Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity

Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations (‘‘TH– Vglut2 Class1’’) also expressed the dopamine transporter (DAT) gene while one did not ("TH–Vglut2 Class2"), and the remaining population did not express TH at all ("TH-Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area

Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity

Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations (‘‘TH– Vglut2 Class1’’) also expressed the dopamine transporter (DAT) gene while one did not ("TH–Vglut2 Class2"), and the remaining population did not express TH at all ("TH-Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area

A Neuropsychological Study Comparing Patients Infected With HCV and HBV Without Psychiatric Comorbidities

Hepatitis C is one of the most common chronic infectious diseases worldwide, with well-documented extra-hepatic manifestations, such as a broad number of cognitive deficits. These impairments may be explained by psychiatric comorbidities, which have not been investigated properly in the literature. In order to elucidate a specific hepatitis C virus (HCV) induced cognitive impairment not related to mental disorders, neuropsychological performance of patients infected with HCV was compared with that of patients infected with hepatitis B virus cognitive impairment, especially psychiatric comorbidities. A total of 33 patients infected with HCV and 22 patients infected with HBV were included in the study. There were no significant differences between the two groups with regard to age or years of education. The group of patients infected with HCV performed significantly worse on visuo-spatial memory tasks after adjusting for years of education and age. There were no significant differences between patients infected with HCV and patients infected with HBV with regards to other neuropsychological functions. The data indicate that patients infected with HCV patients have poorer visuo-spacial memory performance than patients infected with HBV, suggesting that the cognitive deficit may be specific to HCV infection and not to secondary comorbid psychiatric disorders. J. Med. Virol. 81: 1184-1188, 2009. (C) 2009 Wiley-Liss, Inc.

Specific vs general cognitive remediation for executive functioning in schizophrenia: A multicenter randomized trial.

BACKGROUND: This study assesses the benefits of an individualized therapy (RECOS program) compared with the more general cognitive remediation therapy (CRT). METHODS: 138 participants took part with 65 randomized to CRT and 73 to RECOS. In the RECOS group, participants were directed towards one of five training modules (verbal memory, visuo-spatial memory and attention, working memory, selective attention or reasoning) corresponding to their key cognitive concern whereas the CRT group received a standard program. The main outcome was the total score on BADS (Behavioural Assessment of Dysexecutive Syndrome) and the secondary outcomes were: cognition (executive functions; selective attention; visuospatial memory and attention; verbal memory; working memory) and clinical measures (symptoms; insight; neurocognitive complaints; self-esteem). All outcomes were assessed at baseline (T1), week 12 (posttherapy, T2), and follow-up (week 36, i.e., 6months posttherapy, T3). RESULTS: No difference was shown for the main outcome. A significant improvement was found for BADS' profile score for RECOS at T2 and T3, and for CRT at T3. Change in BADS in the RECOS and CRT arms were not significantly different between T1 and T2 (+0.86, p=0.108), or between T1 and T3 (+0.36, p=0.540). Significant improvements were found in several secondary outcomes including cognition (executive functions, selective attention, verbal memory, and visuospatial abilities) and clinician measures (symptoms and awareness to be hampered by cognitive deficits in everyday) in both treatment arms following treatment. Self-esteem improved only in RECOS arm at T3, and working memory improved only in CRT arm at T2 and T3, but there were no differences in changes between arms. CONCLUSIONS: RECOS (specific remediation) and CRT (general remediation) globally showed similar efficacy in the present trial.

Influência do exercício físico em memória e funções executivas de pessoas com doença de Parkinson

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

O envolvimento da atenção na codificação da informação visuoespacial integrada

O objetivo deste estudo foi investigar o envolvimento de recursos da atenção na codificação e manutenção da informação visual e espacial na memória de trabalho. Utilizou-se um paradigma de tarefas duplas em que uma tarefa primária de localização espacial foi realizada simultaneamente a uma tarefa atentiva secundária de discriminação de tons. O desempenho dos participantes (n = 20) na tarefa primária foi afetado pela presença e pela similaridade entre os tons da tarefa secundária, e também, pela instrução de priorizar uma ou outra tarefa. Os resultados indicam que recursos atentivos (do executivo central) estão envolvidos na codificação e na manutenção ativa da informação integrada na memória visuoespacial, assim como na manutenção dos objetivos das tarefas a serem realizadas simultaneamente.

