Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.230
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Biomed Res Int ; 2019: 9454913, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534969

RESUMO

Aim: To investigate the effect of crocin on the learning and memory acquisition of AD rats and its underlying mechanisms. Methods: A total of 48 healthy male SD rats were randomly divided into control group, AD model group, resveratrol group, and crocin group, with 12 rats per group. AD model was established by injecting Aß 25-35 to the lateral ventricle of rats, and thereafter the rats were administrated with resveratrol (40 mg/kg), crocin (40 mg/kg), or PBS daily for 14 days. Y-maze test and sucrose preference test were used to detect the learning and memory acquisition of rats. Neuronal apoptosis was detected by TUNEL staining and Western blot for apoptosis-related proteins Bax, Bcl-2, and Caspase-3. Immunofluorescence staining and Western blot tests were used to detect the expression of glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) in hippocampal CA1 region (Hippo) and prefrontal cortical neurons (PFC). Results: The learning and memory abilities of AD rats were significantly decreased, which was significantly rescued by resveratrol and crocin. The apoptotic cell number of Hippo and PFC neurons in AD model group was significantly higher than that in control group (P<0.01), while resveratrol and crocin significantly decreased the apoptotic cell number in AD group (P<0.01). Compared with the control group, the expression of Bcl2 in PFC and hippo of AD model group was significantly decreased (P<0.01), while those of Bax, Caspase3, GRP78, and CHOP were significantly increased (P<0.01). Resveratrol and crocin could significantly reverse the expression of these proteins in AD rats (P<0.05). Conclusion: Crocin can improve the learning and memory ability of AD rats possibly by reducing endoplasmic reticulum stress and neuronal apoptosis.


Assuntos
Doença de Alzheimer , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Carotenoides/farmacologia , Cognição/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/fisiopatologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Wistar
2.
Int J Mol Med ; 44(3): 939-948, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31524247

RESUMO

Chemokine C­X3­C motif ligand 1 (CX3CL1) and its sole receptor, CX3CR1, are known to be involved in neuronal damage/death following brain ischemia. In the present study, time­dependent expression changes of CX3CL1 and CX3CR1 proteins were investigated in the hippocampal CA1 field following 5 min of transient global cerebral ischemia (tgCI) in gerbils. To induce tgCI in gerbils, bilateral common carotid arteries were occluded for 5 min using aneurysm clips. Expression changes of CX3CL1 and CX3CR1 proteins were assessed at 1, 2 and 5 days after tgCI using western blotting and immunohistochemistry. CX3CL1 immunoreactivity was strong in the CA1 pyramidal cells of animals in the sham operation group. Weak CX3CL1 immunoreactivity was detected at 6 h after tgCI, recovered at 1 day after tgCI and disappeared from 5 days after tgCI. CX3CR1 immunoreactivity was very weak in CA1 pyramidal cells of the sham animals. CX3CR1 immunoreactivity in CA1 pyramidal cells was significantly increased at 1 days after tgCI and gradually decreased thereafter. On the other hand, CX3CR1 immunoreactivity was significantly increased in microglia from 5 days after tgCI. These results showed that CX3CL1 and CX3CR1 protein expression levels in pyramidal cells and microglia in the hippocampal CA1 field following tgCI were changed, indicating that tgCI­induced expression changes of CX3CL1 and CX3CR1 proteins might be closely associated with tgCI­induced delayed neuronal death and microglial activation.


Assuntos
Isquemia Encefálica/metabolismo , Região CA1 Hipocampal/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Receptor 1 de Quimiocina CX3C/genética , Morte Celular , Quimiocina CX3CL1/genética , Expressão Gênica , Gerbillinae , Imuno-Histoquímica , Masculino , Microglia/metabolismo , Neurônios/metabolismo
3.
Nat Commun ; 10(1): 3756, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434897

