Progress in application of adult endogenous neurogenesis in brain injury repair / 生理学报

Persistent neurogenesis exists in the subventricular zone (SVZ) of the ventricles and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus in the adult mammalian brain. Adult endogenous neurogenesis not only plays an important role in the normal brain function, but also has important significance in the repair and treatment of brain injury or brain diseases. This article reviews the process of adult endogenous neurogenesis and its application in the repair of traumatic brain injury (TBI) or ischemic stroke, and discusses the strategies of activating adult endogenous neurogenesis to repair brain injury and its practical significance in promoting functional recovery after brain injury.

Probiotics improves abnormal behavior and hippocampal injury in pregnant-stressed offspring rats / 中南大学学报(医学版)

OBJECTIVES@#During pregnancy, pregnant women are prone to stress reactions due to external stimuli, affecting their own health and fetal development. At present, there is no good treatment for the stress reactions from pregnant women during pregnancy. This study aims to explore the effect of probiotics on abnormal behavior and hippocampal injury in pregnant stressed offspring.@*METHODS@#SD pregnant rats were divided into a control group, a stress group, and a probiotics group, with 6 rats in each group. The control group was untreated; the stress group was given restraint stress on the 15th-20th day of pregnancy; the probiotics group was given both bifidobacterium trisporus capsules and restraint stress on the 15th-20th day of pregnancy, and the offspring continued to be fed with probiotics until 60 days after birth (P60). The offspring rats completed behavioral tests such as the open field test, the elevated plus maze test, the new object recognition test, and the barnes maze test at 60-70 d postnatally. Nissl's staining was used to reflect the injury of hippocampal neurons; immunohistochemical staining was used to detect the expression of microglia marker ionized calcium binding adapter molecule 1 (IBA-1) which can reflect microglia activation; ELISA was used to detect the content of plasma TNF-α and IL-1β; Western blotting was used to detect the expression of Bax, Bcl-2, and caspase-3.@*RESULTS@#The retention time of offspring rats in the stress group in the central area of the open field was significantly less than that in the control group (P<0.01), and the retention time of offspring rats in the probiotic group in the central area of the open field was significantly more than that in the stress group (P<0.05). The offspring rats in the stress group stayed in the open arm for a shorter time than the control group (P<0.05) and entered the open arm less often than the control group (P<0.01); the offspring rats in the probiotic group stayed in the open arm for a longer time than the stress group and entered the open arm more often than the stress group (both P<0.05). The discrimination ratio for new to old objects in the offspring rats of the stress group was significantly lower than that of the control group (P<0.01), and the discrimination ratio for new to old objects in the offspring rats of the probiotic group was significantly higher than that of the stress group (P<0.05). The offspring rats in the stress group made significantly more mistakes than the control group (P<0.05), and the offspring rats in the probiotic group made significantly fewer mistakes than the stress group (P<0.05). Compared with the control group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly reduced in the offspring rats of the stress group (all P<0.001), the number of activated microglia in DG area of hippocampus was significantly increased (P<0.01), the contents of TNF-α and IL-1β in peripheral blood were significantly increased (P<0.05 or P<0.01), the protein expression level of Bcl-2 was significantly down-regulated, and the protein expression levels of Bax and caspase-3 were significantly up-regulated (all P<0.001). Compared with the stress group, the numbers of Nissl bodies in CA1, CA3, and DG area were significantly increased in the probiotic group offspring rats (P<0.001, P<0.01, P<0.05), the number of activated microglia in the DG area of hippocampus was significantly reduced (P<0.05), and the TNF-α and IL-1β levels in peripheral blood were significantly decreased (both P<0.05), the protein expression level of Bcl-2 was significantly up-regulated, and the protein expression levels of Bax and caspase-3 were significantly down-regulated (all P<0.001).@*CONCLUSIONS@#Probiotic intervention partially ameliorated anxiety and cognitive impairment in rats offspring of pregnancy stress, and the mechanism may be related to increasing the number of neurons, inhibiting the activation of hippocampal microglia, and reducing inflammation and apoptosis.

