Acetofenonas , Animais , Cognição , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Diabetes Mellitus Experimental/complicações , Hipocampo , Aprendizagem em Labirinto , Estresse Oxidativo , Ratos , Estreptozocina
9.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33435576

RESUMO

A synthetic cathinone, mephedrone is widely abused by adolescents and young adults. Despite its widespread use, little is known regarding its long-term effects on cognitive function. Therefore, we assessed, for the first time, whether (A) repeated mephedrone (30 mg/kg, i.p., 10 days, once a day) exposure during adolescence (PND 40) induces deleterious effects on spatial memory and reversal learning (Barnes maze task) in adult (PND 71-84) rats and whether (B) these effects were comparable to amphetamine (2.5 mg/kg, i.p.). Furthermore, the influence of these drugs on MMP-9, NMDA receptor subunits (GluN1, GluN2A/2B) and PSD-95 protein expression were assessed in adult rats. The drug effects were evaluated at doses that per se induce rewarding/reinforcing effects in rats. Our results showed deficits in spatial memory (delayed effect of amphetamine) and reversal learning in adult rats that received mephedrone/amphetamine in adolescence. However, the reversal learning impairment may actually have been due to spatial learning rather than cognitive flexibility impairments. Furthermore, mephedrone, but not amphetamine, enhanced with delayed onset, MMP-9 levels in the prefrontal cortex and the hippocampus. Mephedrone given during adolescence induced changes in MMP-9 level and up-regulation of the GluN2B-containing NMDA receptor (prefrontal cortex and hippocampus) in young adult (PND 63) and adult (PND 87) rats. Finally, in adult rats, PSD-95 expression was increased in the prefrontal cortex and decreased in the hippocampus. In contrast, in adult rats exposed to amphetamine in adolescence, GluN2A subunit and PSD-95 expression were decreased (down-regulated) in the hippocampus. Thus, in mephedrone-but not amphetamine-treated rats, the deleterious effects on spatial memory were associated with changes in MMP-9 level. Because the GluN2B-containing NMDA receptor dominates in adolescence, mephedrone seems to induce more harmful effects on cognition than amphetamine does during this period of life.


Assuntos
Anfetamina/farmacologia , Hipocampo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Metanfetamina/análogos & derivados , Córtex Pré-Frontal/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Fatores Etários , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Cognição/efeitos dos fármacos , Proteína 4 Homóloga a Disks-Large/metabolismo , Hipocampo/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Metanfetamina/farmacologia , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo
10.
Chem Biol Interact ; 337: 109400, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33516661

RESUMO

The effects of long-term alcohol consumptions on cognitive function remain elusive with contradictory results. Whilst it is widely accepted that long-term intoxication can cause cognitive impairment, moderate drinking can improve cognitive function. In reality, many older people and those with chronic medical conditions are long-term alcohol consumers in Asian countries. Our previous studies have suggested that long-term alcohol consumption can damage blood-brain barrier (BBB) integrity and aggravate cognitive deficit in APPswe/PS1De9 mice, but little is known about the underlying mechanisms, especially whether this consumption can cause cognitive decline via aggravating BBB damage in people who are exposed to the risk factors for cognitive disorders such as aging or inflammation. These questions were addressed in this study. The mouse models of cognitive deficit induced by d-galactose or lipopolysaccharide, the important risk conditions in human on cognitive function, were used to evaluate the effects of long-term alcohol consumption on the BBB integrity. After alcohol administration for 30 days in these models the BBB integrity was significantly destroyed with remarkably increased permeability and down-regulated protein expression of zonula occludens-1, VE-cadherin, occludin, low-density lipoprotein receptor-related protein-1, receptor for advanced glycation end products, major facilitator superfamily domain-containing protein-2a and aquaporin-4, which is the most closely related with the structure and function of BBB integrity. Meanwhile, the level of oxidative stress in d-galactose mice or inflammatory factors in cortex and serum in lipopolysaccharide mice, which might be involved in the cognitive dysfunctions, was significantly amplified. Furthermore, the impaired memory and hippocampal neuron damage induced by d-galactose and lipopolysaccharide were concurrently aggravated. Collectively, our study provided novel and compelling evidence that the structural and functional proteins for BBB integrity may be the primary targets for the detrimental effects of alcohol abuse that lead to cognitive dysfunction and neurological deficits in high risk populations.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Etanol/toxicidade , Alcoolismo/metabolismo , Alcoolismo/patologia , Animais , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Galactose/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Lipopolissacarídeos/toxicidade , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Ocludina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/metabolismo
11.
Arch Oral Biol ; 123: 105039, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33454419