RESUMO

Under physiological conditions, strength and persistence of memory must be regulated in order to produce behavioral flexibility. In fact, impairments in memory flexibility are associated with pathologies such as post-traumatic stress disorder or autism; however, the underlying mechanisms that enable memory flexibility are still poorly understood. Here, we identify transcriptional repressor Wilm's Tumor 1 (WT1) as a critical synaptic plasticity regulator that decreases memory strength, promoting memory flexibility. WT1 is activated in the hippocampus following induction of long-term potentiation (LTP) or learning. WT1 knockdown enhances CA1 neuronal excitability, LTP and long-term memory whereas its overexpression weakens memory retention. Moreover, forebrain WT1-deficient mice show deficits in both reversal, sequential learning tasks and contextual fear extinction, exhibiting impaired memory flexibility. We conclude that WT1 limits memory strength or promotes memory weakening, thus enabling memory flexibility, a process that is critical for learning from new experiences.


Assuntos
Hipocampo/fisiologia , Memória/fisiologia , Proteínas Repressoras/metabolismo , Animais , Comportamento Animal/fisiologia , Região CA1 Hipocampal/metabolismo , Medo/fisiologia , Potenciação de Longa Duração/fisiologia , Masculino , Transtornos da Memória/patologia , Camundongos , Camundongos Knockout , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Proteínas Repressoras/genética
4.
Nutrients ; 11(9)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461895

RESUMO

Creatine plays a crucial role in developing the brain, so much that its genetic deficiency results in mental dysfunction and cognitive impairments. Moreover, creatine supplementation is currently under investigation as a preventive measure to protect the fetus against oxidative stress during difficult pregnancies. Although creatine use is considered safe, posing minimal risk to clinical health, we found an alteration in morpho-functional maturation of neurons when male rats were exposed to creatine loads during brain development. In particular, increased excitability and enhanced long-term potentiation (LTP) were observed in the hippocampal pyramidal neurons of weaning pups. Since these effects were observed a long time after creatine treatment had been terminated, long-lasting modifications persisting into adulthood were hypothesized. Such modifications were investigated in the present study using morphological, electrophysiological, and calcium imaging techniques applied to hippocampal Cornu Ammonis 1 (CA1) neurons of adult rats born from dams supplemented with creatine. When compared to age-matched controls, the treated adult offspring were found to retain enhanced neuron excitability and an improved LTP, the best-documented neuronal substrate for memory formation. While translating data from rats to humans does have limitations, our findings suggest that prenatal creatine supplementation could have positive effects on adult cognitive abilities.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Creatina/administração & dosagem , Suplementos Nutricionais , Plasticidade Neuronal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Células Piramidais/efeitos dos fármacos , Fatores Etários , Fenômenos Fisiológicos da Nutrição Animal , Animais , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/crescimento & desenvolvimento , Região CA1 Hipocampal/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Cognição/efeitos dos fármacos , Feminino , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Memória/efeitos dos fármacos , Gravidez , Células Piramidais/metabolismo , Ratos Sprague-Dawley , Fatores de Tempo
5.
Chin J Nat Med ; 17(6): 424-434, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262455

RESUMO

To examine the effects of Populus tomentiglandulosa (PT) extract on the expressions of antioxidant enzymes and neurotrophic factors in the cornu ammonis 1 (CA1) region of the hippocampus at 5 min after inducing transient global cerebral ischemia (TGCI) in gerbils, TGCI was induced by occlusion of common carotid arteries for 5 min. Before ischemic surgery, 200 mg·kg-1 PT extract was orally administrated once daily for 7 d. We performed neuronal nuclear antigen immunohistochemistry and Fluoro-Jade B staining. Furthermore, we determined in situ production of superoxide anion radical, expression levels of SOD1 and SOD2 as antioxidant enzymes and brain-derived neurotrophic factor (BDNF) and insulin-like growth factor I (IGF-I) as neurotrophic factors. Pretreatment with 200 mg·kg-1 PT extract prevented neuronal death (loss). Furthermore, pretreatment with 200 mg·kg-1 PT extract significantly inhibited the production of superoxide anion radical, increased expressions of SODs and maintained expressions of BDNF and IGF-I. Such increased expressions of SODs were maintained in the neurons after IRI. In summary, pretreated PT extract can significantly increase levels of SODs and protect the neurons against TGCI, suggesting that PT can be a useful natural agent to protect against TGCI.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Extratos Vegetais/administração & dosagem , Populus/química , Células Piramidais/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Superóxido Dismutase/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Região CA1 Hipocampal/metabolismo , Gerbillinae , Humanos , Fator de Crescimento Insulin-Like I/genética , Masculino , Fármacos Neuroprotetores/administração & dosagem , Células Piramidais/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/genética , Regulação para Cima/efeitos dos fármacos
6.
J Mol Neurosci ; 68(4): 590-602, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31054091