Assessment of serotonergic system in formation of memory and learning / Avaliação do sistema serotonérgico na formação de memória e aprendizagem

Abstract We evaluated the involvement of the serotonergic system on memory formation and learning processes in healthy adults Wistar rats. Fifty-seven rats of 5 groups had one serotonergic nuclei damaged by an electric current. Electrolytic lesion was carried out using a continuous current of 2mA during two seconds by stereotactic surgery. Animals were submitted to learning and memory tests. Rats presented different responses in the memory tests depending on the serotonergic nucleus involved. Both explicit and implicit memory may be affected after lesion although some groups showed significant difference and others did not. A damage in the serotonergic nucleus was able to cause impairment in the memory of Wistar. The formation of implicit and explicit memory is impaired after injury in some serotonergic nuclei.

Resumo Avaliar a participação do sistema serotoninérgico em processos de formação de memória e aprendizagem em ratos Wistar adultos saudáveis. Cinquenta e sete ratos de 5 grupos tinham um núcleo serotoninérgico danificado por uma corrente elétrica. A lesão eletrolítica foi realizada utilizando uma corrente contínua de 2 mA durante dois segundos por cirurgia estereotáxica. Os animais foram submetidos a testes de aprendizagem e memória. Os ratos apresentaram respostas diferentes nos testes de memória, dependendo do núcleo serotoninérgica envolvido. A memória explícita e implícita pode ser afetada após a lesão, embora alguns grupos apresentaram diferença significativa e outros não. A lesão no núcleo serotoninérgico foi capaz de causar danos na memória de Wistar. A formação da memória implícita e explícita é prejudicada após a lesão em alguns núcleos serotoninérgicos.

Effects of maternal and postweaning high-fat diet exposure on the hippocampal functions and morphology / Efectos de la exposición de la dieta alta en grasa materna y pos lactancia en la función del hipocampo y la morfología

Unbalanced nutrition during perinatal period causes varying degrees of perturbations in the metabolism and cognitive functions of offspring. The aim of this study was to investigate effects of maternal and postweaning high-fat diet (HFD) exposure on the growth parameters, hippocampal functions and morphology of offspring in a sex-dependent manner. Spraque-Dawley rats were fed either standard (10 % fat) or saturated-fat (65 % fat) diet during their gestation and lactation period. After weaning, pups were sustained in same diet for 6 more weeks. Body mass index (BMI) of pups were monitored weekly, then spontaneous locomotor activities were recorded. Spatial learning and memory functions were analyzed by Morris Water Maze (MWM) test. Total volumetric changes of hippocampal subfields were estimated by Cavalieri method. HFD exposure produced sex-dependent alterations in BMI, serum lipid and activity levels. MWM results showed no significant difference among groups. However, retrieval indexes were higher in HFD-fed males. Total volumetric analysis of the dentate gyrus was comparable, but the pyramidal cell layer volume of HFD-fed males was lower than those of SD-fed males. Despite alterations in some growth and lipid parameters, maternal and perinatal exposure to HFD did not markedly affect cognitive functions and hippocampal morphology of offspring.

La nutrición desequilibrada durante el período perinatal causa diversos grados de perturbaciones en el metabolismo y las funciones cognitivas en neonatos. El objetivo de este estudio fue investigar los efectos de la exposición a una dieta alta en grasas (HFD) materna y posdestete en los parámetros de crecimiento, las funciones del hipocampo y la morfología de neonatos de una manera dependiente del sexo. Ratas SpragueDawley fueron alimentadas con dieta estándar (10 % grasa) o grasa saturada (65 % grasa) durante su período de gestación y lactancia. Después del destete, las crías se mantuvieron en la misma dieta durante 6 semanas. El índice de masa corporal (IMC) de las crías se controló semanalmente, luego se registraron las actividades locomotoras espontáneas. El aprendizaje espacial y las funciones de memoria se analizaron mediante la prueba Morris Water Maze (MWM). Los cambios volumétricos totales de los subcampos del hipocampo se estimaron mediante el método de Cavalieri. La exposición a HFD produjo alteraciones dependientes del sexo en el IMC, los niveles de lípidos séricos y los niveles de actividad. Los resultados de MWM no mostraron diferencias significativas entre los grupos. Sin embargo, los índices de recuperación fueron más altos en machos alimentados con HFD. El análisis volumétrico total del giro dentado fue comparable, pero el volumen de la capa de células piramidales de los machos alimentados con HFD fue menor que el de los machos alimentados con SD. A pesar de las alteraciones en algunos parámetros lipídicos y de crecimiento, la exposición materna y perinatal a HFD no afectó marcadamente las funciones cognitivas y la morfología del hipocampo de la descendencia.

