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ABSTRACT. The immediate early gene exhibits activation markers in the nervous system consisting of ARC, EGR-1, and c-Fos and is related to synaptic plasticity, especially in the hippocampus. Immediate early gene expression is affected by physical exercise, which induces direct ARC, EGR-1, and c-Fos expression. Objective: To assess the impact of exercise, we conducted a literature study to determine the expression levels of immediate early genes (ARC, c-Fos, and EGR-1). Methods: The databases accessed for online literature included PubMed-Medline, Scopus, and ScienceDirect. The original English articles were selected using the following keywords in the title: (Exercise OR physical activity) AND (c-Fos) AND (Hippocampus), (Exercise OR physical activity) AND (ARC) AND (Hippocampus), (Exercise OR physical activity) AND (EGR-1 OR zif268) AND (Hippocampus). Results: Physical exercise can affect the expression of EGR-1, c-Fos, and ARC in the hippocampus, an important part of the brain involved in learning and memory. High-intensity physical exercise can increase c-Fos expression, indicating neural activation. Furthermore, the expression of the ARC gene also increases due to physical exercise. ARC is a gene that plays a role in synaptic plasticity and regulation of learning and memory, changes in synaptic structure and increased synaptic connections, while EGR-1 also plays a role in synaptic plasticity, a genetic change that affects learning and memory. Overall, exercise or regular physical exercise can increase the expression of ARC, c-Fos, and EGR-1 in the hippocampus. This reflects the changes in neuroplasticity and synaptic plasticity that occur in response to physical activity. These changes can improve cognitive function, learning, and memory. Conclusion: c-Fos, EGR-1, and ARC expression increases in hippocampal neurons after exercise, enhancing synaptic plasticity and neurogenesis associated with learning and memory.
RESUMO. O gene precoce imediato (GPI) exibe marcadores de ativação no sistema nervoso constituídos por ARC, EGR-1 e c-Fos e está relacionado à plasticidade sináptica, especialmente no hipocampo. A expressão do GPI é afetada pelo exercício físico, que induz a expressão direta de ARC, EGR-1 e c-Fos. Objetivo: Para avaliar o impacto do exercício físico, realizamos um estudo de literatura para determinar os níveis de expressão dos GPIs (ARC, c-Fos e EGR-1). Métodos: A base de dados utiliza literatura on-line, PubMed-Medline, Scopus e ScienceDirect. O artigo original em inglês usa as seguintes palavras-chave em seu título: (Exercise) AND (c-Fos) AND (Hippocampus), (Exercise) AND (ARC) AND (Hippocampus), (Exercise) AND (EGR-1) AND (Hippocampus). Resultados: O exercício físico pode afetar a expressão de EGR-1, c-fos e ARC no hipocampo, uma parte importante do cérebro envolvida na aprendizagem e na memória. O exercício físico aumenta a expressão do gene c-Fos; sua alta intensidade pode aumentar a expressão de c-Fos, indicando ativação neural. Além disso, a expressão do gene ARC aumentou devido ao exercício físico, onde ARC é um gene que desempenha um papel na plasticidade sináptica e na regulação da aprendizagem e da memória, nas mudanças na estrutura sináptica e no aumento das conexões sinápticas, enquanto o EGR-1 também desempenha um papel na plasticidade sináptica, uma mudança genética que afeta o aprendizado e a memória. De maneira geral, o exercício físico regular pode aumentar a expressão de ARC, c-fos e EGR-1 no hipocampo. Isso reflete as mudanças na neuroplasticidade e na plasticidade sináptica que ocorrem em resposta à atividade física. Essas mudanças podem melhorar a função cognitiva, o aprendizado e a memória. Conclusão: A expressão de c-Fos, EGR-1 e ARC aumenta após o exercício físico nos neurônios do hipocampo, para aumentar a plasticidade sináptica, a neurogênese associada ao aprendizado e à memória.
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ObjectiveTo investigate the mechanism of Baihuan Xiaoyao Decoction （Xiaoyaosan added with Lilii Bulbus and Albiziae Cortex） in alleviating depression-like behaviors of juvenile rats by regulating the polarization of microglia. MethodSixty juvenile SD rats were randomized into normal control， model， fluoxetine， and low-， medium-， and high-dose （5.36， 10.71， 21.42 g·kg-1， respectively） Baihuan Xiaoyao decoction groups. The rat model of juvenile depression was established by chronic unpredictable mild stress （CUMS）. The sucrose preference test （SPT） was carried out to examine the sucrose preference of rats. Forced swimming test （FST） was carried out to measure the immobility time of rats. The open field test （OFT） was conducted to measure the total distance， the central distance， the number of horizontal crossings， and the frequency of rearing. Morris water maze （MWM） was used to measure the escape latency and the number of crossing the platform. The immunofluorescence assay was employed to detect the expression of inducible nitric oxide synthase （iNOS， the polarization marker of M1 microglia） and CD206 （the polarization marker of M2 microglia）. Real-time polymerase chain reaction was employed to determine the mRNA levels of iNOS， CD206， pro-inflammatory cytokines ［tumor necrosis factor （TNF）-α， interleukin （IL）-1β， and IL-6］ and anti-inflammatory cytokines （IL-4 and IL-10） in the hippocampus. Western blotting was employed to determine the protein levels of iNOS and CD206 in the hippocampus. The levels of IL-4 and IL-6 in the hippocampus were detected by enzyme-linked immunosorbent assay. ResultCompared with the normal control group， the model rats showed a reduction in sucrose preference （P<0.05）， an increase in immobility time （P<0.05）， decreased motor and exploratory behaviors （P<0.05）， and weakened learning and spatial memory （P<0.05）. In addition， the model rats showed up-regulated mRNA and protein levels of iNOS and mRNA levels of IL-1β， IL-6， and TNF-α （P<0.05）. Compared with the model group， Baihuan Xiaoyao decoction increased the sucrose preference value （P<0.05）， shortened the immobility time （P<0.01）， increased the motor and exploratory behaviors （P<0.05）， and improved the learning and spatial memory （P<0.01）. Furthermore， the decoction down-regulated the positive expression and protein level of iNOS， lowered the levels of TNF-α， IL-1β， and IL-6 （P<0.01）， promoted the positive expression of CD206， and elevated the levels of IL-4 and IL-10 （P<0.01） in the hippocampus of the high dose group. Moreover， the high-dose Baihuan Xiaoyao decoction group had higher sucrose preference value （P<0.01）， shorter immobility time （P<0.01）， longer central distance （P<0.01）， stronger learning and spatial memory （P<0.01）， higher positive expression and protein level of iNOS （P<0.01）， lower levels of TNF-α， IL-1β， and IL-6 （P<0.05， P<0.01）， lower positive expression and mRNA level of iNOS （P<0.05）， and higher levels of IL-4 and IL-10 （P<0.05， P<0.01） than the fluoxetine group. ConclusionBaihuan Xiaoyao decoction can improve the depression-like behavior of juvenile rats by inhibiting the M1 polarization and promoting the M2 polarization of microglia in the hippocampus.