RESUMO

Erythropoietin, a multitarget molecule exhibited neuroprotective properties, especially against cerebral ischemia. However, little effort has been made to determinate both the administration pathway and doses that diminishes neuronal damage. In this study, we investigate the effect on CA1 region of different intranasal doses of rHuEPO (500, 1000 and 2500 IU/kg) applied in distinct post-damage times (1, 6, and 24 h) against ischemic cellular damage. Furthermore, most effective dose and time were used to evaluate gen and protein expression changes in 3 key molecules (EPO, EPOR, and ßcR). We established that CA1-region present histopathological damage in this ischemia model and that rHuEPO protects cells against damage, particularly at 1000 IU dose. Molecular data shows that EPO and EPOR gene expression are upregulated in a short term after damage treatment with rHuEPO (1 h); oppositely, BcR is upregulated in ischemic and Isc + EPO. Protein expression data displays no changes on EPO expression in evaluated times after treatment, but a tendency to increase 24 h after damage; in the opposite way, EPOR is upregulated significantly 6 h after treatment and this effect last until 24 h. So, our data suggest that a single intranasal dose of rHuEPO (1 h post-injury) provides histological neurorestoration in CA1 hippocampal region, even if we did not observe a dose-dependent dose effect, the medium dose evaluated (1000 UI/kg of b.w.) was more effective and sufficient for induces molecular changes that provides a platform for neuroprotection.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Região CA1 Hipocampal/efeitos dos fármacos , Eritropoetina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Administração Intranasal , Animais , Região CA1 Hipocampal/metabolismo , Eritropoetina/administração & dosagem , Eritropoetina/farmacologia , Humanos , Masculino , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar
7.
eNeuro ; 6(2)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058213

RESUMO

Microglia are in a privileged position to both affect and be affected by neuroinflammation, neuronal activity and injury, which are all hallmarks of seizures and the epilepsies. Hippocampal microglia become activated after prolonged, damaging seizures known as status epilepticus (SE). However, since SE causes both hyperactivity and injury of neurons, the mechanisms triggering this activation remain unclear, as does the relevance of the microglial activation to the ensuing epileptogenic processes. In this study, we use electroconvulsive shock (ECS) to study the effect of neuronal hyperactivity without neuronal degeneration on mouse hippocampal microglia. Unlike SE, ECS did not alter hippocampal CA1 microglial density, morphology, or baseline motility. In contrast, both ECS and SE produced a similar increase in ATP-directed microglial process motility in acute slices, and similarly upregulated expression of the chemokine C-C motif chemokine ligand 2 (CCL2). Whole-cell patch-clamp recordings of hippocampal CA1sr microglia showed that ECS enhanced purinergic currents mediated by P2X7 receptors in the absence of changes in passive properties or voltage-gated currents, or changes in receptor expression. This differs from previously described alterations in intrinsic characteristics which coincided with enhanced purinergic currents following SE. These ECS-induced effects point to a "seizure signature" in hippocampal microglia characterized by altered purinergic signaling. These data demonstrate that ictal activity per se can drive alterations in microglial physiology without neuronal injury. These physiological changes, which up until now have been associated with prolonged and damaging seizures, are of added interest as they may be relevant to electroconvulsive therapy (ECT), which remains a gold-standard treatment for depression.