Thiamine deficiency contributes to synapse and neural circuit defects

BACKGROUND: The previous studies have demonstrated the reduction of thiamine diphosphate is specific to Alzheimer's disease (AD) and causal factor of brain glucose hypometabolism, which is considered as a neurodegenerative index of AD and closely correlates with the degree of cognitive impairment. The reduction of thiamine diphosphate may contribute to the dysfunction of synapses and neural circuits, finally leading to cognitive decline. RESULTS: To demonstrate this hypothesis, we established abnormalities in the glucose metabolism utilizing thiamine deficiency in vitro and in vivo, and we found dramatically reduced dendrite spine density. We further detected lowered excitatory neurotransmission and impaired hippocampal long-term potentiation, which are induced by TPK RNAi in vitro. Importantly, via treatment with benfotiamine, Aß induced spines density decrease was considerably ameliorated. CONCLUSIONS: These results revealed that thiamine deficiency contributed to synaptic dysfunction which strongly related to AD pathogenesis. Our results provide new insights into pathogenesis of synaptic and neuronal dysfunction in AD.

Amnésia global transitória: epidemiologia, fisiopatologia, clínica e terapêutica / Global transient amnesia: epidemiology, pathophysiology, clinical features and therapeutics

A amnésia global transitória (AGT) é um quadro súbito de amnésia global, não acompanhada de outros déficits neurológicos, com duração de duas a 24 horas e cuja recuperação se dá espontaneamente. A incidência na população geral está estimada em 5-10 casos/100.000 pessoas/ano. Diferentes mecanismos fisiopatológicos, como fatores vasculares ou epiléticos, têm sido propostos para explicar a AGT, sendo consensual que haja acometimento transitório de regiões do hipocampo e do giro para-hipocampal. Além da amnésia anterógrada acompanhada por amnésia retrógrada, o paciente apresenta desorientação (tempo/espaço), estando preservadas outras habilidades cognitivas, como memória semântica e capacidades visuo-construtivas. Esses déficits tendem a remitir após 24h, sendo o prognóstico favorável na maioria dos casos. O diagnóstico diferencial de AGT é amplo e diversas condições clínicas, como eventos cérebro-vasculares, epilepsias, infecções e intoxicações podem mimetizá-lo, de modo que uma investigação clínica cuidadosa é imperativa. As recorrências não são frequentes nos quadros típicos. A AGT não requer tratamento específico, mas devem ser tratados fatores de risco cardiovascular eventualmente identificados durante a propedêutica de AGT. O clínico deve esclarecer o paciente a respeito do caráter benigno da AGT. Estudos com seguimento longitudinal dos pacientes são necessários para maior compreensão dos mecanismos fisiopatológicos da AGT e para melhor compreensão clínica e neuro- biológica dos déficits cognitivos apresentados por esses pacientes.

Global transient amnesia (GTA) is a clinical syndrome characterized by the sudden onset of anterograde and retrograde amnesia, without permanent neurological deficits, and which presents complete remission spontaneously within 2 to 24 hours. The incidence of GTA in the general population ranges from 5 to 10 cases per 100.000 individuals/ year. Different pathophysiological mechanisms have been proposed for GTA, such as vascular or epileptic factors, and it is consensual that there is transitory involvement of hippocampal and parahippocampal gyri in this condition. In addition to anterograde and retrograde amnesia, GTA patients typically present time-space disorientation, with the preservation of other cognitive abilities, such as semantic memory and visuoconstructive capacities. The differential diagnosis includes stroke, epilepsy, infections and intoxication, and a careful clinical investigation is essential to establish the GTA diagnosis. Recurrence is uncommon in typical cases and, in general, no specific treatment is required. However, clinical investigation of GTA may eventually disclose cardiovascular risk factors; these factors should be treated when identified. GTA is considered a benign condition, with good clinical and cognitive prognostics in most of the cases. More studies are needed to advance the current knowledge on the pathophysiology and on the neural basis of the transitory cognitive impairment observed in GTA.