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ObjectiveTo explore the mechanism of Wenyang Jieyu prescription in regulating hippocampal neuron apoptosis and improving synaptic plasticity in the mouse model of depression induced by maternal separation combined with restraint stress. MethodThe mice on postnatal day 0 （PD0） were randomly assigned into a control group （n=10） and a modeling group （n=50）. Maternal separation combined with restraint stress was adopted to establish the mouse model of depression， and the modeled mice were randomized into model， Wenyang prescription， Jieyu prescription， Wenyang Jieyu prescription， and fluoxetine groups （n=10） on the weaning day （PD21）. From PD21 to PD111， the mice were fed with the diets mixed with corresponding medicines. The sucrose preference test， open field test， O-maze test， and novel object recognition test were then conducted to evaluate the depression， memory， and learning abilities of mice. Immunohistochemistry （IHC） was employed to measure the atomic absorbance （AA） of postsynaptic density protein 95 （PSD95） in the hippocampus. Terminal-deoxynucleoitidyl transferase-mediated nick-end labeling （TUNEL） was employed to detect the apoptosis of hippocampal neurons. Western blot was employed to determine the protein levels of brain-derived neurotrophic factor （BDNF）， phosphorylated tyrosine kinase receptor B/tyrosine kinase receptor B （p-TrkB/TrkB）， phosphorylated protein kinase B/protein kinase B （p-Akt/Akt）， phosphorylated mammalian target of rapamycin/mammalian target of rapamycin （p-mTOR/mTOR）， B-cell lymphoma-2 （Bcl-2）， Bcl-2-associated X （Bax）， cysteinyl aspartate-specific proteinase-3 （Caspase-3）， synaptophysin （Syn）， and PSD95. ResultCompared with the control group， the modeling decreased the sucrose preference rate， time spent in central zone within 5 min， total movement distance， time spent in the open arm， and cognition index （P<0.01）. Furthermore， it decreased the expression of PSD95， increased the neuron apoptosis in the hippocampus （P<0.01）， down-regulated the protein levels of BDNF， p-TrkB/TrkB， p-Akt/Akt， p-mTOR/mTOR， Bcl-2， PSD95， and Syn （P<0.01）， and up-regulated the protein levels of Bax and Caspase-3 （P<0.05） in the hippocampus. Compared with the model group， Wenyang Jieyu prescription and fluoxetine increased the sucrose preference rate， time spent in central zone within 5 min， total movement distance， time spent in the open arm， and cognition index （P<0.05， P<0.01）. Moreover， the drugs increased the expression of PSD95， reduced the neuron apoptosis （P<0.01）， up-regulated the protein levels of BDNF， p-TrkB/TrkB， p-Akt/Akt， p-mTOR/mTOR， Bcl-2， PSD95， and Syn （P<0.01）， and down-regulated the protein levels of Bax and Caspase-3 （P<0.01）. ConclusionWenyang Jieyu prescription outperformed Wenyang prescription and Jieyu prescription in the treatment of the depressive behavior induced by maternal separation combined with restraint stress in mice. It exerted the therapeutic effect by reducing the hippocampal neuron apoptosis and improving the synaptic plasticity via the BDNF/Akt/mTOR pathway.
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The prefrontal cortex and hippocampus may support sequential working memory beyond episodic memory and spatial navigation. This stereoelectroencephalography (SEEG) study investigated how the dorsolateral prefrontal cortex (DLPFC) interacts with the hippocampus in the online processing of sequential information. Twenty patients with epilepsy (eight women, age 27.6 ± 8.2 years) completed a line ordering task with SEEG recordings over the DLPFC and the hippocampus. Participants showed longer thinking times and more recall errors when asked to arrange random lines clockwise (random trials) than to maintain ordered lines (ordered trials) before recalling the orientation of a particular line. First, the ordering-related increase in thinking time and recall error was associated with a transient theta power increase in the hippocampus and a sustained theta power increase in the DLPFC (3-10 Hz). In particular, the hippocampal theta power increase correlated with the memory precision of line orientation. Second, theta phase coherences between the DLPFC and hippocampus were enhanced for ordering, especially for more precisely memorized lines. Third, the theta band DLPFC → hippocampus influence was selectively enhanced for ordering, especially for more precisely memorized lines. This study suggests that theta oscillations may support DLPFC-hippocampal interactions in the online processing of sequential information.