Working memory in schizophrenia and mania: Acute and subacute phases

Baekground: Patients with schizophrenia tend to have impaired performance on tests of working memory (WM). Neurocognitive models have linked WM to certain symptoms of schizophrenia. This study aimed to assess WM in schizophrenia and mania in the acute and subacute phases of the illness and explore correlations between WM and symptom clusters. Methods: A visuo-spatial delayed response task was used to assess WM in schizophrenia (n=20), mania (n= 14) and well controls (n=20). Patients were tested during the first week of an acute admission, and subjects were retested after four weeks. WM, symptoms (PANSS, TLC) and executive ability (COWAT, Stroop, Trail Making) were assessed at both time points. Results: When assessed for overall WM errors (both sensory and memory), there was a significant group difference (F- 11.53, df 2, 40; p

Predicting performance on fluid intelligence from speed of processing, working memory, and controlled attention

Fluid inteliigence has been defined as an innate ability to reason which is measured commonly by the Raven's Progressive Matrices (RPM). Individual differences in fluid intelligence are currently explained by the Cascade model (Fry & Hale, 1996) and the Controlled Attention hypothesis (Engle, Kane, & Tuholski, 1999; Kane & Engle, 2002). The first theory is based on a complex relation among age, speed, and working memory which is described as a Cascade. The alternative to this theory, the Controlled Attention hypothesis, is based on the proposition that it is the executive attention component of working memory that explains performance on fluid intelligence tests. The first goal of this study was to examine whether the Cascade model is consistent within the visuo-spatial and verbal-numerical modalities. The second goal was to examine whether the executive attention component ofworking memory accounts for the relation between working memory and fluid intelligence. Two hundred and six undergraduate students between the ages of 18 and 28 completed a battery of cognitive tests selected to measure processing speed, working memory, and controlled attention which were selected from two cognitive modalities, verbalnumerical and visuo-spatial. These were used to predict performance on two standard measures of fluid intelligence: the Raven's Progressive Matrices (RPM) and the Shipley Institute of Living Scales (SILS) subtests. Multiple regression and Structural Equation Modeling (SEM) were used to test the Cascade model and to determine the independent and joint effects of controlled attention and working memory on general fluid intelligence. Among the processing speed measures only spatial scan was related to the RPM. No other significant relations were observed between processing speed and fluid intelligence. As 1 a construct, working memory was related to the fluid intelligence tests. Consistent with the predictions for the RPM there was support for the Cascade model within the visuo-spatial modality but not within the verbal-numerical modality. There was no support for the Cascade model with respect to the SILS tests. SEM revealed that there was a direct path between controlled attention and RPM and between working memory and RPM. However, a significant path between set switching and RPM explained the relation between controlled attention and RPM. The prediction that controlled attention mediated the relation between working memory and RPM was therefore not supported. The findings support the view that the Cascade model may not adequately explain individual differences in fluid intelligence and this may be due to the differential relations observed between working memory and fluid intelligence across different modalities. The findings also show that working memory is not a domain-general construct and as a result its relation with fluid intelligence may be dependent on the nature of the working memory modality.