Persistência de imagem de hiperintensidade no hipocampo após episódio de amnésia global transitória / Persistence of hyperintensity image in the hippocampus after an episode of transient global amnesia

A patogenia da amnésia global transitória (AGT) continua obscura. Estudos recentes demonstraram que, em alguns pacientes, a sequência de difusão (DWI) da ressonância magnética pode revelar apresença de sinal pequeno e pontual hipersinal no hipocampo, após a fase aguda do episódio. Esse sinal é principalmente visualizado nas primeiras 6 horas do início do evento, sendo 114 horas o tempo máximo que foi registrado até o momento. Estamos apresentando um caso em que essa imagem persistiu por 11 dias após o episódio. Discutem-se as conhecidas causas, as teorias da patogenia da AGT e a possível conexão entre um efeito vascular e a depressão alastrante, como relatada na enxaqueca com aura.

The pathogenesis of transient global amnesia (TGA) remains obscure.Recent studies revealed that small and punctate signal on diffusion-weighted imaging (DWI) in the hippocampus after the post-acute phase. This signal is mainly seen in the first 6 hours of the onset of the event, and so far the maximum time registered was 114 hours. We present one case where this image persisted for 11 days after the episode. Known causes, theories on pathogenesis of TGA and a possible relation between a vascular mechanism and the spreading depression, as reported in migraine with aura, are discussed.

Depressed nNOS expression during spine transition in the developing hippocampus of FMR1 KO mice

Nitric oxide (NO), synthesized as needed by NO synthase (NOS), is involved in spinogenesis and synaptogenesis. Immature spine morphology is characteristic of fragile X syndrome (FXS). The objective of this research was to investigate and compare changes of postnatal neuronal NOS (nNOS) expression in the hippocampus of male fragile X mental retardation 1 gene knockout mice (FMR1 KO mice, the animal model of FXS) and male wild-type mice (WT) at postnatal day 7 (P7), P14, P21, and P28. nNOS mRNA levels were analyzed by real-time quantitative PCR (N = 4-7) and nNOS protein was estimated by Western blot (N = 3) and immunohistochemistry (N = 1). In the PCR assessment, primers 5’-GTGGCCATCGTGTCCTACCATAC-3’ and 5’-GTTTCGAGGCAGGTGGAAGCTA-3’ were used for the detection of nNOS and primers 5’-CCGTTTCTCCTGGCTCAGTTTA-3’ and 5’-CCCCAATACCACATCATCCAT-3’ were used for the detection of β-actin. Compared to the WT group, nNOS mRNA expression was significantly decreased in FMR1 KO mice at P21 (KO: 0.2857 ± 0.0150, WT: 0.5646 ± 0.0657; P < 0.05). Consistently, nNOS immunoreactivity also revealed reduced staining intensity at P21 in the FMR1 KO group. Western blot analysis validated the immunostaining results by demonstrating a significant reduction in nNOS protein levels in the FMR1 KO group compared to the WT group at P21 (KO: 0.3015 ± 0.0897, WT: 1.7542 ± 0.5455; P < 0.05). These results suggest that nNOS was involved in the postnatal development of the hippocampus in FXS and impaired NO production may retard spine maturation in FXS.

Psychiatric comorbidities in temporal lobe epilepsy: possible relationships between psychotic disorders and involvement of limbic circuits / Comorbidades psiquiátricas na epilepsia do lobo temporal: possíveis relações entre desordens psicóticas e comprometimento de circuitos límbicos

OBJECTIVE: Mounting evidence suggests that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological and connectivity changes might contribute to the development of psychosis and to the potential neurobiological mechanisms that cause schizophrenia-like psychosis in TLE patients. METHODS: In this review, clinical and neuropathological findings, especially brain circuitry of the limbic system, were examined together to enhance our understanding of the association between TLE and psychosis. Finally, the importance of animal models in epilepsy and psychiatric disorders was discussed. CONCLUSIONS: TLE and psychiatric symptoms coexist more frequently than chance would predict. Damage and deregulation among critical anatomical regions, such as the hippocampus, amygdala, thalamus, and the temporal, frontal and cingulate cortices, might predispose TLE brains to psychosis. Studies of the effects of kindling and injection of neuroactive substances on behavior and electrophysiological patterns may offer a model of how limbic seizures in humans increase the vulnerability of TLE patients to psychiatric symptoms.