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Adulte , Femelle , Humains , Jeune adulte , Mâle , Épilepsie , Hippocampe , Mémoire à court terme , Rappel mnésique , Cortex préfrontal , Rythme thêtaRésumé
5-Hydroxytryptamine (5-HT) type 3 receptor (5-HT3R) is the only type of ligand-gated ion channel in the 5-HT receptor family. Through the high permeability of Na+, K+, and Ca2+ and activation of subsequent voltage-gated calcium channels (VGCCs), 5-HT3R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system (CNS). 5-HT3Rs are widely expressed in the medial prefrontal cortex (mPFC), amygdala (AMYG), hippocampus (HIP), periaqueductal gray (PAG), and other brain regions closely associated with anxiety reactions. They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions. 5-HT3Rs mediate the activation of the cholecystokinin (CCK) system in the AMYG, and the γ-aminobutyric acid (GABA) "disinhibition" mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons (IINs). In contrast, a 5-HT3R-induced GABA "disinhibition" mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects. 5-HT2R-mediated regulation of anxiety reactions are also activated by 5-HT3R-activated 5-HT release in the HIP and PAG. This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT3Rs. However, given the circuit specific modulation of 5-HT3Rs on emotion, systemic use of 5-HT3R agonism or antagonism alone seems unlikely to remedy anxiety, which deeply hinders the current clinical application of 5-HT3R drugs. Therefore, the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.
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Sérotonine , Récepteurs sérotoninergiques 5-HT3 , Anxiété , Neurones , Acide gamma-amino-butyriqueRésumé
ObjectiveTo investigate the effects of Lactobacillus rhamnosus GG （LGG）on microglia and Tau phosphorylation in the hippocampus of aged mice induced by anesthesia and surgery. MethodsA total of thirty 18-month-old C57BL/6J mice were randomly divided into three groups： control group， anesthesia surgery group， and anesthesia surgery + LGG group （10 mice/group）. The aged mice were oral administered by NS or LGG 109 CFU 150 μL once a day for 20 days. Then anesthesia surgery group and anesthesia surgery +LGG group received anesthesia with isoflurane and exploratory laparotomy. The activation status of microglia in the hippocampus was detected by immunofluorescence staining 12 hours after surgery. IL-6 concentration changes was detected by ELISA. The expression changes of Tau protein phosphorylation site （Tau-pS202/pT205） and total Tau protein was detected by western blot. ResultsThe microglia in the hippocampus of the control group were in a resting state， and the concentration of inflammatory factor IL-6 was （82.08 ± 12.07） pg/mL in control group. Compared to the control group， the anesthesia surgery group showed microglial cell Microglia were activated， the concentration of inflammatory factors IL-6 increased significantly to （123.7±5.72） pg/mL （P=0.000）， and the expression of phosphorylated Tau-pS202/pT205 increased the hippocampus （P=0.002）. Compared to the anesthesia surgery group， the activated microglia were inhibited， the concentration of IL-6 decreased to （96.68±9.59） pg/mL （P=0.008）， and the expression of phosphorylated Tau-pS202/pT205 reduced significantly in the AS+LGG group （P=0.002）. While there were no significant changes in total Tau protein among 3 groups. ConclusionPreoperative administration of probiotic LGG can alleviate the activation of microglia， increased secretion of inflammatory factors， and increased Tau protein phosphorylation levels in the hippocampus of elderly mice caused by anesthesia surgery.
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ObjectiveTo investigate the effects of epigallocatechin-3-gallate （EGCG） on learning and memory abilities of amygdala electrical kindling-induced epilepsy in rats and its mechanism. MethodMale SD rats were randomly divided into the normal group， model group， intervention group （model+25 mg·kg-1 EGCG）， and EGCG group （25 mg·kg-1 EGCG）. Rats in the EGCG group were only given EGCG intraperitoneal injection， those in the normal group were only given electrode implantation， and those in the other experimental groups were given amygdala electrical kindling stimulation to establish a chronic kindling epilepsy model. EGCG was injected intraperitoneally daily before electrical stimulation. Twenty-four hours after the last electrical stimulation， the escape latency and percentage of target quadrant were recorded by the Morris water maze. Twenty-four hours after the behavioral test， rats in each group were sacrificed by decapitation. The number of hippocampal neurons was observed by Nissl staining. The thickness of postsynaptic density in the hippocampus， synaptic cleft， length of active zone and the curvature of synaptic interface were observed by transmission electron microscopy （TEM）. The expressions of synapse-related proteins synaptotagmin （Syt）， postsynaptic density-95 （PSD-95） and Kalirin-7 in the hippocampus were examined by Western blot. ResultCompared with those in the normal group， the escape latency was significantly prolonged （P<0.05， P<0.01） and the target quadrant ratio was significantly decreased in the model group （P<0.05）. The number of hippocampus neurons decreased significantly （P<0.01）. The synaptic cleft of the hippocampus was widened significantly， and the length of active zone and the thickness of postsynaptic density were significantly decreased （P<0.05， P<0.01）. The expressions of synapse-related proteins Syt， PSD-95 and Kalirin-7 in the hippocampus were significantly decreased （P<0.05，P<0.01）. Compared with those in the model group， the escape latency was significantly shortened and the percentage of target quadrant was significantly increased in the intervention group （P<0.05， P<0，01）. The number of hippocampal neurons significantly increased （P<0.01）. The synaptic cleft of the hippocampus was significantly shortened， and the length of active zone and postsynaptic density were significantly increased （P<0.05， P<0.01）. The expressions of synaptic related proteins Syt， PSD-95 and Kalirin-7 were significantly increased （P<0.05， P<0.01）. ConclusionEGCG can effectively improve cognitive dysfunction after epilepsy. Its protective effect may be achieved by protecting the ultrastructure of hippocampal synapses and regulating the expressions of synapse-related proteins Syt， PSD-95 and Kalirin-7.
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Resumen Objetivo: En pacientes con enfermedad de Alzheimer (EA) se han descrito cambios neuropatológicos tempranos en la corteza entorrinal, que anteceden el compromiso temporomesial. La evaluación de la atrofia hipocampal mediante escalas visuales y volumetría son herramientas útiles en la valoración de pacientes con deterioro cognitivo. Nuestro objetivo es establecer la correlación entre la evaluación visual de la atrofia de la corteza entorrinal (ACE), la atrofia temporomesial (ATM) y el volumen hipocampal. Material y métodos: Estudio retrospectivo de corte transversal. Se incluyeron pacientes con queja cognitiva y resonancia magnética (RM) cerebral. Se utilizaron escalas visuales de ACE y ATM. Se midió el volumen hipocampal mediante el software volBrain 1.0. Resultados: Se incluyeron 48 pacientes, 31 eran mujeres (64,6%). Mediana de edad: 76,5 (RIQ: 69-83). La correlación entre las escalas visuales ACE y la ATM del lado derecho fue de 0,67 p < 0,0001) y del lado izquierdo de 0,69 (p < 0,0001). Encontramos correlación negativa moderada entre la ACE y el volumen hipocampal, del lado derecho fue de 0,59 (p < 0,0001) y del lado izquierdo de 0,42 (p = 0,003). Conclusión: La escala de ACE muestra moderada correlación con la escala de ATM y con el volumen hipocampal. Su uso podría aportar información valiosa para valoración de trastornos cognitivos.
Abstract Objective: In patients with Alzheimers disease (AD), early neuropathological changes in the entorhinal cortex have been described, which precede temporomesial involvement. The evaluation of hippocampal atrophy using visual scales and volumetry are useful tools in the assessment of patients with cognitive impairment. Our objective is to establish the correlation between the visual evaluations of entorhinal cortex atrophy (ECA), temporomesial atrophy (TMA), and hippocampal volume. Material and methods: Retrospective cross-sectional study. Patients with cognitive complaint and brain magnetic resonance imaging (MRI) were included. ACE and TMA visual scales were used. Hippocampal volume was measured using the volBrain 1.0 software. Results: Forty-eight patients were included, 31 were women (64.6%). Median age was 76.5 (IQR: 69-83). The correlation between ECA and TMA on the right side was 0.67 (p < 0.0001) and on the left side was 0.69 (p < 0.0001). We found a negative moderate correlation between ECA and hippocampal volume, on the right side it was 0.59 (p < 0.0001) and on the left side it was 0.42 (p = 0.003). Conclusion: The ECA scale shows high correlation with the TMA scale and moderate correlation with hippocampal volume. Its use could provide valuable information for the assessment of cognitive disorders.
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Introducción: En pacientes con epilepsia del lóbulo temporal refractarios que no son candidatos a cirugía, se debe considerar la estimulación eléctrica cerebral como una opción. Contenido: La estimulación eléctrica cerebral es la administración directa de pulsos eléctricos al tejido nervioso que permite modular un sustrato patológico, interrumpir la manifestación clínica de las crisis y reducir la gravedad de estas. Así, dada la importancia de estos tratamientos para los pacientes con epilepsia del lóbulo temporal refractaria, se hace una revisión de cuatro tipos de estimulación eléctrica. La primera, la del nervio vago, es una buena opción en crisis focales y crisis generalizadas o multifocales. La segunda, la del hipocampo, es más útil en pacientes no candidatos a lobectomía por riesgo de pérdida de memoria, con resonancia magnética normal o sin esclerosis mesial temporal. La tercera, la del núcleo anterior, es pertinente principalmente en pacientes con crisis focales, pero debe realizarse con precaución en pacientes con alto riesgo de cambios cognitivos, como los ancianos, o en los que presentan alteración del estado de ánimo basal, y, por último, la del núcleo centromediano se recomienda para el tratamiento crisis focales en el síndrome de Rasmussen y crisis tónico-clónicas en el síndrome de Lennox-Gastaut. Conclusiones: El interés por la estimulación eléctrica cerebral ha venido aumentando, al igual que las estructuras diana en las cuales se puede aplicar, debido a que es un tratamiento seguro y eficaz en pacientes con epilepsia del lóbulo temporal para controlar las crisis, pues disminuye la morbimortalidad y aumenta la calidad de vida.
Introduction: In patients with refractory temporal lobe epilepsy who are not candidates for surgery, electrical brain stimulation should be considered as another option. Contents: Electrical brain stimulation is the direct administration of electrical pulses to nerve tissue that modulates a pathological substrate, interrupts the clinical manifestation of seizures, and reduces their severity. Thus, given the importance of these treatments for patients with refractory temporal lobe epilepsy, four types of electrical stimulation are reviewed. The first, vagus nerve stimulation, is a good option in focal seizures and generalized or multifocal seizures. The second, hippocampal stimulation, is more useful in patients who are not candidates for lobectomy due to the risk of memory loss, with normal MRI or without mesial temporal sclerosis. The third, the anterior nucleus, is mainly in patients with focal seizures, but with caution in patients at high risk of cognitive changes such as the elderly, or in those with baseline mood disturbance and, finally, the centromedian nucleus is recommended for the treatment of focal seizures in Rasmussen's syndrome and tonic-clonic seizures in Lennox-Gastaut syndrome. Conclusions: the interest in brain electrical stimulation has been increasing as well as the target structures in which it can be applied because it is a safe and effective treatment in patients with temporal lobe epilepsy to control seizures, decreasing morbidity and mortality and increasing quality of life
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Noyaux antérieurs du thalamus , Noyaux intralaminaires du thalamus , Épilepsie temporale , Stimulation du nerf vague , Stimulation électrique , HippocampeRésumé
Introducción: Con la experiencia de los registros electroencefalográficos invasivos y el fracaso quirúrgico después de la cirugía, se ha hecho evidente que la epilepsia del lóbulo temporal es mucho más compleja de lo que se creía, y en la actualidad es considerada una enfermedad de redes anatomofuncionales y no de lesiones estructurales. Contenido: La información neurofisiológica e imagenológica actual permite concluir que en esta epilepsia están involucradas varias redes neuronales temporales y extratemporales que contribuyen a la extensión de la zona epileptógena. Una forma de entender el concepto de red epiléptica en la epilepsia del lóbulo temporal es a partir del conocimiento de la corteza piriforme. Varios estudios clínicos han mostrado que en pacientes con epilepsia del lóbulo temporal asociada a esclerosis hipocampal existe una disfunción interictal del procesamiento olfatorio que es más significativa, en comparación con pacientes con epilepsia focal extrahipocampal y controles sanos. Esta alteración es, probablemente, la consecuencia de una red neuronal disfuncional que se extiende más allá del hipocampo y que afecta a otras estructuras cercanas, incluida la corteza piriforme. Conclusión: En este artículo llevamos a cabo una revisión narrativa de la literatura con el objetivo de establecer un vínculo entre la corteza piriforme y la epileptogénesis del lóbulo temporal, y demostramos que esta enfermedad es la consecuencia de una disfunción de redes neuronales que no depende exclusivamente de una anormalidad estructural en el hipocampo o en estructuras cercanas.
Introduction: With the experience of invasive EEG recordings and surgical failure after surgery, it has become clear that temporal lobe epilepsy is much more complex than previously thought, and currently, is conceptualized as a disease of anatomical networks instead of structural lesions. Content: The current neurophysiological and imaging information allows us to conclude that several temporal and extratemporal anatomical networks are involved in this type of epilepsy. One way of understanding the concept of the epileptic network in temporal lobe epilepsy is from the knowledge of the piriform cortex. Several clinical studies have shown that in patients with temporal lobe epilepsy associated with hippocampal sclerosis exists an interictal dysfunction of olfactory processing that is more significant compared to patients with focal extra-hippocampal epilepsy and healthy controls. This alteration is probably the consequence of a dysfunctional neural network that extends beyond the hippocampus and affects other nearby structures, including the piriform cortex. Conclusion: In this article, we carry out a narrative review of the literature with the aim of establishing a link between the piriform cortex and temporal lobe epileptogenesis, demonstrating that this disease is the consequence of a dysfunctional network that does not depend exclusively of a hippocampal structural abnormality.
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Odorat , Lobe temporal , Cortex piriforme , Hippocampe , Épilepsies partiellesRésumé
Background: Exposure to high levels of aluminium (Al) leads to neurotoxicity. Hippocampus is one of the preferred sites of aluminium accumulation. Nevertheless, the role of Al in Alzheimer’s disease (AD) remains controversial and there is little proof directly interlinking Al to AD. Aims: The present study was undertaken to find out the occurrence of AD pathogenesis in Hippocampus under moderate aluminium exposure in rats. Materials and Methods: Adult rats were divided into control (C) and aluminium treated (E) groups having eight animal each. The rats in group E were exposed to aluminium 4.2 mg/kg body weight for three months with due approval from Institute Animal Ethics Committee. The hippocampus was processed for histopathological and electron microscopy observation. Results: Moderate Al intake produces significant reduction in the count of Pyramidal cells in hippocampus identified by shrunken cells as well as pyknosis in cell bodies. The differences between the cell numbers in all groups were found to be statistically significant (P < 0.05). Cornu Ammonis (CA) exhibited significantly reduced nissl bodies with a marked reduction in neuronal cell loss. Neurofibrillary tangle and plaques were not seen in the given dose of Al exposure. Electron microscopy from experimental group showed that the majority of neurons were disintegrating, the nuclear membrane has ruptured, and nucleoli appeared significantly distorted. The chromatin condensed and the mitochondria had disintegrated. Many vacuoles and lipofuscin sediment in cytoplasm, as compared to the control group noted. Conclusion: Present data demonstrated that moderate chronic aluminium exposure 4.2mg/kg body weight induced neurodegeneration in hippocampus but not significant for Alzheimer’s disease pathogenesis.
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Abstract Background Cognitive event-related potentials (ERPs) allow for lateralization of the epileptogenic zone (EZ) to estimate the reserve of memory in the contralateral non-epileptogenic hemisphere, and to investigate the prognosis of temporal lobe seizure control in unilateral temporal lobe epilepsy (TLE). Objective To define the accuracy of cognitive evoked anterior mesial temporal lobe (AMTL-N400) and P600 potentials in detecting the epileptogenic zone in temporal lobe epilepsy (TLE), and second, to evaluate the possibility of using them as markers of cognitive outcome. Methods The systematic review using Medline/PubMed, Embase, and Lilacs database was conducted in September 2021. Only articles published in English from 1985 to June 2021 were included. We searched for studies with: (1) depth intracranial electroencephalography (iEEG) recordings analysis of rhinal and hippocampal activity (2) correlations between ERP results obtained in the mesial temporal regions (AMTL-N400 and P600) and the epileptogenic zone. Results Six out of the seven studies included in this review defined the laterality of the epileptogenic zone (EZ) during presurgical investigation using ERPs. One study showed that the contralateral AMTL-N400 predicts seizure control. Another study found correlation between the amplitudes of the right AMTL-N400 and postoperative memory performance. Conclusions There is evidence that the reduced amplitude of the AMTL-N400 has high accuracy in identifying the epileptogenic zone, as it does in estimating the extent of seizure control and memory impairment in postoperative patients.
Resumo Antecedentes Potenciais relacionados a eventos (PREs) cognitivos permitem a lateralização da zona epileptogênica (ZE), estimar a reserva de memória no hemisfério contralateral não-epileptogênico, e estimar o prognóstico pós-operatório em pacientes com epilepsia do lobo temporal (ELT) unilateral quanto ao controle de crises. Objetivo Definir a acurácia dos potenciais evocados cognitivos do lobo temporal mesial anterior (LTMA-N400) e P600 na detecção da zona epileptogênica na epilepsia do lobo temporal (ELT), além de avaliar a possibilidade de usá-los como marcadores de desfecho cognitivo. Métodos A revisão sistemática foi realizada em setembro de 2021 usando as bases de dados Medline/PubMed, Embase e Lilacs. Apenas artigos publicados em inglês no período entre 1985 e junho de 2021 foram incluídos. Buscamos estudos com: (1) análises dos registros de electroencefalografia intracraniana (EEGi) da atividade rinal e hipocampal (2) correlações entre os resultados de PREs obtidos nas regiões temporais mesiais (AMTL-N400 e P600) e a zona epileptogênica. Resultados Seis dos sete estudos incluídos nesta revisão definiram a lateralidade da zona epileptogênica (ZE) durante a investigação pré-cirúrgica usando PREs. Um estudo mostrou que o AMTL-N400 contralateral prediz o controle das crises. Outro estudo encontrou correlação entre as amplitudes do AMTL-N400 direito e o desempenho da memória pós-operatória. Conclusões Há evidências de que a amplitude reduzida do AMTL-N400 tem alta precisão na identificação da zona epileptogênica, assim como na estimativa do prognóstico quanto ao controle de crises a longo prazo e prejuízo da memória em pacientes submetidos à cirurgia ressectiva.
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Abstract Introduction The CA1 region of the hippocampus has an important role in learning and memory. It has been shown that estrogen deficiency may reduce the synaptic density in the region and that hormone replacement therapy may attenuate the reduction. Objectives This study aimed to evaluate the effects of estrogen and raloxifene on the synaptic density profile in the CA1 region of the hippocampus in ovariectomized rats. Methods Sixty ovariectomized three-month-old virgin rats were randomized into six groups (n = 10). Treatments started either three days (early treatment) or sixty days (late treatment) after ovariectomy. The groups received propylene glycol vehicle (0.5 mL/animal/day), equine conjugated estrogens (50 μg/animal/day), or raloxifene (3 mg/kg/day) either early or late after ovariectomy. The drugs were administered orally by gavage for 30 days. At the end of the treatments, the animals were anesthetized and transcardially perfused with ether and saline solution. The brains were removed and prepared for analysis under transmission electron microscopy and later fixed. Results Results showed a significant increase in the synaptic density profile of the hippocampal CA1 region in both the early estrogen (0.534 ± 0.026 µ/m2) and the early raloxifene (0.437 ± 0.012 µ/m2) treatment groups compared to the early or late vehicle-treated control groups (0.338 ± 0.038 µ/m2 and 0.277 ± 0.015 µ/m2 respectively). Conclusions The present data suggest that the raloxifene effect may be lower than that of estrogen, even early or late treatment, on synaptic density in the hippocampus.
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Brain glucose hypometabolism and neuroinflammation are early pathogenic manifestations in neurological disorders. Neuroinflammation may also disrupt leptin signaling, an adipokine that centrally regulates appetite and energy balance by acting on the hypothalamus and exerting neuroprotection in the hippocampus. The Goto-Kakizaki (GK) rat is a non-obese type 2 diabetes mellitus (T2DM) animal model used to investigate diabetes-associated molecular mechanisms without obesity jeopardizing effects. Wistar and GK rats received the maintenance adult rodent diet. Also, an additional control group of Wistar rats received a high-fat and high-sugar diet (HFHS) provided by free consumption of condensed milk. All diets and water were provided ad libitum for eight weeks. Brain glucose uptake was evaluated by 2-deoxy-2-[fluorine-18] fluoro-D-glucose under basal (saline administration) or stimulated (CL316,243, a selective β3-AR agonist) conditions. The animals were fasted for 10-12 h, anesthetized, and euthanized. The brain was quickly dissected, and the hippocampal area was sectioned and stored at -80°C in different tubes for protein and RNA analyses on the same animal. GK rats exhibited attenuated brain glucose uptake compared to Wistar animals and the HFHS group under basal conditions. Also, the hippocampus of GK rats displayed upregulated leptin receptor, IL-1β, and IL-6 gene expression and IL-1β and the subunit of the transcription factor NF-κB (p-p65) protein expression. No significant alterations were detected in the hippocampus of HFHS rats. Our data indicated that a genetic predisposition to T2DM has significant brain deteriorating features, including brain glucose hypometabolism, neuroinflammation, and leptin signaling disruption in the hippocampal area.
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Amyloid fibrils are characteristic of several disorders including Alzheimer's disease (AD), with no cure or preventive therapy. Diminishing amyloid deposits using aromatic compounds is an interesting approach toward AD treatment. The present study examined the anti-fibrillogenic effects of silibinin and trans-chalcone in vitro, in vivo, and in silico on insulin amyloids. In vitro incubation of insulin at 37°C for 24 h induced amyloid formation. Addition of trans-chalcone and silibinin to insulin led to reduced amounts of fibrils as shown by thioflavin S fluorescence and Congo red absorption spectroscopy, with a better effect observed for silibinin. In vivo bilateral injection of fibrils formed by incubation of insulin in the presence or absence of silibinin and trans-chalcone or insulin fibrils plus the compounds in rats' hippocampus was performed to obtain AD characteristics. Passive avoidance (PA) test showed that treatment with both compounds efficiently increased latency compared with the model group. Histological investigation of the hippocampus in the cornu ammonis (CA1) and dentate gyrus (DG) regions of the rat's brain stained with hematoxylin-eosin and thioflavin S showed an inhibitory effect on amyloid aggregation and markedly reduced amyloid plaques. In silico, a docking experiment on native and fibrillar forms of insulin provided an insight onto the possible binding site of the compounds. In conclusion, these small aromatic compounds are suggested to have a protective effect on AD.
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Objective:To evaluate the role of Homer1a/metabotropic glutamate receptor 5 (mGluR5) signaling pathway in sleep deprivation-induced cognitive dysfunction in aged rats.Methods:One hundred and four SPF healthy male Sprague-Dawley rats, aged 22-24 months, weighing 320-360 g, were divided into 4 groups ( n=26 each) using a random number table method: normal control group (group Control), sleep deprivation+ vehicle group (group SD+ Vehicle), sleep deprivation+ mGluR5 forward allosteric agent CDPPB group (group SD+ CDPPB), and sleep deprivation+ mGluR5 antagonist MPEP group (group SD+ MPEP). A 48-h sleep deprivation model was developed by sleep-deprived rod method. At the beginning of developing the model and 24 h after developing the model, CDPPB 10 mg/kg, MPEP 10 mg/kg and the equal volume of 1% Tween 80 were intraperitoneally injected in group SD+ CDPPB, group SD+ MPEP and group SD+ Vehicle, respectively.Morris water maze and novel object recognition tests were conducted to evaluate cognitive function after development of the model. The expression of Homer1a and mGluR5 in the hippocampus was detected by Western blot, the dendritic spine density in the hippocampal CA1 region was detected by Golgi staining, and the field excitatory postsynaptic potential (fEPSP) slope in the hippocampal CA1 region was detected by isolated electrophysiology. Results:Compared with Control group, the number of crossing the original platform, time of staying at the target quadrant, and novel object recognition index at 1 and 24 h after training were significantly decreased, the expression of Homer1a in the hippocampus was up-regulated, the expression of mGluR5 in the hippocampus was down-regulated, and the density of dendritic spine and fEPSP slope in the hippocampal CA1 region were decreased in group SD+ Vehicle ( P<0.05). Compared with group SD+ Vehicle, the number of crossing the original platform, time of staying at target quadrant, and novel object recognition index at 1 and 24 h after training were significantly increased, the expression of mGluR5 in hippocampus was up-regulated, and the density of dendritic spines and fEPSP slope in the hippocampal CA1 region were increased in group SD+ MPEP( P<0.05), and no statistically significant change was found in the parameters mentioned above in group SD+ CDPPB ( P>0.05). Conclusions:Sleep deprivation impairs the synaptic plasticity of hippocampal neurons by regulating Homer1a/mGluR5 signaling pathway, and thus mediating the process of cognitive dysfunction in aged rats.
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Objective:To evaluate the effect of edaravone on the extracellular signal-regulated kinase (ERK)-cAMP responsive element binding protein (CREB) signaling pathway in the hippocampus of aged rats with postoperative cognitive dysfunction (POCD).Methods:Sixty SPF healthy male Sprague-Dawley rats, aged 20 months, weighing 650-700 g, were divided into 4 groups ( n=15 each) using a random number table method: control group (group C), POCD group (group P), edaravone group (group E) and ERK inhibitor group (group I). The rats received laparotomy under 3% sevoflurane anesthesia to prepare POCD model in P, E and I groups. Edaravone 3 mg/kg was intraperitoneally injected at 30 min before operation in E and I groups, ERK inhibitor PD98059 0.3 mg/kg was injected via the tail vein in group I. The open field test was performed at 3 days after operation to evaluate the spontaneous activity of rats, then Morris water maze test was performed to evaluate the cognitive function of rats on 3-7 days after operation. The rats were sacrificed after the end of Morris water maze test, and hippocampal tissues were obtained for determination of the expression of phosphorylated ERK (p-ERK), phosphorylated CREB (p-CREB), synaptophysin and postsynaptic density protein 95 (PSD-95) (by Western blot) and dendrite length and density of dendrites in hippocampal CA1 area (using Golgi staining). Results:Compared with group C, the escape latency was significantly prolonged after operation, the number of crossing the original platform was reduced, the expression of p-ERK, p-CREB, synaptophysin and PSD-95 was down-regulated, and the dendritic length and density of hippocampal neurons were reduced in group P ( P<0.05). Compared with group P, the escape latency was significantly shortened, the number of crossing the original platform was increased, the expression of p-ERK, p-CREB, synaptophysin and PSD-95 was up-regulated, and the dendritic length and density of hippocampal neurons were increased in group E ( P<0.05). Compared with group E, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, the expression of p-ERK, p-CREB, synaptophysin and PSD-95 was down-regulated, the dendritic length of hippocampal neurons was shortened, and the density of hippocampal neurons was decreased in group I( P<0.05). Conclusions:The mechanism by which edaravone improves POCD may be related to activating ERK/CREB signaling pathway and changing synaptic plasticity in hippocampal CA1 region in aged rats.
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Objective:To evaluate the effect of sleep fragmentation on postoperative cognitive dysfunction (POCD) and hippocampal glutaminergic metabolism in aged mice anesthetized with isoflurane.Methods:Forty healthy SPF-grade male C57BL/6J mice, aged 18 months, weighing 20-30 g, were divided into 4 groups ( n= 10 each) by the random number table method: normal control group (group C), sleep fragmentation group (group SF), isoflurane anesthesia/surgery group (group I/S), and sleep fragmentation plus isoflurane anesthesia/surgery group (group SF+ I/S). Group C did not received any treatment. Group SF received sleep fragmentation for 24 h. The right carotid artery exposure was performed under isoflurane anesthesia in group I/S. Group SF+ I/S received isoflurane anesthesia/right carotid artery exposure at 24 h after sleep fragmentation. The metabolic levels of glutamate (Glu), glutamine (Gln), Glu/Gln complex (Glx), and N-acetylaspartate (NAA) and their ratio to creatine (Cr) were measured by in vivo 9.4T hydrogen proton magnetic resonance spectroscopy at 2 h after anaesthesia. Y maze and Morris water maze tests were used to evaluate the cognitive function at 1-7 days after surgery. The mice were sacrificed after the behavioral testing, brain tissues were immediately obtained, and the number of Nissl bodies and density of dendritic spines in the hippocampal CA1 region were measured by Nissl staining and Golgi staining, respectively. Results:Compared with group C, the percentage of exploration time and shuttle times at the novel arm were significantly decreased, the number of crossing the original platform was decreased, the time of stay at the target quadrant was shortened, the ratios of Glu/Cr, Gln/Cr and Glx/Cr in the hippocampal CA1 region were increased, and the ratio of NAA/Cr was decreased, and the number of Nissl bodies and density of dendritic spines were decreased in SF, I/S and SF+ I/S groups ( P<0.05). Compared with group SF and group I/S, the percentage of exploration time and shuttle times at the novel arm were significantly decreased, the number of crossing the original platform was decreased, the time of stay at the target quadrant was shortened, the ratios of Glu/Cr and Glx/Cr in hippocampal CA1 region was increased, the ratio of NAA/Cr was decreased, and the number of Nissl bodies and density of dendritic spines were decreased in group SF+ I/S ( P<0.05). Conclusions:Sleep fragmentation exacerbates POCD in aged mice anesthetized with isoflurane, and the mechanism is related to nerve injury induced by abnormality in hippocampal glutaminergic metabolism excitability.
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Objective:To evaluate the role of orphan nuclear receptor Nur77 in tunicamycin(TM)-induced injury to hippocampal neurons and the relationship with endoplasmic reticulum stress in mice.Methods:Mouse HT22 cells were divided into 4 groups ( n=10 each) using a random number table method: control group (C group), Nur77 specific agonist Csn-B group (Csn-B group), endoplasmic reticulum stress inducer TM group (TM group), and TM+ Csn-B group. Cells in C group were cultured for 24 h under normal condition. In Csn-B group, Csn-B at a final concentration of 10 μg/ml was added to the culture medium, and the cells were incubated for 24 h. In TM group, TM at a final concentration of 200 ng/ml was added to the culture medium and the cells were incubated for 24 h to induce cell endoplasmic reticulum stress injury. Cells in TM+ Csn-B group were pretreated with Csn-B at a final concentration of 10 μg/ml for 15 min, then TM at a final concentration of 200 ng/ml was added, and the cells were co-incubated for 24 h. The cell viability was examined by CCK-8 assay kit after treatment in each group. The expression of endoplasmic reticulum stress-related protein CCAAT/enhancer-binding protein homologous protein (CHOP), glucose regulated protein 78 (GRP78)and apoptosis-associated protein Bcl-2, Bax, caspase-3 and cleaved-caspase-3 was detected by Western blot. Results:Compared with C group, the cell viability was significantly decreased, and the expression of CHOP, GRP78, Bax and cleaved-caspase-3 was up-regulated, and the expression of Bcl-2 and caspase-3 was down-regulated in TM group ( P<0.05 or 0.01). Compared with TM group, the cell viability was significantly increased, the expression of CHOP, GRP78, Bax and cleaved-caspase-3 was down-regulated, and the expression of Bcl-2 and caspase-3 was up-regulated in TM+ Csn-B group ( P<0.05 or 0.01). Conclusions:Orphan nuclear receptor Nur77 is involved in TM-induced injury to hippocampal neurons, which is related to activation of the endoplasmic reticulum stress in mice.
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Objective:To investigate the effect of electroacupuncture on calcium homeostasis in hippocampal neurons of mice with sepsis-associated encephalopathy (SAE).Methods:Twenty-four healthy male C57BL/6J mice, weighing 18-22 g, were divided into 4 groups ( n=6 each) using a random number table method: sham operation group (Sham group), SAE group, SAE plus electroacupuncture group (SAE+ EA group), and SAE plus sham electroacupuncture group (SAE+ SEA group). The virus carrying calcium ion (Ca 2+ ) fluorescent probes was injected and then an optical fiber was implanted into the hippocampal CA1 area to record the fluorescence signals of Ca 2+ . SAE was induced by cecal ligation and puncture in anesthetized mice at 3 weeks after administration. Starting from 3 days before surgery, Baihui and bilateral Quchi and bilateral Zusanli acupoints were stimulated for 30 min per day for 7 consecutive days in SAE+ EA group. In SAE+ SEA group, electroacupuncture was performed at the points 0.2 mm lateral to the corresponding acupoints without electrical stimulation. Open field tests were conducted at 5 days after surgery to record the number of rearing and changes in related Ca 2+ signals in hippocampal CA1 neurons. Novel object recognition tests were conducted at 6-7 days after surgery to record the recognition time and changes in related Ca 2+ signals in hippocampal CA1 neurons. Mice were sacrificed after the end of behavioral testing on 7 days after surgery, and brain tissues ipsilateral to the optical fiber implant were obtained and the fluorescence intensity of Ca 2+ in the hippocampal CA1 neurons was acquired using a fluorescent microscope. Results:Compared with Sham group, the number of rearing and amplitudes of related Ca 2+ signals in hippocampal CA1 neurons while rearing were significantly decreased in SAE group and SAE+ SEA group ( P<0.05), and no statistically significant changes were found in the parameters mentioned above in SAE+ EA group ( P>0.05), and the recognition index and amplitudes of related Ca 2+ signals while recognizing were significantly deceased, and the fluorescence intensity of Ca 2+ in hippocampal CA1 neurons was increased in SAE, SAE+ EA and SAE+ SEA groups ( P<0.05). Compared with SAE group and SAE+ SEA group, the number of rearing and amplitudes of related Ca 2+ signals in hippocampal CA1 neurons while rearing were significantly increased, the recognition index and amplitudes of related Ca 2+ signals in hippocampal CA1 neurons while recognizing were increased, and the fluorescence intensity of Ca 2+ in hippocampal CA1 neurons was decreased in SAE+ EA group ( P<0.05). There were no statistically significant differences in the parameters mentioned above between SAE group and SAE+ SEA group ( P>0.05). Conclusions:The mechanism by which electroacupuncture alleviates SAE may be related to regulation of Ca 2+ homeostasis in hippocampal neurons of mice.