RESUMO

OBJECTIVE: Prolonged mild stress due to tooth loss leads to morphologic and functional alterations of the hippocampus, as well as cognitive memory impairments in aged animals. An enriched environment improves stress-induced hippocampus-dependent cognitive impairments. The potential mechanisms underlying the beneficial effects of an enriched environment, however, remain unclear. In the present study, we investigated whether an enriched environment affects morphologic remodeling of the hippocampal myelin, synapses, and spatial learning deficits caused by tooth loss in aged senescence-accelerated mouse strain P8 (SAMP8) mice. DESIGN: SAMP8 mice (8 months old) with either teeth intact or teeth extracted were raised in a standard or enriched environment for three weeks. Spatial learning and memory ability was evaluated in a Morris water maze test. The morphologic features of the myelin sheath and synapses in the hippocampus were investigated by electron microscopy. RESULTS: Mice with tooth loss had a thinner myelin sheaths and shorter postsynaptic densities in the hippocampal CA1 region, and impaired hippocampus-dependent spatial learning ability. Exposure to an enriched environment ameliorated the hypomyelination and synaptic alterations, and spatial learning and memory impairments induced by tooth loss in aged SAMP8 mice. CONCLUSION: Our findings indicate that an enriched environment ameliorates hippocampal hypomyelination and synapse morphologic abnormalities, as well as learning deficits induced by tooth loss in aged SAMP8 mice.


Assuntos
Meio Ambiente , Hipocampo/fisiopatologia , Transtornos da Memória/etiologia , Bainha de Mielina , Sinapses/patologia , Perda de Dente/complicações , Animais , Aprendizagem em Labirinto , Camundongos
12.
J Ethnopharmacol ; 265: 113293, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32841698

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Kava extract (Piper methysticum) is a phytotherapic mainly used for the treatment of anxiety. Although the reported effects of Kava drinking improving psychotic symptoms of patients when it was introduced to relieve anxiety in aboriginal communities, its effects on models of psychosis-like symptoms are not investigated. AIM OF THE STUDY: To investigate the effects of Kava extract on behavioral changes induced by amphetamine (AMPH) and its possible relation with alterations in monoamine oxidase (MAO) activity. MATERIALS AND METHODS: Mice received vehicle or Kava extract by gavage and, 2 h after vehicle or AMPH intraperitoneally. Twenty-five minutes after AMPH administration, behavioral (elevated plus maze, open field, stereotyped behavior, social interaction and Y maze) and biochemical tests (MAO-A and MAO-B activity in cortex, hippocampus and striatum) were sequentially evaluated. RESULTS: Kava extract exhibited anxiolytic effects in plus maze test, increased the locomotor activity of mice in open field test and decreased MAO-A (in cortex) and MAO-B (in hippocampus) activity of mice. Kava extract prevented the effects of AMPH on stereotyped behavior and, the association between Kava/AMPH increased the number of entries into arms in Y maze test as well as MAO-B activity in striatum. However, Kava extract did not prevent hyperlocomotion induced by AMPH in open field test. The social interaction was not modified by Kava extract and/or AMPH. CONCLUSION: The results showed that Kava extract decreased the stereotyped behavior induced by AMPH at the same dose that promotes anxiolytic effects, which could be useful to minimize the psychotic symptoms in patients.