Strategies and biases in location memory in Williams syndrome

Individuals with Williams syndrome (WS) demonstrate impaired visuo-spatial abilities in comparison to their level of verbal ability. In particular, visuo-spatial construction is an area of relative weakness. It has been hypothesised that poor or atypical location coding abilities contribute strongly to the impaired abilities observed on construction and drawing tasks [Farran, E. K., & Jarrold, C. (2005). Evidence for unusual spatial location coding in Williams syndrome: An explanation for the local bias in visuo-spatial construction tasks? Brain and Cognition, 59, 159-172; Hoffman, J. E., Landau, B., & Pagani, B. (2003). Spatial breakdown in spatial construction: Evidence from eye fixations in children with Williams syndrome. Cognitive Psychology, 46, 260-301]. The current experiment investigated location memory in WS. Specifically, the precision of remembered locations was measured as well as the biases and strategies that were involved in remembering those locations. A developmental trajectory approach was employed; WS performance was assessed relative to the performance of typically developing (TD) children ranging from 4- to 8-year-old. Results showed differential strategy use in the WS and TD groups. WS performance was most similar to the level of a TD 4-year-old and was additionally impaired by the addition of physical category boundaries. Despite their low level of ability, the WS group produced a pattern of biases in performance which pointed towards evidence of a subdivision effect, as observed in TD older children and adults. In contrast, the TD children showed a different pattern of biases, which appears to be explained by a normalisation strategy. In summary, individuals with WS do not process locations in a typical manner. This may have a negative impact on their visuo-spatial construction and drawing abilities. (c) 2007 Elsevier Ltd. All rights reserved.

Phenolic acid intake, delivered via moderate champagne wine consumption, improves spatial working memory via the modulation of hippocampal and cortical protein expression/activation.

Aims: While much data exist for the effects of flavonoid-rich foods on spatial memory in rodents, there are no such data for foods/beverages predominantly containing hydroxycinnamates and phenolic acids. To address this, we investigated the effects of moderate Champagne wine intake, which is rich in these components, on spatial memory and related mechanisms relative to the alcohol- and energy-matched controls. Results: In contrast to the isocaloric and alcohol-matched controls, supplementation with Champagne wine (1.78 ml/kg BW, alcohol 12.5% vol.) for 6 weeks led to an improvement in spatial working memory in aged rodents. Targeted protein arrays indicated that these behavioral effects were paralleled by the differential expression of a number of hippocampal and cortical proteins (relative to the isocaloric control group), including those involved in signal transduction, neuroplasticity, apoptosis, and cell cycle regulation. Western immunoblotting confirmed the differential modulation of brain-derived neurotrophic factor, cAMP response-element-binding protein (CREB), p38, dystrophin, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, mammalian target of rapamycin (mTOR), and Bcl-xL in response to Champagne supplementation compared to the control drink, and the modulation of mTOR, Bcl-xL, and CREB in response to alcohol supplementation. Innovation: Our data suggest that smaller phenolics such as gallic acid, protocatechuic acid, tyrosol, caftaric acid, and caffeic acid, in addition to flavonoids, are capable of exerting improvements in spatial memory via the modulation in hippocampal signaling and protein expression. Conclusion: Changes in spatial working memory induced by the Champagne supplementation are linked to the effects of absorbed phenolics on cytoskeletal proteins, neurotrophin expression, and the effects of alcohol on the regulation of apoptotic events in the hippocampus and cortex. Antioxid. Redox Signal. 00, 000-000.

Envelhecimento, linguagem e memória visuo-espacial: um estudo comparativo exploratório do desempenho humano em testes neuropsicológicos selecionados