Assuntos
Região CA1 Hipocampal , Movimento Celular/fisiologia , Eletrochoque , Inflamação , Microglia/fisiologia , Estado Epiléptico , Trifosfato de Adenosina/metabolismo , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiopatologia , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos , Feminino , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Microglia/metabolismo , Técnicas de Patch-Clamp , Receptores Purinérgicos P2X7/metabolismo , Estado Epiléptico/metabolismo , Estado Epiléptico/fisiopatologia , Regulação para Cima
8.
Neurosci Lett ; 705: 177-182, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31051223

RESUMO

In the present study, the effect of tramadol - an opioid painkiller drug with abuse potential- on amnesia and state-dependent memory and its interaction with the opioidergic system was investigated in male Wistar rats. Intra CA-1 administration of tramadol (0.5, 1, and 2 µg/rat) before training, dose-dependently decreased the learning ability in passive avoidance task. Amnesia induced by pre-train tramadol administration was significantly reversed by pre-test administration of tramadol (1 µg/rat). Pre-test administration of naltrexone (a µ-opioid receptor (MOR) antagonist) inhibited the effect of tramadol on memory retrieval. In addition, the pre-test administration of morphine (1 µg/rat, intra-CA1) also reversed memory impairment induced by pre-train tramadol administration. Although, pre-train morphine administration (1 µg/rat, intra-CA1), induced memory impairment reversed by pre-test tramadol administration (1 µg/rat, intra-CA1). In addition, the level of MOR in the hippocampus decreased in animals with memory impairment due to using tramadol in the training day. However, state-dependent retrieval using tramadol or cross state-dependent retrieval using morphine enhanced the MOR level in the hippocampus. The results of the study suggested that intra-CA1 tramadol administration induced memory impairment, improved by pre-test administration of either tramadol or morphine (MOR agonist). It could be concluded that tramadol is capable to induced state-dependent memory and also, it has a cross state-dependent memory with morphine in the hippocampus, done possibly through MOR.


Assuntos
Amnésia/induzido quimicamente , Região CA1 Hipocampal/efeitos dos fármacos , Memória/efeitos dos fármacos , Morfina/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Tramadol/farmacologia , Amnésia/prevenção & controle , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Relação Dose-Resposta a Droga , Interações de Medicamentos , Masculino , Rememoração Mental/efeitos dos fármacos , Microinjeções , Morfina/farmacocinética , Naltrexona/farmacologia , Ratos , Tramadol/antagonistas & inibidores
9.
Mol Brain ; 12(1): 32, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953515

RESUMO

Calcium/Calmodulin-dependent protein kinase II (CaMKII) plays a key role in the molecular mechanism of memory formation. CaMKII is known to be activated specifically in the activated spines during memory formation. However, it is unclear whether the specific activation of CaMKII is necessary for encoding information. Here, we overexpressed active form of CaMKII (CaMKII*) in the hippocampal CA1 region to activate CaMKII nonspecifically. Moreover, we examined context-discrimination performance of mice. We found that the mice with overexpression of CaMKII* showed impaired context-discrimination ability, while the contextual fear conditioning remained intact. These results indicate that spatial specificity of CaMKII activation is necessary for context discrimination.


Assuntos
Região CA1 Hipocampal/enzimologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Condicionamento Clássico , Animais , Região CA1 Hipocampal/metabolismo , Ativação Enzimática , Células HEK293 , Humanos , Camundongos
10.
Neurobiol Learn Mem ; 161: 175-191, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30991091