Assuntos
Anfetamina/farmacologia , Kava/química , Extratos Vegetais/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos
13.
J Ethnopharmacol ; 264: 113285, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32827660

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge (Danshen), a traditional Chinese medicine, has demonstrated in modern studies for its pharmacological activities in treatments of CNS disorders like insomnia, dysphoria. However, its application on anxiolytic effect from the ethanol extract of Salvia miltiorrhiza Bunge (SMEtOH) has not yet been reported. MATERIALS AND METHODS: This study investigated the anxiolytic effect of the SMEtOH using the elevated plus-maze test (EPM) and the hole-board test (HBT) with diazepam and buspirone as positive controls. Also, the spontaneous locomotor activity of mice had been investigated in the open field. Further, we have illustrated the anxiolytic mechanisms of SMEtOH with its influencing upon GABAergic and/or serotonergic nervous systems via a method that SMEtOH was co-administered with flumazenil, a benzodiazepine (BZD) antagonist, or a drug (WAY-100635), a selective 5HT1A receptor antagonist. RESULTS: In hole-board test, results presented that SMEtOH increased head-dip counts and duration time. On the other hand, a decrease in spontaneous locomotor activity was observed. In the EPM test, SMEtOH increased the percentage of open-arm entries and the percentage of time spent in open arms. However, when SMEtOH co-administered with flumazenil or WAY-100635, the anxiolytic effect of SMEtOH was significantly counteracted. CONCLUSION: From these results, we can conclude that the anxiolytic mechanism of SMEtOH is exerted through an activation of the BZD and 5HT1A receptors.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/psicologia , Medicamentos de Ervas Chinesas/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Salvia miltiorrhiza , Animais , Ansiolíticos/isolamento & purificação , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/uso terapêutico , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/fisiologia , Resultado do Tratamento
14.
Metabolism ; 116: 154463, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33309713

RESUMO

OBJECTIVES: GDI1 gene encodes for αGDI, a protein controlling the cycling of small GTPases, reputed to orchestrate vesicle trafficking. Mutations in human GDI1 are responsible for intellectual disability (ID). In mice with ablated Gdi1, a model of ID, impaired working and associative short-term memory was recorded. This cognitive phenotype worsens if the deletion of αGDI expression is restricted to neurons. However, whether astrocytes, key homeostasis providing neuroglial cells, supporting neurons via aerobic glycolysis, contribute to this cognitive impairment is unclear. METHODS: We carried out proteomic analysis and monitored [18F]-fluoro-2-deoxy-d-glucose uptake into brain slices of Gdi1 knockout and wild type control mice. d-Glucose utilization at single astrocyte level was measured by the Förster Resonance Energy Transfer (FRET)-based measurements of cytosolic cyclic AMP, d-glucose and L-lactate, evoked by agonists selective for noradrenaline and L-lactate receptors. To test the role of astrocyte-resident processes in disease phenotype, we generated an inducible Gdi1 knockout mouse carrying the Gdi1 deletion only in adult astrocytes and conducted behavioural tests. RESULTS: Proteomic analysis revealed significant changes in astrocyte-resident glycolytic enzymes. Imaging [18F]-fluoro-2-deoxy-d-glucose revealed an increased d-glucose uptake in Gdi1 knockout tissue versus wild type control mice, consistent with the facilitated d-glucose uptake determined by FRET measurements. In mice with Gdi1 deletion restricted to astrocytes, a selective and significant impairment in working memory was recorded, which was rescued by inhibiting glycolysis by 2-deoxy-d-glucose injection. CONCLUSIONS: These results reveal a new astrocyte-based mechanism in neurodevelopmental disorders and open a novel therapeutic opportunity of targeting aerobic glycolysis, advocating a change in clinical practice.