OBJETIVO: Existem cada vez mais evidências de que o sistema límbico está envolvido na patologia das comorbidades psiquiátricas em pacientes com epilepsia do lobo temporal (ELT). Nosso objetivo foi elaborar um desenho conceitual descrevendo como aspectos neuropatológicos e de conectividade podem contribuir para o desenvolvimento de psicose em pacientes com ELT. MÉTODOS: Nesta revisão, achados clínicos e neuropatológicos, e especialmente os aspectos da circuitaria límbica, foram examinados em conjunto para auxiliar nossa compreensão sobre a associação entre ELT e psicose. Achados em modelos animais de epilepsia e esquizofrenia também foram levados em consideração. CONCLUSÕES: ELT e comorbidades psiquiátricas coexistem com maior frequência que o predito pela associação ao acaso. Dano e desregulação entre estruturas anatômicas críticas, como hipocampo, amígdala, tálamo, e córtices temporal, frontal e cingulado podem predispor o cérebro com ELT à psicose. Estudos sobre efeitos comportamentais e eletrofisiológicos do abrasamento elétrico e injeções de substâncias neuroativas em modelos animais podem oferecer pistas sobre como crises límbicas em humanos aumentam a vulnerabilidade de pacientes com ELT a sintomas psiquiátricos.

Sex-dependent behavioral effects and morphological changes in the hippocampus after prenatal invasive interventions in rats: implications for animal models of schizophrenia

OBJECTIVES: Although schizophrenia affects both human genders, there are gender-dependent differences with respect to age of onset, clinical characteristics, course and prognosis of the disease. METHODS: To investigate sex-dependent differences in motor coordination and activity as well as in cognitive and social behavior, we repeatedly tested female (n = 14) and male (n = 12) Fisher rats (postnatal days, PD 56-174) that had received intracerebroventricular injections of kainic acid as well as female (n = 15) and male (n = 16) control animals. The hippocampus was examined histologically. RESULTS: Compared to male controls, in the alcove test both female controls and female animals with prenatal intervention spent less time in a dark box before entering an unknown illuminated area. Again, animals that received prenatal injection (particularly females) made more perseveration errors in the T-maze alternation task compared to controls. Female rats exhibited a higher degree of activity than males, suggesting these effects to be sex-dependent. Finally, animals that received prenatal intervention maintained longer lasting social contacts. Histological analyses showed pyramidal cells in the hippocampal area CA3 (in both hemispheres) of control animals to be longer than those found in treated animals. Sex-dependent differences were found in the left hippocampi of control animals and animals after prenatal intervention. CONCLUSION: These results demonstrate important differences between males and females in terms of weight gain, response to fear, working memory and social behavior. We also found sex-dependent differences in the lengths of hippocampal neurons. Further studies on larger sample sets with more detailed analyses of morphological changes are required to confirm our data.

Improvement in hippocampal kindling analysis through computational processing data / Aprimorando a análise do modelo de kindling hipocampal com o auxílio de processamento computacional

The kindling phenomenon is classically investigated in epileptology research. The present study aims to provide further information about hippocampal kindling through computational processing data. Adult Wistar rats were implanted with dorsal hippocampal and frontal neocortical electrodes to perform the experiment. The processing data was obtained using the Spike2 and Matlab softwares. An inverse relationship between the number of "wet dog shakes" and the Racine's motor stages development was found. Moreover it was observed a significant increase in the afterdischarge (AD) duration and its frequency content. The highest frequencies were, however, only reached at the beginning of behavioral seizures. During the primary AD, fast transients (ripples) were registered in both hippocampi superimposed to slower waves. This experiment highlights the usefulness of computational processing applied to animal models of temporal lobe epilepsy and supports a relevant role of the high frequency discharges in temporal epileptogenesis.