RESUMO

Arc (Activity-regulated cytoskeleton-associated protein) is an effector neuronal immediate-early gene (IEG) and has been closely linked to behaviorally-induced neuronal plasticity. The present studies examined the regionally-selective, dissociable patterns of Arc expression induced by Pavlovian trace fear conditioning, delay fear conditioning, and contextual fear conditioning as well as novel context exposure. This research was guided by anatomical studies identifying heterogeneity of connectivity across the transverse (CA1, CA3) and septo-temporal (dorsal vs. ventral) axes of the hippocampus; companion neuropsychological experiments suggest that these subregions likely play functionally dissociable roles in different forms of hippocampal-dependent learning. Hence the primary goal of the present study was to characterize the expression of Arc protein across both the septotemporal and transverse axes of the hippocampus induced by hippocampal dependent trace fear conditioning and compare these expression patterns to those induced by other fear conditioning paradigms. A second goal of these studies was to explore which specific paradigmatic features of the fear conditioning task itself are responsible for the observed patterns of Arc expression. The results of these studies suggest that, within the dorsal hippocampus, Arc expression in CA3 induced by trace fear conditioning may play a unique role in representing the context, while Arc protein expression within ventral CA3 may reflect CS processing. Arc protein expression in dorsal and ventral CA1 are likely not meaningfully involved in trace fear conditioning as there is either a lack of significant enhancement (dorsal CA1) or enhancement is not unique to subjects trained in trace fear conditioning (ventral CA1). The specific regional pattern of Arc protein enhancement induced by trace fear conditioning may reflect the unique temporal parameters of the task which critically engages the hippocampus in processing both contextual representations as well as the explicit CS. This additional hippocampal processing may account for the greater enhancement in Arc protein in dorsal and ventral CA3 for subjects trained in trace fear conditioning compared to novel context exposure, or contextual and delay fear conditioning.


Assuntos
Região CA1 Hipocampal/metabolismo , Região CA3 Hipocampal/metabolismo , Condicionamento Clássico/fisiologia , Proteínas do Citoesqueleto/metabolismo , Medo/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Animais , Comportamento Animal/fisiologia , Expressão Gênica/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
11.
Neurobiol Learn Mem ; 161: 149-157, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31002880

RESUMO

Transcriptional changes in the hippocampus are required for memory formation, and these changes are regulated by numerous post-translational modifications of chromatin-associated proteins. One of the epigenetic marks that has been implicated in memory formation is histone 3 lysine 4 trimethylation (H3K4me3), and this modification is found at the promoters of actively transcribed genes. The total levels of H3K4me3 are increased in the CA1 region of the hippocampus during memory formation, and genetic perturbation of the K4 methyltransferases and demethylases interferes with forming memories. Previous chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) analyses failed to detect changes in H3K4me3 levels at the promoters of memory-linked genes. Since the breadth of H3K4me3 marks was recently reported to be associated with the transcriptional outcome of a gene, we re-analyzed H3K4me3 ChIP-seq data sets to identify the role of H3K4me3 broad domains in CA1 neurons, as well as identify differences in breadth that occur during contextual fear conditioning. We found that, under baseline conditions, broad H3K4me3 peaks mark important learning and memory genes and are often regulated by super-enhancers. The peaks at many learning-associated genes become broader during novel environment exposure and memory formation. Furthermore, the important learning- and memory-associated lysine methyltransferases, Kmt2a and Kmt2b, are involved in maintaining H3K4me3 peak width. Our findings highlight the importance of analyzing H3K4me3 peak shape, and demonstrate that breadth of H3K4me3 marks in neurons of the hippocampus is regulated during memory formation.


Assuntos
Região CA1 Hipocampal/metabolismo , Condicionamento Clássico/fisiologia , Epigênese Genética/fisiologia , Histonas/metabolismo , Memória/fisiologia , Transcrição Genética/fisiologia , Ativação Transcricional/fisiologia , Animais , Medo/fisiologia , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Leucina Linfoide-Mieloide/metabolismo
12.
Pharmacol Rep ; 71(3): 449-456, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003156

RESUMO

BACKGROUND: Hippocampus and entorhinal cortex are key players of learning and memory. Despite their established role in memory processes, the contribution of muscarinic receptor activity in these brain regions during memory retrieval remains elusive. This study was aimed to assess the role of hippocampal CA1 and medial entorhinal cortex muscarinic receptors in memory retrieval. METHOD: Mice were implanted with bilateral cannulas in the hippocampus CA1 and medial entorhinal cortex. After recovery they were trained for Morris water maze test, novel object recognition test and contextual fear conditioning. Scopolamine was infused 10 min prior to retrieval test. RESULTS: Pre-test scopolamine infusion in hippocampal CA1 and medial entorhinal cortex significantly reduced overall exploration of objects (p<0.001). Similarly, pre-retrieval inactivation dorsal hippocampal CA1 and medial entorhinal cortex muscarinic activity caused significant impairment of spatial and fear memories retrieval (p<0.05). CONCLUSION: These findings showed vital role of muscarinic activity in retrieving hippocampal and entorhinal cortex dependent memories and suggest a possible target for treating retrograde amnesia.


