Network supporting contextual fear learning after dorsal hippocampal damage has increased dependence on retrosplenial cortex.

Hippocampal damage results in profound retrograde, but no anterograde amnesia in contextual fear conditioning (CFC). Although the content learned in the latter have been discussed, alternative regions supporting CFC learning were seldom proposed and never empirically addressed. Here, we employed network analysis of pCREB expression quantified from brain slices of rats with dorsal hippocampal lesion (dHPC) after undergoing CFC session. Using inter-regional correlations of pCREB-positive nuclei between brain regions, we modelled functional networks using different thresholds. The dHPC network showed small-world topology, equivalent to SHAM (control) network. However, diverging hubs were identified in each network. In a direct comparison, hubs in both networks showed consistently higher centrality values compared to the other network. Further, the distribution of correlation coefficients was different between the groups, with most significantly stronger correlation coefficients belonging to the SHAM network. These results suggest that dHPC network engaged in CFC learning is partially different, and engage alternative hubs. We next tested if pre-training lesions of dHPC and one of the new dHPC network hubs (perirhinal, Per; or disgranular retrosplenial, RSC, cortices) would impair CFC. Only dHPC-RSC, but not dHPC-Per, impaired CFC. Interestingly, only RSC showed a consistently higher centrality in the dHPC network, suggesting that the increased centrality reflects an increased functional dependence on RSC. Our results provide evidence that, without hippocampus, the RSC, an anatomically central region in the medial temporal lobe memory system might support CFC learning and memory.

Lithium prevents REM sleep deprivation-induced impairments on memory consolidation.

BACKGROUND: Pre-training rapid eye movement sleep (REMS) deprivation affects memory acquisition and/or consolidation. It also produces major REMS rebound at the cost of waking and slow wave sleep (SWS). Given that both SWS and REMS appear to be important for memory processes, REMS rebound after training may disrupt the organization of sleep cycles, i.e., excessive amount of REMS and/or little SWS after training could be harmful for memory formation. OBJECTIVE: To examine whether lithium, a drug known to increase SWS and reduce REMS, could prevent the memory impairment induced by pre-training sleep deprivation. DESIGN: Animals were divided in 2 groups: cage control (CC) and REMS-deprived (REMSDep), and then subdivided into 4 subgroups, treated either with vehicle or 1 of 3 doses of lithium (50, 100, and 150 mg/kg) 2 h before training on the multiple trial inhibitory avoidance task. Animals were tested 48 h later to make sure that the drug had been already metabolized and eliminated. Another set of animals was implanted with electrodes and submitted to the same experimental protocol for assessment of drug-induced sleep-wake changes. SUBJECTS: Wistar male rats weighing 300-400 g. RESULTS: Sleep deprived rats required more trials to learn the task and still showed a performance deficit during test, except from those treated with 150 mg/kg of lithium, which also reduced the time spent in REM sleep during sleep recovery. CONCLUSION: Lithium reduced rapid eye movement sleep and prevented memory impairment induced by sleep deprivation. These results indicate that these phenomena may be related, but cause-effect relationship cannot be ascertained.

Musicians' working memory for tones, words, and pseudowords.

Studies investigating factors that influence tone recognition generally use recognition tests, whereas the majority of the studies on verbal material use self-generated responses in the form of serial recall tests. In the present study we intended to investigate whether tonal and verbal materials share the same cognitive mechanisms, by presenting an experimental instrument that evaluates short-term and working memories for tones, using self-generated sung responses that may be compared to verbal tests. This paradigm was designed according to the same structure of the forward and backward digit span tests, but using digits, pseudowords, and tones as stimuli. The profile of amateur singers and professional singers in these tests was compared in forward and backward digit, pseudoword, tone, and contour spans. In addition, an absolute pitch experimental group was included, in order to observe the possible use of verbal labels in tone memorization tasks. In general, we observed that musical schooling has a slight positive influence on the recall of tones, as opposed to verbal material, which is not influenced by musical schooling. Furthermore, the ability to reproduce melodic contours (up and down patterns) is generally higher than the ability to reproduce exact tone sequences. However, backward spans were lower than forward spans for all stimuli (digits, pseudowords, tones, contour). Curiously, backward spans were disproportionately lower for tones than for verbal material-that is, the requirement to recall sequences in backward rather than forward order seems to differentially affect tonal stimuli. This difference does not vary according to musical expertise.

Anterior thalamus deep brain stimulation at high current impairs memory in rats.

Deep brain stimulation (DBS) of the anterior thalamic nucleus (AN), an important relay in the circuitry of memory, is currently being proposed as a treatment for epilepsy. Despite the encouraging results with the use of this therapy, potential benefits and adverse effects are yet to be determined. We show that AN stimulation at relatively high current disrupted the acquisition of contextual fear conditioning and impaired performance on a spatial alternating task in rats. This has not been observed at parameters generating a charge density that approximated the one used in clinical practice. At settings that impaired behavior, AN stimulation induced a functional depolarization block nearby the electrode, increased c-Fos expression in cerebral regions projecting to and receiving projections from the AN, and influenced hippocampal activity. This suggests that complex mechanisms might be involved in the effects of AN DBS, including a local target inactivation and the modulation of structures at a distance. Though translating data from animals to humans has to be considered with caution, our study underscores the need for carefully monitoring memory function while selecting stimulation parameters during the clinical evaluation of AN DBS.

Effects of semantic relations, repetition of words, and list length in word list recall of Alzheimer's patients.

INTRODUCTION: Semantic relations among words and repetition enhance free recall, but it is unknown if these facilitating factors are effective in dementia. METHOD: Alzheimer's patients (MILD-Alz, MOD-Alz) were compared to healthy elderly. Fifteen-word lists were read out to the subjects. In four sets of lists the words in intermediary input positions were semantically related or not, or the midlist words were repeated, or they were repeated and semantically related. RESULTS: The usual third peak of recall of semantically related words was not observed in MOD-Alz, repetition of words did not increase recall of the patients, and the combination of relatedness and repetition benefited only MID-Alz. In a second experiment, with related or unrelated midlist words, and list length shortened from 15 to 9 words, semantic facilitation was observed in mild and moderate Alzheimer s patients, although diminished compared to controls. CONCLUSION: Progression of dementia turns facilitating factors of recall less effective.

Effects of semantic relations, repetition of words, and list length in word list recall of Alzheimer's patients / Efeitos da relação semântica, repetição de palavras e extensão das listas na recordação de pacientes com doença de Alzheimer

INTRODUCTION: Semantic relations among words and repetition enhance free recall, but it is unknown if these facilitating factors are effective in dementia. METHOD: Alzheimer's patients (MILD-Alz, MOD-Alz) were compared to healthy elderly. Fifteen-word lists were read out to the subjects. In four sets of lists the words in intermediary input positions were semantically related or not, or the midlist words were repeated, or they were repeated and semantically related. RESULTS: The usual third peak of recall of semantically related words was not observed in MOD-Alz, repetition of words did not increase recall of the patients, and the combination of relatedness and repetition benefited only MID-Alz. In a second experiment, with related or unrelated midlist words, and list length shortened from 15 to 9 words, semantic facilitation was observed in mild and moderate Alzheimer´s patients, although diminished compared to controls. CONCLUSION: Progression of dementia turns facilitating factors of recall less effective.

INTRODUÇÃO: Relacionamento semântico e repetição facilitam a recordação livre mas não se sabe se esses fatores continuam efetivos na demência. MÉTODO: O desempenho de pacientes com doença de Alzheimer (MILD-Alz e MOD-Alz) foi comparado com o de idosos sadios na recordação livre de listas de 15 palavras, utilizando quatro diferentes conjuntos de listas que continham ou não palavras relacionadas nas posições intermediárias, palavras repetidas, ou ainda palavras repetidas e semanticamente relacionadas. RESULTADOS: O terceiro pico usual na recordação das palavras semanticamente relacionadas não foi observado em MOD-Alz; a repetição não aumentou a recordação dos pacientes; a combinação de relacionamento e repetição beneficiou apenas MILD-Alz. Em outro experimento, com palavras intermediárias relacionadas ou não, e em que a extensão das listas foi reduzida para 9 palavras, observou-se facilitação semântica em MILD-Alz e MOD-Alz. CONCLUSÃO: A progressão da demência diminui a eficácia de fatores facilitadores da recordação.

Intermittent hypoxia and sleep restriction: motor, cognitive and neurochemical alterations in rats.

The present study evaluated the effects of intermittent hypoxia (IH) and sleep restriction (SR) upon motor and cognitive function in rats. Also evaluated were catecholamine concentrations and tyrosine hydroxylase (TH) protein expression in different regions of the forebrain. Wistar Hannover rats were submitted to IH for 4 days or 21 days (2 min room air to 2 min 10% O(2) for 10:00-16:00 h), followed by SR for 18 h (16:00-10:00 h). Rats were randomly assigned into four experimental groups: (1) control (2) IH (3) SR and (4) IH-SR. In the inhibitory avoidance task, an additional group of rats was submitted to paradoxical sleep deprivation (PSD) for 96 consecutive hours. Results showed that SR induced an increase in motor activity without modifying catecholaminergic turnover in the frontal cortex and striatum. The increase in exploratory activity in SR rats could be the result of impaired habituation. Neither SR periods induced cognitive deficits in the inhibitory avoidance task after 5 or 21 days. However, 96 h of PSD impaired acquisition/retention in rats. Exposure to IH did not affect motor and cognitive function but IH was associated with SR in increased motor activity. After 21 days, IH and IH-SR reduced striatal norepinephrine concentration although neither SR nor IH affected TH protein expression. The results presented here suggest that hypoxia and sleep loss exert distinct deleterious effects upon the central nervous system.

Effects of brief and long maternal separations on the HPA axis activity and the performance of rats on context and tone fear conditioning.

Previous studies show that early life events result in neurobehavioural alterations that may be either beneficial or detrimental to the stress response. Given the close relationship between corticosterone secretion and mnemonic processes, the purpose of the present study was to investigate the effects of brief (BMS, 15 min) and long maternal separations (LMS, 180 min) on memory tasks in adult rats, assessed by context and tone fear conditioning. At adulthood, males were evaluated for behavioural and hormonal reaction to the training environment, being tested for context fear conditioning; tone fear conditioning; and learning curve in the context fear conditioning, in which rats were daily re-exposed to the context, followed by a brief footshock and in the last day of the experiment (day 5) animals were exposed to the context. Corticosterone and ACTH plasma levels were determined in naïve rats (basal) or 5, 25 or 45 min after each test. Peak ACTH and corticosterone levels were similar among the groups after context fear conditioning; however, levels of CTL rats remained elevated for a longer time. In the learning curve of context fear conditioning, both BMS and LMS rats exhibited less freezing behaviour than CTL rats, without differences in hormone secretion. There was neither an association between activity of the HPA axis and performance on memory tasks nor different activational properties of the tasks on the HPA axis between BMS and LMS rats, i.e., both manipulations lead to similar performance in hippocampus-dependent and independent memory tasks.

Semantic relations and repetition of items enhance the free recall of words by multiple sclerosis patients.

We compared 25 patients with multiple sclerosis (MS) and 24 normal controls on a test of free recall of words. Some lists contained words that were all unrelated, while in others the intermediary words were semantically related. In another set, the mid-list words were repeated across the lists, or, in addition to the repetition, were semantically associated. Immediate recall was assessed using these lists. Delayed recall was assessed using different lists (delay-unrelated and delay-related) after distractor tasks. Recency was not affected in MS patients, but the primacy effect was lower than in controls, this effect being interpreted as due to a deficiency in articulatory rehearsal. The delay interval after each list abolished recency in both groups and resulted in impaired recall in MS patients. However the patients, like the controls, benefited from semantic relations in the middle of the lists and from spaced repetition of words across the lists, in either immediate and delayed recall. The enhancing effects of word relatedness and of spaced repetition are seen as being due to automatic processes preserved in MS patients.

Effects of dorsal striatum lesions in tone fear conditioning and contextual fear conditioning.

It has been suggested that the striatum mediates hippocampus-independent memory tasks. Classical fear conditioning to a discrete stimulus such as a tone is not affected by hippocampal lesion, whereas contextual fear conditioning is an hippocampus dependent task. The purpose of the present study was to verify the effect of dorsal striatal lesions on tone and contextual fear conditioning. The lesioned rats were not impaired in contextual fear conditioning but in tone fear conditioning both electrolytically and neurotoxically lesioned animals showed less freezing compared with controls. The lesion effect was observed after a postoperative recovery period of 14 days but not after 2 months. The results support the hypothesis that the dorsal striatum is involved in hippocampus-independent memory tasks, but, in spite of this involvement, it does not seem to be a critical structure.

Deficits in avoidance responding after paradoxical sleep deprivation are not associated with altered [3H]pirenzepine binding to M1 muscarinic receptors in rat brain.

Previous work had indicated that animals that were sleep-deprived and then trained on a passive avoidance task show poor retention of the task 24 h later after being allowed to sleep freely again. Cholinergic involvement is suggested by the fact that this effect is prevented by treatment with the muscarinic agonist pilocarpine during sleep deprivation. The observation that similar deficits are observed in non-deprived rats after treatment with M1-selective antagonist compounds such as dicyclomine or pirenzepine cause similar impairments, and gave rise to the hypothesis that sleep deprivation might induce significant reductions in M1 binding in brain areas involved in learning and memory processes. Rats were deprived of sleep for 96 h and then either immediately killed, or allowed to recover sleep for 24 h before being killed. [3H]pirenzepine binding to M1 sites was examined by quantitative autoradiography in 39 different brain areas in cage controls, sleep-deprived and sleep-recovered animals (N=8 per group). No significant differences among groups were found in any brain region. A separate group of animals was subjected to the sleep deprivation procedure and then trained in a simple avoidance task. Animals were then allowed to sleep and retested 24 h later. This group showed a significant impairment in the avoidance task compared to cage controls, in agreement with previous observations. These data suggest that proactive learning/memory deficits induced by sleep deprivation cannot be attributed to altered M1 binding either immediately after deprivation (when avoidance training occurs) or after sleep has recovered (when acquisition/retention are tested). The possibility remains that alterations in M1 function occur at post-membrane second messenger systems.

Social stress does not interact with paradoxical sleep deprivation-induced memory impairment.

Extensive evidence has linked both paradoxical sleep (PS) and stress to memory processing. The purpose of the present study was to examine the effect of social instability stress on memory and to verify whether this stress interferes with the amnesic effect of PS deprivation using the modified multiple platform method. In addition to the PS-deprived group (put onto narrow platforms inside the deprivation tanks) two control groups were used: one of them remained in its home-cages and the other was placed inside the deprivation tanks, onto a grid that contained large platforms on it. All groups were subdivided in socially stable and unstable conditions. Immediately after 96 h of sleep deprivation, the animals were trained in three different memory tasks: inhibitory avoidance, classical fear conditioning to a discrete stimulus and contextual fear conditioning. Twenty-four hours after training, the animals were tested in order to assess task acquisition. The results showed that social instability did not impair the performance of animals nor interacted with PS deprivation in any of the tasks. Grid control animals presented a selective impairment in the inhibitory avoidance task and contextual, but not in the classical, fear conditioning task, compared to cage control rats. This finding could be due to the stress to which grid control animals were exposed (humidity and luminosity) during the manipulation period. PS-deprived animals exhibited poorer performance than the other groups in all tasks. As they also showed an increased threshold to shock-induced vocalisation, but not to flinch response, it is not possible to completely rule out a decreased response to noxious stimulation as a contributing factor for the present results with PS deprivation.

Cognitive profile of patients with relapsing remitting multiple slcerosis

Multiple sclerosis (MS) is a common disease in Western countries of temperate/cold climate, but in tropical countries an increasing number of cases have been diagnosticated Moved by the lack of information about cognitive dysfunction of Brazilian MS patients, the present study attempted to describe features of neuropsychological alterations in patients with relapsing remiting MS living in the city of São Paulo. They were compared to healthy volunteers, matched for age and education. In the absence of global intellectual deterioration, the patients had a deficit: a) in learning and verbal long-term memory tasks and in visual long-term memory of complex figure; b) in timed tasks, accounted for by a slowness of mental processes; c) in tasks with a motor component. Tendency to depression was observed; anxiety levels were normal.

Memoria de figuras com conteudo emocional em pacientes com doenca de Alzheimer / Figure memories with emotional content in patients with Alzheimer's disease

O presente trabalho consiste de um relato preliminar de um projeto de estudo sobre o processamento de estimulos visuais com conteudo emocional em pacientes com demencia do tipo Alzheimer. Foram avaliados 14 pacientes com provavel demencia de Alzheimer e 14 sujeitos controles pareados de acordo com a idade e anos de escolaridade. Foram apresentadas 16 figuras-alvo com diferentes conteudos emocionais (paisagens, pessoas mutiladas, figuras com criancas, figuras de sexo e figuras geometricas, entre outras); imediatamente apos a apresentacao das figuras foi dada uma tarefa distratora de 30 minutos, e em seguida foi feito o reconhecimento das figuras-alvo dispersas entre outras 34; de cada figura-alvo reconhecida foi solicitada a identificacao e classificacao como agradavel, desagradavel ou indiferente...