O fenômeno de kindling é classicamente utilizado no campo da epileptologia experimental. Este trabalho objetiva aprofundar a análise do modelo kindling hipocampal através de processamento computacional. Ratos wistar adultos receberam eletrodos hipocampais dorsais e neocorticais frontais para a realização do experimento. O processamento dos dados encontrados foi realizado pelos softwares Matlab e Spike2. Encontrou-se uma relação inversa entre wet dog shakes e o desenvolvimento dos estágios motores de Racine. A duração e o conteúdo de freqüência das pós-descargas hipocampais aumentaram durante o processo, sendo observadas descargas de alta freqüência (ripples) em ambos os hipocampos durante as pós-descargas primárias, superimpostas a ondas lentas. As mais altas freqüências, entretanto, foram apenas atingidas com o início das crises epilépticas. A utilização de sistemas computacionais para a confecção e análise do modelo de epilepsia temporal é ressaltada e reforça-se a relevância do papel das altas freqüências na epileptogênese temporal.

Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders

Hippocampal output is increased in affective disorders and is mediated by increased glutamatergic input via N-methyl-D-aspartate (NMDA) receptor and moderated by antidepressant treatment. Activation of NMDA receptors by glutamate evokes the release of nitric oxide (NO) by the activation of neuronal nitric oxide synthase (nNOS). The human hippocampus contains a high density of NMDA receptors and nNOS-expressing neurons suggesting the existence of an NMDA-NO transduction pathway which can be involved in the pathogenesis of affective disorders. We tested the hypothesis that nNOS expression is increased in the human hippocampus from affectively ill patients. Immunocytochemistry was used to demonstrate nNOS-expressing neurons in sections obtained from the Stanley Consortium postmortem brain collection from patients with major depression (MD, N = 15), bipolar disorder (BD, N = 15), and schizophrenia (N = 15) and from controls (N = 15). nNOS-immunoreactive (nNOS-IR) and Nissl-stained neurons were counted in entorhinal cortex, hippocampal CA1, CA2, CA3, and CA4 subfields, and subiculum. The numbers of Nissl-stained neurons were very similar in different diagnostic groups and correlated significantly with the number of nNOS-IR neurons. Both the MD and the BD groups had greater number of nNOS-IR neurons/400 µm² in CA1 (mean ± SEM: MD = 9.2 ± 0.6 and BD = 8.4 ± 0.6) and subiculum (BD = 6.7 ± 0.4) when compared to control group (6.6 ± 0.5) and this was significantly more marked in samples from the right hemisphere. These changes were specific to affective disorders since no changes were seen in the schizophrenic group (6.7 ± 0.8). The results support the current view of the NMDA-NO pathway as a target for the pathophysiology of affective disorders and antidepressant drug development.

Psiconeuroendocrinologia do transtorno de estresse pós-traumático / Psychoneuroendocrinology of posttraumatic stress disorder

OBJETIVO: Os autores realizaram uma revisão tradicional da literatura sobre os achados neurobiológicos das disfunções do eixo hipotálamo-pituitária-adrenal associados ao transtorno de estresse pós-traumático. MÉTODO: Os achados científicos relevantes foram descritos de acordo com a ordem cronológica de publicação e as características dos estudos, se eram pré-clínicos, relacio-nados à violência precoce como fator de risco e, finalmente, achados clínicos em pacientes portadores de transtorno de estresse pós-traumático. RESULTADOS: Foi encontrada uma literatura rica de achados a respeito de disfunções do eixo hipotálamo-pituitária-adrenal e transtorno de estresse pós-traumático. Os achados mostraram que o transtorno de estresse pós-traumático está associado a disfunções deste eixo e de estruturas cerebrais como o córtex pré-frontal, hipocampo e amídala. Os pacientes com transtorno de estresse pós-traumático apresentam um aumento da responsividade dos receptores de glicocorticóides, sugerindo que a inibição do feedback negativo tem um papel importante na fisiopatologia do quadro. Estudos pré-clínicos com modelos animais de deprivação maternal evidenciaram que, dependendo de quando o trauma ocorre, a disfunção do eixo será diferente. Os estudos clínicos mostram que o estresse precoce está relacionado ao desenvolvimento de psicopatologia durante a vida adulta. CONCLUSÕES: As disfunções do eixo hipotálamo-pituitária-adrenal relacionadas ao transtorno de estresse pós-traumático são evidências robustas e os mecanismos subjacentes a ele são cada vez mais compreendidos.

OBJECTIVE: To review the literature on neurobiological findings related to hypothalamic-pituitary-adrenal axis dysfunctions associated with posttraumatic stress disorder. METHOD: The relevant scientific findings were described according to the date of publication and the characteristics of the studies: preclinical studies, studies on early life violence as a risk factor, and clinical findings related to patients diagnosed with posttraumatic stress disorder. RESULTS: A rich literature on hypothalamic-pituitary-adrenal axis dysfunctions and posttraumatic stress disorder was found. Neurobiological findings showed that posttraumatic stress disorder is associated with hypothalamic-pituitary-adrenal axis dysfunctions and other brain-related structures: prefrontal cortex, hippocampus, and amygdala. Posttraumatic stress disorder patients have low plasma levels of cortisol and present increased responsivity of glucocorticoid receptors, suggesting that the inhibition of negative feedback plays a significant role in the disorder pathology. Preclinical studies using animal models of maternal deprivation showed that depending on the moment the trauma occurred during the development, different hypothalamic-pituitary-adrenal axis dysfunctions were produced. Clinical studies showed that early life stress is related to the development of psychopathologies during adulthood. CONCLUSIONS: There is robust evidence of hypothalamic-pituitary-adrenal axis dysfunctions related to posttraumatic stress disorder, and the mechanisms underlying this association are being better understood.

Linkage study of voltage-gated potassium channels in familial mesial temporal lobe epilepsy

Voltage-gated potassium channels (VGKCs) play a critical role in the regulation of neuronal excitability and have been implicated in some types of epilepsies. Recently, autoimmune limbic encephalitis (LE) was associated with antibodies against VGKC. In addition, patients with LE showed partial epilepsy and increased T2 signal abnormalities in limbic structures. We have reported familial mesial temporal lobe epilepsy (FMTLE) associated with hippocampal atrophy (HA) and other signs of mesial temporal sclerosis detected by magnetic resonance imaging (MRI). In order to investigate whether VGKC may be associated to HA present in FMTLE, we perform linkage study in these candidate genes. Seventy-three microsatellites markers were genotyped in different human autosomal chromosome. Two-point LOD scores did not show evidence for linkage with any of the microsatellite markers genotyped (Zmax ranging from 0.11to-9.53 at theta=0.00). In the present study, linkage data showed no evidence that VGKC are involved in the determination of HA in FMTLE.

Canais de potássio voltagem-dependentes (CPVD) desempenham importante papel na excitabilidade neuronal e estão associados a determinados tipos de epilepsia. Recentemente, um tipo de encefalite límbica autoimune (EL) foi associado com anticorpos contra CPVD. Além disso, há relatos de pacientes com EL e epilepsia parcial, além de hipersinal em regiões límbicas detectadas em imagens de ressonância magnética (IRM). Nós temos descrito a epilepsia de lobo temporal mesial familial (ELTMF) associada à atrofia hipocampal (AH) e outros sinais de esclerose mesial temporal observadas em IRM. Para investigar se os CPVD podem estar associados com a AH identificada na ELTMF, empregamos o estudo de ligação genética nesses genes candidatos. Setenta e três marcadores microssatélites foram genotipados e o LOD score de dois pontos mostrou Zmax variando de 0.11 a -9.53 para teta=0.00. No presente estudo, os dados obtidos com a análise de ligação mostram que os CPVD não estão envolvidos na determinação da AH na ELTMF.

Neurogênese e depressão: etiologia ou nova ilusão? / Neurogenesis and depression: etiology or new ilusion?

Novos neurônios continuam sendo gerados no cérebro adulto de diversas espécies animais. Muitos estudos têm demonstrado que diversos fatores ambientais, inclusive o estresse, influenciam a proliferacão de células hipocampais. Nesse sentido, a diminuicão da neurogênese induzida pelo estresse parece ser um importante fator na etiologia da depressão. Nessa revisão, a relacão entre neurogênese e depressão é enfatizada.