O reconhecimento dos limites entre o envelhecimento normal e o patológico é essencial para a adoção de políticas de saúde baseadas em evidências para o grupo etário acima de 65 anos. Este estudo é parte de um esforço sistemático que o grupo de pesquisa do Laboratório de Investigações em Neurodegeneração e Infecção da Universidade Federal do Pará tem feito para fornecer informações translacionais sobre a neurobiologia do envelhecimento normal e alterada. A meta principal em longo prazo é permitir políticas públicas para o envelhecimento saudável na Região Amazônica. No presente trabalho investigamos os efeitos do envelhecimento sobre os desempenhos em testes neuropsicológicos selecionados para avaliar aprendizagem, memória e alterações de linguagem. 29 adultos jovens (29,9 ± 1,06 anos) e 31 idosos (74,1 ± 1,15 anos) saudáveis foram submetidos aos testes e os resultados de seus desempenhos foram comparados por testes paramétricos e estatística multivariada. Uma anamnese e uma variedade de testes cognitivos, incluindo Mini Exame do Estado Mental, tarefas visuo-espaciais de aprendizagem e de memória da bateria de testes neuropsicológicos automatizados - CANTAB e testes de linguagem incluindo fluência verbal semântica e fonológica, teste de nomeação de Boston reduzido, performance narrativa utilizando a figura “o roubo dos biscoitos” e alguns testes da Bateria Montreal de Comunicação - MAC. O programa BioEstat versão 5.0 e o pacote estatístico SPSS foram utilizados para a análise. O teste paramétrico t de Student ou o não paramétrico de Mann-Whitney foram aplicados para detectar diferenças significativas (fixadas em valores de p <0,05). Os grupos foram pareados por escolaridade e incluiu homens e mulheres. A análise das subcategorias que compõem o MEEM mostrou diferença significativa apenas na recuperação da memória de evocação de lista de palavras, em que o grupo de idosos apresentou pior desempenho em comparação com o grupo de jovens. Foram encontradas diferenças estatisticamente significativas entre os desempenhos de idosos e jovens adultos nos seguintes testes de linguagem: 1) Nomeação de Boston, 2) Testes de Narrativa, 3) Metáforas; 4) Prosódia Emocional e Linguística. Em comparação com os adultos jovens, indivíduos idosos apresentaram pior desempenho em 10 medidas diferentes nos testes de memória visuo-espacial e de aprendizagem do CANTAB. Distâncias Euclidianas e análise discriminante obtidas a partir do CANTAB e dos testes de linguagem demonstraram que os primeiros distinguem os grupos com maior resolução. Os efeitos do envelhecimento sobre o desempenho nos testes neuropsicológicos selecionados revelam que a Bateria CANTAB, empregada para testar a memória visuo-espacial, é mais sensível e discrimina melhor a formação de subgrupos tanto no grupo de adultos jovens quanto no grupo de idosos. Por essa razão sugerimos que a aplicação em larga escala de testes selecionados da bateria CANTAB, tanto em estudos transversais como em longitudinais, vai aumentar nossa capacidade de resolução na distinção dos limites entre o envelhecimento normal e o patológico.

Role of entorhinal cortical plasticity in spatial and contextual memory

It is well accepted that the hippocampus (HIP) is important for spatial and contextual memories, however, it is not clear if the entorhinal cortex (EC), the main input/output structure for the hippocampus, is also necessary for memory storage. Damage to the EC in humans results in memory deficits. However, animal studies report conflicting results on whether the EC is necessary for spatial and contextual memory. Memory consolidation requires gene expression and protein synthesis, mediated by signaling cascades and transcription factors. Extracellular-signal regulated kinase (ERK) cascade activity is necessary for long-term memory in several tasks, including those that test spatial and contextual memory. In this work, we explore the role of ERK-mediated plasticity in the EC on spatial and contextual memory. ^ To evaluate this role, post-training infusions of reversible pharmacological inhibitors specific for the ERK cascade that do not affect normal neuronal activity were targeted directly to the EC of awake, behaving animals. This technique provides spatial and temporal control over the inhibition of the ERK cascade without affecting performance during training or testing. Using the Morris water maze to study spatial memory, we found that ERK inhibition in the EC resulted in long-term memory deficits consistent with a loss of spatial strategy information. When animals were allowed to learn and consolidate a spatial strategy for solving the task prior to training and ERK inhibition, the deficit was alleviated. To study contextual memory, we trained animals in a cued fear-conditioning task and saw an increase in the activation of ERK in the EC 90 minutes following training. ERK inhibition in the EC over this time point, but not at an earlier time point, resulted in increased freezing to the context, but not to the tone, during a 48-hour retention test. In addition, animals froze maximally at the time the shock was given during training; similar to naïve animals receiving additional training, suggesting that ERK-mediated plasticity in the EC normally suppresses the temporal nature of the freezing response. These findings demonstrate that plasticity in the EC is necessary for both spatial and contextual memory, specifically in the retention of behavioral strategies. ^