Assuntos
Córtex Entorrinal/metabolismo , Medo/fisiologia , Hipocampo/metabolismo , Memória/fisiologia , Rememoração Mental/fisiologia , Receptores Muscarínicos/metabolismo , Animais , Região CA1 Hipocampal/metabolismo , Córtex Entorrinal/fisiologia , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Escopolamina/metabolismo
13.
Neuroreport ; 30(8): 544-549, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-30964765

RESUMO

Early exposure to anesthetics may interfere with synaptic development and lead to cognitive deficits. We previously demonstrated a decrease in vesicles docked at and within 100 nm from the presynaptic membrane in hippocampal nerve terminals of neonatal rats after anesthesia. Hence, we designed this study to assess the effects of neonatal anesthesia on synapsin 1 (Syn1) and synaptotagmin 1 (Syt1), two key regulators of vesicle docking and fusion. To test the link between changes in Syn1 and Syt1 and behavioral deficits observed after neonatal anesthesia, we also assessed retention memory and fear conditioning in adolescent rats after neonatal anesthesia. Pups received a combination of clinical anesthetics, then Syn1 and Syt1 mRNA and protein expression were determined at the peak (postnatal day 8, P8), part-way through (P12) and end of synaptogenesis (P24) in the CA1-subiculum by qPCR and western blotting. Anesthesia decreased Syn1 and Syt1 mRNA expression at P8 (P<0.01 and <0.001) and P12 (P=0.001 and 0.017), but not P24 (P=0.538 and 0.671), and impaired Syn1, p-Syn1, and Syt1 protein levels at P8 (P=0.038, 0.041, and 0.004, respectively), P12 (P<0.001, P=0.001, and P<0.0001), and P24 (P=0.025, 0.031, and 0.001). Anesthetic-challenged rats displayed deficient long-term retention memory (P=0.019) and hippocampus-dependent fear conditioning (P<0.001). These results suggest that anesthetics alter Syn1 and Syt1 during synapse assembly and maturation, raising the possibility that anesthetic interference with Syn1 and Syt1 could initiate changes in synaptic function that contribute to the cognitive deficits observed after neonatal anesthesia.


Assuntos
Anestésicos Inalatórios/administração & dosagem , Região CA1 Hipocampal/efeitos dos fármacos , Isoflurano/administração & dosagem , Sinapsinas/metabolismo , Vesículas Sinápticas/efeitos dos fármacos , Sinaptotagmina I/metabolismo , Animais , Animais Recém-Nascidos , Região CA1 Hipocampal/metabolismo , Feminino , Masculino , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Vesículas Sinápticas/metabolismo
14.
Neurobiol Learn Mem ; 161: 122-134, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30965113

RESUMO

A clue to hippocampal function has been the discovery of place cells, leading to the 'spatial map' theory. Although the firing attributes of place cells are well documented, little is known about the organization of the spatial map. Unit recording studies, thus far, have reported a low coherence between neighboring cells and geometric space, leading to the prevalent view that the spatial map is not topographically organized. However, the number of simultaneously recorded units is severely limited, rendering construction of the spatial map nearly impossible. To visualize the functional organization of place cells, we used the activity-dependent immediate-early gene Zif268 in combination with behavioral, pharmacological and electrophysiological methods, in mice and rats exploring an environment. Here, we show that in animals confined to a small part of a maze, principal cells in the CA1/CA3 subfields of the dorsal hippocampus immunoreactive (IR) for Zif268 adhere to a 'cluster-type' organization. Unit recordings confirmed that the Zif268 IR clusters correspond to active place cells, while blockade of NMDAR (which alters place fields) disrupted the Zif268 IR clusters. Contrary to the prevalent view that the spatial map consists of a non-topographic neural network, our results provide evidence for a 'cluster-type' functional organization of hippocampal neurons encoding for space.