Assuntos
Desoxiglucose/farmacologia , Glicólise/efeitos dos fármacos , Inibidores de Dissociação do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Transtornos da Memória/prevenção & controle , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Desoxiglucose/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Glucose/metabolismo , Inibidores de Dissociação do Nucleotídeo Guanina/deficiência , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/genética , Camundongos , Camundongos Knockout
15.
Neural Netw ; 135: 115-126, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33383526

RESUMO

Modular Reinforcement Learning decomposes a monolithic task into several tasks with sub-goals and learns each one in parallel to solve the original problem. Such learning patterns can be traced in the brains of animals. Recent evidence in neuroscience shows that animals utilize separate systems for processing rewards and punishments, illuminating a different perspective for modularizing Reinforcement Learning tasks. MaxPain and its deep variant, Deep MaxPain, showed the advances of such dichotomy-based decomposing architecture over conventional Q-learning in terms of safety and learning efficiency. These two methods differ in policy derivation. MaxPain linearly unified the reward and punishment value functions and generated a joint policy based on unified values; Deep MaxPain tackled scaling problems in high-dimensional cases by linearly forming a joint policy from two sub-policies obtained from their value functions. However, the mixing weights in both methods were determined manually, causing inadequate use of the learned modules. In this work, we discuss the signal scaling of reward and punishment related to discounting factor γ, and propose a weak constraint for signaling design. To further exploit the learning models, we propose a state-value dependent weighting scheme that automatically tunes the mixing weights: hard-max and softmax based on a case analysis of Boltzmann distribution. We focus on maze-solving navigation tasks and investigate how two metrics (pain-avoiding and goal-reaching) influence each other's behaviors during learning. We propose a sensor fusion network structure that utilizes lidar and images captured by a monocular camera instead of lidar-only and image-only sensing. Our results, both in the simulation of three types of mazes with different complexities and a real robot experiment of an L-maze on Turtlebot3 Waffle Pi, showed the improvements of our methods.


Assuntos
Aprendizado Profundo , Punição , Reforço Psicológico , Recompensa , Robótica/métodos , Animais , Simulação por Computador , Aprendizagem em Labirinto/fisiologia , Motivação/fisiologia
16.
Sheng Li Xue Bao ; 72(6): 777-784, 2020 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-33349836

RESUMO

The objective of this study was to elucidate the effect of chronic stress (CS) on dopamine (DA) level and synaptic efficiency in the hippocampal dentate gyrus (DG) during spatial learning and memory. Sprague Dawley (SD) male rats were randomly divided into control group and CS group (n = 10). CS group was treated with chronic mild unpredictable stress, and control group did not receive any treatments. The levels of epinephrine and corticosterone (CORT) in serum were measured by using enzyme-linked immunosorbent assay (ELISA); the spatial learning and memory abilities of rats were measured by Morris water maze (MWM) test. Meanwhile, the amplitude of field excitatory postsynaptic potential (fEPSP) and concentration of DA in the DG region were determined by in vivo electrophysiology, microdialysis and HPLC techniques during MWM test in rats. After that, the DA D1 receptor (D1R) and its key downstream members in DG were examined by immunohistochemistry or Western blot assay. The results showed that the levels of epinephrine and CORT in the serum of the rats in CS group were significantly increased compared with those in the control group (P < 0.05). In CS group rats, the escape latency was significantly prolonged and the number of platform crossing was markedly decreased during MWM test, compared with those in control group (P < 0.05). Furthermore, the amplitude of fEPSP in the DG was not changed during MWM test in CS rats, while it was significantly increased on the 3rd day of MWM test in control group (P < 0.05). Compared with baseline or control group, CS group showed significantly increased DA level from the 1st to 3rd days of MWM test in the DG (P < 0.05). In addition, the protein expression of D1R was markedly up-regulated in the DG in CS group, while the protein expression levels of p-PKA, p-CREB and BDNF were significantly reduced, compared with those in control group. These results suggest that CS may impair spatial learning and memory abilities in rats through the enhancement of the DA levels in the hippocampal DG.