The contributions of the hippocampal formation, perirhinal cortex and areas TH/TF to object, spatial and contextual recognition memory in primates

Adult monkeys (Macaca mulatta) with lesions of the hippocampal formation, perirhinal cortex, areas TH/TF, as well as controls were tested on tasks of object, spatial and contextual recognition memory. ^ Using a visual paired-comparison (VPC) task, all experimental groups showed a lack of object recognition relative to controls, although this impairment emerged at 10 sec with perirhinal lesions, 30 sec with areas TH/TF lesions and 60 sec with hippocampal lesions. In contrast, only perirhinal lesions impaired performance on delayed nonmatching-to-sample (DNMS), another task of object recognition memory. All groups were tested on DNMS with distraction (dDNMS) to examine whether the use of active cognitive strategies during the delay period could enable good performance on DNMS in spite of impaired recognition memory (revealed by the VPC task). Distractors affected performance of animals with perirhinal lesions at the 10-sec delay (the only delay in which their DNMS performance was above chance). They did not affect performance of animals with areas TH/TF lesions. Hippocampectomized animals were impaired at the 600-sec delay (the only delay at which prevention of active strategies would likely affect their behavior). ^ While lesions of areas TH/TF impaired spatial location memory and object-in-place memory, hippocampal lesions impaired only object-in-place memory. The pattern of results for perirhinal cortex lesions on the different task conditions indicated that this cortical area is not critical for spatial memory. ^ Finally, all three lesions impaired contextual recognition memory processes. The pattern of impairment appeared to result from the formation of only a global representation of the object and background, and suggests that all three areas are recruited for associating information across sources. ^ These results support the view that (1) the perirhinal cortex maintains storage of information about object and the context in which it is learned for a brief period of time, (2) areas TH/TF maintain information about spatial location and form associations between objects and their spatial relationship (a process that likely requires additional time) and (3) the hippocampal formation mediates associations between objects, their spatial relationship and the general context in which these associations are formed (an integrative function that requires additional time). ^

Síndrome do X Frágil com variante de Dandy-Walker: estudo clínico das manifestações comunicativas orais e escritas

A síndrome do X Frágil é a causa mais frequente de deficiência intelectual hereditária. A variante de Dandy-Walker trata-se de uma constelação específica de achados neurorradiológicos. Este estudo relata achados da comunicação oral e escrita de um menino de 15 anos com diagnóstico clínico e molecular da síndrome do X-Frágil e achados de neuroimagem do encéfalo compatíveis com variante de Dandy-Walker. A avaliação fonoaudiológica foi realizada por meio da Observação do Comportamento Comunicativo, aplicação do ABFW - Teste de Linguagem Infantil - Fonologia, Perfil de Habilidades Fonológicas, Teste de Desempenho Escolar, Teste Illinois de Habilidades Psicolinguísticas, avaliação do sistema estomatognático e avaliação audiológica. Observou-se: alteração de linguagem oral quanto às habilidades fonológicas, semânticas, pragmáticas e morfossintáticas; déficits nas habilidades psicolinguísticas (recepção auditiva, expressão verbal, combinação de sons, memória sequencial auditiva e visual, closura auditiva, associação auditiva e visual); e alterações morfológicas e funcionais do sistema estomatognático. Na leitura verificou-se dificuldades na decodificação dos símbolos gráficos e na escrita havia omissões, aglutinações e representações múltiplas com o uso predominante de vogais e dificuldades na organização viso-espacial. Em matemática, apesar do reconhecimento numérico, não realizou operações aritméticas. Não foram observadas alterações na avaliação audiológica periférica. A constelação de sintomas comportamentais, cognitivos, linguísticos e perceptivos, previstos na síndrome do X-Frágil, somada às alterações estruturais do sistema nervoso central, pertencentes à variante de Dandy-Walker, trouxeram interferências marcantes no desenvolvimento das habilidades comunicativas, no aprendizado da leitura e escrita e na integração social do indivíduo.