Estudo qualitativo da formação hipocampal de animais hipertensos com epilepsia / Qualitative study of hippocampal formation in hypertensive rats with epilepsy

O objetivo deste estudo foi avaliar qualitativamente o hipocampo e o giro dentado de ratos espontaneamente hipertensos (SHR) com epilepsia. MÉTODO: Os animais foram divididos em 4 grupos: Wistar controle, Wistar com epilepsia, SHR controle e SHR com epilepsia. Para indução da epilepsia, utilizamos o modelo da pilocarpina. Após os animais apresentarem crises espontâneas e recorrentes, o tecido cerebral dos animais foi encaminhado para análise histológica através dos métodos de Nissl e neo-Timm. RESULTADOS: Nos animais Wistar e SHR controle submetidos à coloração de Nissl observamos a manutenção das camadas celulares da formação hipocampal. Nos animais Wistar com epilepsia verificamos intensa morte neuronal na região CA1 e CA3 do hipocampo e no hilo do giro dentado. Nos animais SHR com epilepsia verificou-se a presença de atrofia hipocampal com dilatação do sistema ventricular. A coloração de neo-Timm revelou a presença de brotamento supragranular em todos os animais com epilepsia. CONCLUSÃO: Foram encontradas alterações neuropatológicas na citoarquitetura hipocampal nos animais Wistar com epilepsia e SHR com epilepsia, demonstrando que a epilepsia isoladamente ou associadamente à hipertensão são capazes de causar destruição neuronal.

effect of pistacia vera L. Gum extract on oxidative damage during experimental cerebral ischemia-reperfusion in rats

Oxygen free radicals may be implicated in the pathogenesis of ischemia reperfusion damage. As the antioxidant effects of some species of Pistacia have been reported, the protective effects of Pistacia vera L. gum extract [0.1-0.5 g/kg] on oxidative damage following cerebral ischemia were studied in rats. Ischemia was induced using four-vessel occlusion model and evaluated using measurement of malondialdehyde [MDA] and antioxidant power in hippocampus. MDA and antioxidant power were assayed with the thiobarbituric acid [TBA] and ferric reducing-antioxidant power [FRAP] tests, respectively. The extract and saline were administered intraperitoneally 10 min subsequent to ischemia. Results have shown that the MDA level increased by 47% and antioxidant power decreased by 117% in control group in comparison with sham-operated animals [P< 0.001]. Treatment with P. vera L. gum extract significantly and in a non-dose-dependent manner reduced brain MDA level by 63% [P<0.001] and increased antioxidant power of brain by 235% [P<0.001] in comparison to the controls. P. vera L. gum comprised of saponins, tannins, and flavonoids. According to these results, it is suggested that P. vera gum may exhibit neuroprotective effects against ischemia

Estresse, depressäo e hipocampo / Stress, depression and the hippocampus

A exposiçäo a fatores estressantes tem papel importante no desenvolvimento de transtornos depressivos. Os mecanismos envolvidos nesta relaçäo, no entanto, ainda säo pouco conhecidos, mas algumas evidências sugerem a participaçäo da formaçäo hipocampal: 1. o estresse pode causar alteraçöes plásticas no hipocampo, que incluem remodelaçäo dendrítica e inibiçäo de neurogênese. Drogas antidepressivas impendem estes efeitos, possivelmente por aumentarem a expressäo de fatores neurotróficos; 2. a facilitaçäo da neurotransmissäo serotoninérgica no hipocampo atenua conseqüências comportamentais do estresse e produz efeitos antidepressivos em modelos animais; 3. o antagonismo do principal neurotransmissor excitatório no hipocampo, o glutamato, produz efeitos semelhantes; 4. o hipocampo parece estar "hiperativo" em animais mais sensíveis em modelos de depressäo e em humanos resistentes à antidepressivos; 5. o hipocampo, em conjunto com o complexo amigdalar, parece ter papel fundamental na consolidaçäo e evocaçäo de memórias aversivas. Näo obstante estas evidências, o desafio futuro será o de tentar integrar os resultados destes diferentes campos (farmacológico, molecular, eletrofisiológico, clínico) em uma teoria unificadora sobre o papel do hipocampo na regulaçäo do humor e seus transtornos bem como nos efeitos de tratamentos antidepressivos