Assuntos
Dopamina , Aprendizagem Espacial , Animais , Giro Denteado , Hipocampo , Masculino , Aprendizagem em Labirinto , Ratos , Ratos Sprague-Dawley , Memória Espacial
17.
Elife ; 92020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33357380

RESUMO

The prefrontal cortex (PFC)'s functions are thought to include working memory, as its activity can reflect information that must be temporarily maintained to realize the current goal. We designed a flexible spatial working memory task that required rats to navigate - after distractions and a delay - to multiple possible goal locations from different starting points and via multiple routes. This made the current goal location the key variable to remember, instead of a particular direction or route to the goal. However, across a broad population of PFC neurons, we found no evidence of current-goal-specific memory in any previously reported form - that is differences in the rate, sequence, phase, or covariance of firing. This suggests that such patterns do not hold working memory in the PFC when information must be employed flexibly. Instead, the PFC grouped locations representing behaviorally equivalent task features together, consistent with a role in encoding long-term knowledge of task structure.


Assuntos
Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiologia , Memória Espacial/fisiologia , Animais , Objetivos , Masculino , Aprendizagem em Labirinto/fisiologia , Plasticidade Neuronal/fisiologia , Ratos , Ratos Long-Evans
18.
PLoS One ; 15(12): e0244725, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382797

RESUMO

The pathogenesis of human immunodeficiency virus associated neurological disorders is still not well understood, yet is known to result in neurological declines despite combination anti-retroviral therapy. HIV-1 transgenic (Tg26) mice contain integrated non-infectious HIV-1 proviral DNA. We sought to assess the integrity of neurocognitive function and sensory systems in HIV-1 Tg26 mice using a longitudinal design, in both sexes, to examine both age- and sex-related disease progression. General neurological reflexive testing showed only acclimation to repeated testing by all groups. Yet, at 2.5 months of age, female Tg26 +/- mice showed hyposensitivity to noxious hot temperatures, compared to wild types (both sexes) and male Tg26 +/- mice, that worsened by 10 months of age. Female Tg26 +/- mice had short-term spatial memory losses in novel object location memory testing at 2.5 and 7 months, compared to female wild types; changes not observed in male counterparts. Female Tg26 +/- mice showed mild learning deficits and short- and long-term spatial memory deficits in olfactory and visually cued Barnes Maze testing at 3 months of age, yet greater learning and memory deficits by 8 months. In contrast, male Tg26 +/- mice displayed no learning deficits and fewer spatial memory deficits (mainly heading errors in nontarget holes). Thus, greater sex-specific temperature hyposensitivity and spatial memory declines were observed in female HIV Tg26 +/- mice, than in male Tg26 +/- mice, or their wild type littermates, that increased with aging. Additionally, tibial bones were examined using ex vivo micro-CT after tissue collection at 11 months. Sex-dependent increases in bone volume and trabecular number were seen in males, matching their greater weights at this age. These results indicate that HIV-1 Tg26 mice is a promising model in which to study neuropathic mechanisms underlying peripheral pathology as well as cognitive deficits seen with HIV.


Assuntos
Temperatura Corporal/fisiologia , HIV-1/genética , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Memória Espacial/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Fatores Sexuais
19.
Anesth Analg ; 131(5): 1616-1625, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33079886

RESUMO

BACKGROUND: Anesthesia in pregnant rodents causes neurotoxicity in fetal and offspring rodents. However, the underlying mechanisms and targeted treatments remain largely to be determined. Isoflurane and propofol are among commonly used anesthetics. Thus, we set out to investigate whether propofol can mitigate the isoflurane-induced neurotoxicity in mice. METHODS: Pregnant C57BL/6 mice at gestational day 15 (G15) were randomly assigned to 4 groups: control, isoflurane, propofol, and isoflurane plus propofol. Levels of interleukin (IL)-6 and poly-ADP ribose polymerase (PARP) fragment were measured in the brains of G15 embryos, and levels of postsynaptic density (PSD)-95 and synaptophysin were determined in the hippocampal tissues of postnatal day 31 (P31) offspring using Western blotting and immunohistochemical staining. Learning and memory functions in P31 offspring were determined using a Morris water maze test. RESULTS: Isoflurane anesthesia in pregnant mice at G15 significantly increased brain IL-6 (222.6% ± 36.45% vs 100.5% ± 3.43%, P < .0001) and PARP fragment (384.2% ± 50.87% vs 99.59% ± 3.25%, P < .0001) levels in fetal mice and reduced brain PSD-95 (30.76% ± 2.03% vs 100.8% ± 2.25%, P < .0001) and synaptophysin levels in cornu ammonis (CA) 1 region (57.08% ± 4.90% vs 100.6% ± 2.20%, P < .0001) and dentate gyrus (DG; 56.47% ± 3.76% vs 99.76% ± 1.09%, P < .0001) in P31 offspring. Isoflurane anesthesia also impaired cognitive function in offspring at P31. Propofol significantly mitigated isoflurane-induced increases in brain IL-6 (117.5% ± 10.37% vs 222.6% ± 36.45%, P < .0001) and PARP fragment (205.1% ± 35.99% vs 384.2% ± 50.87%, P < .0001) levels in fetal mice, as well as reductions in PSD-95 (49.79% ± 3.43% vs 30.76% ± 2.03%, P < .0001) and synaptophysin levels in CA1 region (85.57% ± 2.97% vs 57.08% ± 4.90%, P < .0001) and DG (85.05% ± 1.87% vs 56.47% ± 3.76%, P < .0001) in hippocampus of P31 offspring. Finally, propofol attenuated isoflurane-induced cognitive impairment in offspring. CONCLUSIONS: These findings suggest that gestational isoflurane exposure in mice induces neuroinflammation and apoptosis in embryos and causes cognitive impairment in offspring. Propofol can attenuate these isoflurane-induced detrimental effects.


Assuntos
Anestésicos Inalatórios/toxicidade , Anestésicos Intravenosos/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Isoflurano/antagonistas & inibidores , Isoflurano/toxicidade , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/prevenção & controle , Propofol/farmacologia , Animais , Animais Recém-Nascidos , Química Encefálica/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Disfunção Cognitiva/psicologia , Proteína 4 Homóloga a Disks-Large/metabolismo , Feminino , Feto , Interleucina-6/metabolismo , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Poli(ADP-Ribose) Polimerase-1/metabolismo , Gravidez , Sinaptofisina/metabolismo
20.
Sci Total Environ ; 740: 140390, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32927557

RESUMO

Noise is considered one of the environmental hazards that negatively affect health. It can cause damage to the auditory, neurological, hormonal and cardiovascular systems, in addition to impairing psychological and cognitive functions. Considering the significance of vascular disturbances and oxidative stress in the development of the aforementioned negative effects, the purpose of our investigation was to study the level of high density lipoprotein-cholesterol (HDL-Cl), low density lipoprotein-cholesterol (LDL-Cl), and total cholesterol (TCl) in plasma, in addition to the behavioral characteristics of white rats, and the effects of the α2-adrenoblockers beditin and mesedin to reveal their antiatherogenic effect during noise exposure. The "Open field" and "Y-maze" tests were used in order to evaluate the behavioral states of the rats. Investigations were carried out on albino rats divided into 4 groups. The 1st group of rats served as a control. The 2nd, 3rd and 4th groups were exposed to 91 dBA of noise; the duration of exposure was 8 h per day for 60 days. The 3rd group was injected with beditin and the 4th group with mesedin, both intraperitoneally and repeatedly. According to our results, the chronic exposure to high-volume noise leads to the increase of plasma TCl and LDL-Cl concentrations and the decrease of HDL-Cl levels, resulting in increase of the atherogenic coefficient, which is estimated to be one of the main cardiovascular disease risk factors. The "Open field" and "Y-maze" tests revealed that chronic noise exposure caused disturbances in the behavioral activity, a noise duration-dependent delay in movement and orientation, increased anxiety and deficit in the animals' spatial memory. The administration of α2-adrenoblockers to the noise-exposed animals had a regulatoryeffects of varying intensities, depending on the medication used and the studied parameters under the conditions of chronic acoustic stress.


Assuntos
Ansiedade , Memória Espacial , Animais , Colesterol , Aprendizagem em Labirinto , Ratos , Ratos Wistar
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