Assuntos
Região CA1 Hipocampal , Região CA3 Hipocampal , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Aprendizagem em Labirinto/fisiologia , Rede Nervosa , Células de Lugar , Percepção Espacial/fisiologia , Animais , Comportamento Animal/fisiologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/citologia , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/fisiologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/citologia , Rede Nervosa/metabolismo , Rede Nervosa/fisiologia , Células de Lugar/citologia , Células de Lugar/metabolismo , Células de Lugar/fisiologia , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
15.
Nat Commun ; 10(1): 1193, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30867420

RESUMO

Amyloid ß (Aß) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer's disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aß production. High nanomolar synthetic oligomeric Aß42 also suppresses Pr at the SC-CA1 synapse in wild-type mice. This Aß-induced suppression of Pr is mainly due to an mGluR5-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PIP2) in axons. Selectively inhibiting Aß-induced PIP2 hydrolysis in the CA3 region of the hippocampus strongly prevents oligomeric Aß-induced suppression of Pr at the SC-CA1 synapse and rescues synaptic and spatial learning and memory deficits in APP/PS1 mice. These results first reveal the presynaptic mGluR5-PIP2 pathway whereby oligomeric Aß induces early synaptic deficits in AD.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Região CA1 Hipocampal/fisiopatologia , Fragmentos de Peptídeos/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Sinapses/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Animais , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Cognição/fisiologia , Modelos Animais de Doenças , Embrião de Mamíferos , Humanos , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/genética , Presenilina-1/genética , Presenilina-1/metabolismo , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/patologia , Cultura Primária de Células , Multimerização Proteica , Células Piramidais/metabolismo , Células Piramidais/patologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Sinapses/patologia
16.
Mol Neurobiol ; 56(9): 6566-6580, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30874972

RESUMO

A distinct feature of the hippocampus of the brain is its unidirectional tri-synaptic pathway originating from the entorhinal cortex and projecting to the dentate gyrus (DG) then to area CA3 and subsequently, area CA1 of the Ammon's horn. Each of these areas of the hippocampus has its own cellular structure and distinctive function. The principal neurons in these areas are granule cells in the DG and pyramidal cells in the Ammon's horn's CA1 and CA3 areas with a vast network of interneurons. This review discusses the fundamental differences between the CA1 and DG areas regarding cell morphology, synaptic plasticity, signaling molecules, ability for neurogenesis, vulnerability to various insults and pathologies, and response to pharmacological agents.


Assuntos
Região CA1 Hipocampal/metabolismo , Giro Denteado/metabolismo , Envelhecimento/fisiologia , Peptídeos beta-Amiloides/metabolismo , Animais , Cálcio/metabolismo , Humanos , Plasticidade Neuronal
17.
Molecules ; 24(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897756

RESUMO

Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).


Assuntos
Isquemia Encefálica/tratamento farmacológico , Ginsenosídeos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Panax/química , Animais , Isquemia Encefálica/induzido quimicamente , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Cobalto/toxicidade , Masculino , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Células PC12 , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/induzido quimicamente , Traumatismo por Reperfusão/tratamento farmacológico , Sirtuína 1/metabolismo , Receptor 4 Toll-Like/metabolismo
18.
Proc Natl Acad Sci U S A ; 116(15): 7477-7482, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30910984

RESUMO

The hippocampus plays a critical role in episodic memory: the sequential representation of visited places and experienced events. This function is mirrored by hippocampal activity that self organizes into sequences of neuronal activation that integrate spatiotemporal information. What are the underlying mechanisms of such integration is still unknown. Single cell activity was recently shown to combine time and distance information; however, it remains unknown whether a degree of tuning between space and time can be defined at the network level. Here, combining daily calcium imaging of CA1 sequence dynamics in running head-fixed mice and network modeling, we show that CA1 network activity tends to represent a specific combination of space and time at any given moment, and that the degree of tuning can shift within a continuum from 1 day to the next. Our computational model shows that this shift in tuning can happen under the control of the external drive power. We propose that extrinsic global inputs shape the nature of spatiotemporal integration in the hippocampus at the population level depending on the task at hand, a hypothesis which may guide future experimental studies.


Assuntos
Região CA1 Hipocampal/metabolismo , Memória/fisiologia , Modelos Neurológicos , Rede Nervosa/metabolismo , Neurônios/metabolismo , Animais , Região CA1 Hipocampal/citologia , Camundongos , Rede Nervosa/citologia , Neurônios/classificação
19.
Brain Behav ; 9(5): e01265, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30912298

RESUMO

INTRODUCTION: Perineuronal nets (PNNs) are extracellular matrices that encompass parvalbumin-expressing parvalbumin positive (PVALB+) fast-spiking inhibitory interneurons where they protect and stabilize afferent synapses. Recent observations that gonadal hormones influence PVALB+ neuron development suggest that PNN regulation may be sexually dimorphic. Sex differences in PNN abundance and complexity have been reported in sexually dimorphic nuclei in zebra finch brains; however, corresponding differences in mammalian brains have not been investigated. METHODS: In this study we assessed the number of cortical and hippocampal PNNs in juvenile and young adult male and female rats using fluorescent immunohistochemistry for PVALB and the PNN marker Wisteria Floribunda Lectin. RESULTS: We report here that PNNs are numerous and well developed in hippocampal cornu ammonis-1 of adult males but are lower in juvenile and possibly adult females. No significant differences were observed between sexes in cornu ammonis-3 or adjacent neocortex. There was an observed developmental difference in the neocortex as juveniles had more PVALB+ cells, but fewer PNN+ cells, than adults. CONCLUSIONS: Because PNNs are integral for several hippocampal-mediated learning and memory tasks, these observations have potential sex-dependent translational implications for clinical strategies targeting cognitive dysfunction.


Assuntos
Interneurônios/fisiologia , Parvalbuminas/metabolismo , Caracteres Sexuais , Fatores Etários , Animais , Comportamento Animal/fisiologia , Região CA1 Hipocampal/metabolismo , Matriz Extracelular/metabolismo , Feminino , Imuno-Histoquímica , Masculino , Ratos , Lobo Temporal/metabolismo
20.
Neurosci Lett ; 701: 65-70, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-30742936

RESUMO

CA1 hippocampal expression of α4ßδ GABAA receptors (GABARs) increases at the onset of puberty in female mice, an effect dependent upon the decline in hippocampal levels of the neurosteroid THP (3α-OH-5α-pregnan-20-one) which occurs at this time. The present study further characterized the mechanisms underlying α4ßδ expression, assessed in vivo. Blockade of pubertal levels of 17ß-estradiol (E2) (formestane, 0.5 mg/kg, i.p. 3 d) reduced α4 and δ expression by 75-80% (P < 0.05) in CA1 hippocampus of female mice, assessed using Western blot techniques. Conversely, E2 administration increased α4 and δ expression by 50-100% in adults, an effect enhanced by more than 2-fold by concomitant administration of the 5α-reductase blocker finasteride (50 mg/kg, i.p., 3d, P < 0.05), suggesting that both declining THP levels and increasing E2 levels before puberty trigger α4ßδ expression. This effect was blocked by ICI 182,780 (20 mg/kg, s.c., 3 d), a selective blocker of E2 receptor-α (ER-α). These results suggest that both the rise in circulating levels of E2 and the decline in hippocampal THP levels at the onset of puberty trigger maximal levels of α4ßδ expression in the CA1 hippocampus.


Assuntos
Região CA1 Hipocampal/metabolismo , Estradiol/farmacologia , Pregnanolona/análogos & derivados , Receptores de GABA-A/metabolismo , Androstenodiona/análogos & derivados , Androstenodiona/farmacologia , Animais , Inibidores da Aromatase/farmacologia , Antagonistas de Estrogênios , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Pregnanolona/antagonistas & inibidores , Pregnanolona/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA