Formation of a spatial memory trace : a behavioral, cellular and molecular study

THESIS ABSTRACTThis thesis project was aimed at studying the molecular mechanisms underlying learning and memory formation, in particular as they relate to the metabolic coupling between astrocytes and neurons. For that, changes in the metabolic activity of different mice brain regions after 1 or 9 days of training in an eight-arm radial maze were assessed by (14C) 2-deoxyglucose (2DG) autoradiography. Significant differences in the areas engaged during the behavioral task at day 1 (when animals are confronted for the first time to the learning task) and at day 9 (when animals are highly performing) have been identified. These areas include the hippocampus, the fornix, the parietal cortex, the laterodorsal thalamic nucleus and the mammillary bodies at day 1 ; and the anterior cingulate, the retrosplenial cortex and the dorsal striatum at day 9. Two of these cerebral regions (those presenting the greatest changes at day 1 and day 9: the hippocampus and the retrosplenial cortex, respectively) were microdissected by laser capture microscopy and selected genes related to neuron-glia metabolic coupling, glucose metabolism and synaptic plasticity were analyzed by RT-PCR. 2DG and gene expression analysis were performed at three different times: 1) immediately after the end of the behavioral paradigm, 2) 45 minutes and 3) 6 hours after training. The main goal of this study was the identification of the metabolic adaptations following the learning task. Gene expression results demonstrate that the learning task profoundly modulates the pattern of gene expression in time, meaning that these two cerebral regions with high 2DG signal (hippocampus and retrosplenial cortex) have adapted their metabolic molecular machinery in consequence. Almost all studied genes show a higher expression in the hippocampus at day 1 compared to day 9, while an increased expression was found in the retrosplenial cortex at day 9. We can observe these molecular adaptations with a short delay of 45 minutes after the end of the task. However, 6 hours after training a high gene expression was found at day 9 (compared to day 1) in both regions, suggesting that only one day of training is not sufficient to detect transcriptional modifications several hours after the task. Thus, gene expression data match 2DG results indicating a transfer of information in time (from day 1 to day 9) and in space (from the hippocampus to the retrosplenial cortex), and this at a cellular and a molecular level. Moreover, learning seems to modify the neuron-glia metabolic coupling, since several genes involved in this coupling are induced. These results also suggest a role of glia in neuronal plasticity.RESUME DU TRAVAIL DE THESECe projet de thèse a eu pour but l'étude des mécanismes moléculaires qui sont impliqués dans l'apprentissage et la mémoire et, en particulier, à les mettre en rapport avec le couplage métabolique existant entre les astrocytes et les neurones. Pour cela, des changements de l'activité métabolique dans différentes régions du cerveau des souris après 1 ou 9 jours d'entraînement dans un labyrinthe radial à huit-bras ont été évalués par autoradiographie au 2-désoxyglucose (2DG). Des différences significatives dans les régions engagées pendant la tâche comportementale au jour 1 (quand les animaux sont confrontés pour la première fois à la tâche) et au jour 9 (quand les animaux ont déjà appris) ont été identifiés. Ces régions incluent, au jour 1, l'hippocampe, le fornix, le cortex pariétal, le noyau thalamic laterodorsal et les corps mamillaires; et, au jour 9, le cingulaire antérieur, le cortex retrosplenial et le striatum dorsal. Deux de ces régions cérébrales (celles présentant les plus grands changements à jour 1 et à jour 9: l'hippocampe et le cortex retrosplenial, respectivement) ont été découpées par microdissection au laser et quelques gènes liés au couplage métabolique neurone-glie, au métabolisme du glucose et à la plasticité synaptique ont été analysées par RT-PCR. L'étude 2DG et l'analyse de l'expression de gènes ont été exécutés à trois temps différents: 1) juste après entraînement, 2) 45 minutes et 3) 6 heures après la fin de la tâche. L'objectif principal de cette étude était l'identification des adaptations métaboliques suivant la tâche d'apprentissage. Les résultats de l'expression de gènes démontrent que la tâche d'apprentissage module profondément le profile d'expression des gènes dans le temps, signifiant que ces deux régions cérébrales avec un signal 2DG élevé (l'hippocampe et le cortex retrosplenial) ont adapté leurs « machines moléculaires » en conséquence. Presque tous les gènes étudiés montrent une expression plus élevée dans l'hippocampe au jour 1 comparé au jour 9, alors qu'une expression accrue a été trouvée dans le cortex retrosplenial au jour 9. Nous pouvons observer ces adaptations moléculaires avec un retard court de 45 minutes après la fin de la tâche. Cependant, 6 heures après l'entraînement, une expression de gènes élevée a été trouvée au jour 9 (comparé à jour 1) dans les deux régions, suggérant que seulement un jour d'entraînement ne suffit pas pour détecter des modifications transcriptionelles plusieurs heures après la tâche. Ainsi, les données d'expression de gènes corroborent les résultats 2DG indiquant un transfert d'information dans le temps (de jour 1 à jour 9) et dans l'espace (de l'hippocampe au cortex retrosplenial), et ceci à un niveau cellulaire et moléculaire. D'ailleurs, la tâche d'apprentissage semble modifier le couplage métabolique neurone-glie, puisque de nombreux gènes impliqués dans ce couplage sont induits. Ces observations suggèrent un rôle important de la glie dans les mécanismes de plasticité du système nerveux.

Tracking memory's trace

There is strong converging evidence that the intermediate and medial part of the hyperstriatum ventrale of the chick brain is a memory store for information acquired through the learning process of imprinting. Neurons in this memory system come, through imprinting, to respond selectively to the imprinting stimulus (IS) neurons and so possess the properties of a memory trace. Therefore, the responses of the intermediate and medial part of the hyperstriatum ventrale neurons to a visual imprinting stimulus were determined before, during, and after training. Of the total recorded population, the proportions of IS neurons shortly after each of two 1-h training sessions were significantly higher (approximately 2 times) than the pretraining proportion. However, ≈4.5 h later this proportion had fallen significantly and did not differ significantly from the pretraining proportion. Nevertheless, ≈21.5 h after the end of training, the proportion of IS neurons was at its highest (approximately 3 times the pretraining level). No significant fluctuations occurred in the proportions of neurons responding to the alternative stimulus. In addition, nonmonotonic changes were found commonly in the activity of 230 of the neurons tracked individually from before training to shortly after the end of training. Thus the pattern of change in responsiveness both at the population level and at the level of individual neurons was highly nonmonotonic. Such a pattern of change is not consistent with simple models of memory based on synaptic strengthening to asymptote. A model is proposed that accounts for the changes in the population responses to the imprinting stimulus in terms of changes in the responses of individual neurons.

ERP 'old/new' effects: memory strength and decisional factor(s)

Event-related potentials (ERPs) were recorded while subjects made old/new recognition judgments on new unstudied words and old words which had been presented at study either once ('weak') or three times ('strong'). The probability of an 'old' response was significantly higher for strong than weak words and significantly higher for weak than new words. Comparisons were made initially between ERPs to new, weak and strong words, and subsequently between ERPs associated with six strength-by-response conditions. The N400 component was found to be modulated by memory trace strength in a graded manner. Its amplitude was most negative in new word ERPs and most positive in strong word ERPs. This 'N400 strength effect' was largest at the left parietal electrode (in ear-referenced ERPs). The amplitude of the late positive complex (LPC) effect was sensitive to decision accuracy (and perhaps confidence). Its amplitude was larger in ERPs evoked by words attracting correct versus incorrect recognition decisions. The LPC effect had a left > right, centro-parietal scalp topography (in ear-referenced ERPs). Hence, whereas, the majority of previous ERP studies of episodic recognition have interpreted results from the perspective of dual-process models, we provide alternative interpretations of N400 and LPC old/new effects in terms of memory strength and decisional factor(s). (C) 2002 Elsevier Science Ltd. All rights reserved.

Errors in nonword repetition: bridging short- and long-term memory

According to the working memory model, the phonological loop is the component of working memory specialized in processing and manipulating limited amounts of speech-based information. The Children's Test of Nonword Repetition (CNRep) is a suitable measure of phonological short-term memory for English-speaking children, which was validated by the Brazilian Children's Test of Pseudoword Repetition (BCPR) as a Portuguese-language version. The objectives of the present study were: i) to investigate developmental aspects of the phonological memory processing by error analysis in the nonword repetition task, and ii) to examine phoneme (substitution, omission and addition) and order (migration) errors made in the BCPR by 180 normal Brazilian children of both sexes aged 4-10, from preschool to 4th grade. The dominant error was substitution [F(3,525) = 180.47; P < 0.0001]. The performance was age-related [F(4,175) = 14.53; P < 0.0001]. The length effect, i.e., more errors in long than in short items, was observed [F(3,519) = 108.36; P < 0.0001]. In 5-syllable pseudowords, errors occurred mainly in the middle of the stimuli, before the syllabic stress [F(4,16) = 6.03; P = 0.003]; substitutions appeared more at the end of the stimuli, after the stress [F(12,48) = 2.27; P = 0.02]. In conclusion, the BCPR error analysis supports the idea that phonological loop capacity is relatively constant during development, although school learning increases the efficiency of this system. Moreover, there are indications that long-term memory contributes to holding memory trace. The findings were discussed in terms of distinctiveness, clustering and redintegration hypotheses.

The influence of stress on fear memory processes

It is well recognized that stressful experiences promote robust emotional memories, which are well remembered. The amygdaloid complex, principally the basolateral complex (BLA), plays a pivotal role in fear memory and in the modulation of stress-induced emotional responses. A large number of reports have revealed that GABAergic interneurons provide a powerful inhibitory control of the activity of projecting glutamatergic neurons in the BLA. Indeed, a reduced GABAergic control in the BLA is essential for the stress-induced influence on the emergence of associative fear memory and on the generation of long-term potentiation (LTP) in BLA neurons. The extracellular signal-regulated kinase (ERK) subfamily of the mitogen-activated protein kinase (MAPK) signaling pathway in the BLA plays a central role in the consolidation process and synaptic plasticity. In support of the view that stress facilitates long-term fear memory, stressed animals exhibited a phospho-ERK2 (pERK2) increase in the BLA, suggesting the involvement of this mechanism in the promoting influence of threatening stimuli on the consolidation fear memory. Moreover, the occurrence of reactivation-induced lability is prevented when fear memory is encoded under intense stressful conditions since the memory trace remains immune to disruption after recall in previously stressed animals. Thus, the underlying mechanism in retrieval-induced instability seems not to be functional in memories formed under stress. All these findings are indicative that stress influences both the consolidation and reconsolidation fear memory processes. Thus, it seems reasonable to propose that the emotional state generated by an environmental challenge critically modulates the formation and maintenance of long-term fear memory.

Neural correlates of true and false memory in mild cognitive impairment

The goal of this research was to investigate the changes in neural processing in mild cognitive impairment. We measured phase synchrony, amplitudes, and event-related potentials in veridical and false memory to determine whether these differed in participants with mild cognitive impairment compared with typical, age-matched controls. Empirical mode decomposition phase locking analysis was used to assess synchrony, which is the first time this analysis technique has been applied in a complex cognitive task such as memory processing. The technique allowed assessment of changes in frontal and parietal cortex connectivity over time during a memory task, without a priori selection of frequency ranges, which has been shown previously to influence synchrony detection. Phase synchrony differed significantly in its timing and degree between participant groups in the theta and alpha frequency ranges. Timing differences suggested greater dependence on gist memory in the presence of mild cognitive impairment. The group with mild cognitive impairment had significantly more frontal theta phase locking than the controls in the absence of a significant behavioural difference in the task, providing new evidence for compensatory processing in the former group. Both groups showed greater frontal phase locking during false than true memory, suggesting increased searching when no actual memory trace was found. Significant inter-group differences in frontal alpha phase locking provided support for a role for lower and upper alpha oscillations in memory processing. Finally, fronto-parietal interaction was significantly reduced in the group with mild cognitive impairment, supporting the notion that mild cognitive impairment could represent an early stage in Alzheimer’s disease, which has been described as a ‘disconnection syndrome’.

A Mismatch-Based Model for Memory Reconsolidation and Extinction in Attractor Networks

OSAN, R. , TORT, A. B. L. , AMARAL, O. B. . A mismatch-based model for memory reconsolidation and extinction in attractor networks. Plos One, v. 6, p. e23113, 2011.

Errors in nonword repetition: bridging short- and long-term memory

According to the working memory model, the phonological loop is the component of working memory specialized in processing and manipulating limited amounts of speech-based information. The Children's Test of Nonword Repetition (CNRep) is a suitable measure of phonological short-term memory for English-speaking children, which was validated by the Brazilian Children's Test of Pseudoword Repetition (BCPR) as a Portuguese-language version. The objectives of the present study were: i) to investigate developmental aspects of the phonological memory processing by error analysis in the nonword repetition task, and ii) to examine phoneme (substitution, omission and addition) and order (migration) errors made in the BCPR by 180 normal Brazilian children of both sexes aged 4-10, from preschool to 4th grade. The dominant error was substitution [F(3,525) = 180.47; P < 0.0001]. The performance was age-related [F(4,175) = 14.53; P < 0.0001]. The length effect, i.e., more errors in long than in short items, was observed [F(3,519) = 108.36; P < 0.0001]. In 5-syllable pseudowords, errors occurred mainly in the middle of the stimuli, before the syllabic stress [F(4,16) = 6.03; P = 0.003]; substitutions appeared more at the end of the stimuli, after the stress [F(12,48) = 2.27; P = 0.02]. In conclusion, the BCPR error analysis supports the idea that phonological loop capacity is relatively constant during development, although school learning increases the efficiency of this system. Moreover, there are indications that long-term memory contributes to holding memory trace. The findings were discussed in terms of distinctiveness, clustering and redintegration hypotheses.

A perceptual memory for low-contrast visual signals

Detection of a visual signal can be facilitated by simultaneous presentation of a similar subthreshold signal. Here we show that the facilitatory effect of a subthreshold signal can persist for more than 16 s. Presenting a near-threshold Gabor signal (prime) produced a phase-independent increase in contrast sensitivity (40%) to similar successive signals (target) for a period of up to 16 s. This effect was obtained only when both prime and target were presented to the same eye. We further show that the memory trace is inactivated by presenting high-contrast signals before the target. These results suggest that activated neurons in the primary visual cortex retain a near-threshold memory trace that persists until reactivated.

In search of a theory of list memory: an inquiry into the efects of long-term information on short-term recall

Over recent years, evidence has been accumulating in favour of the importance of long-term information as a variable which can affect the success of short-term recall. Lexicality, word frequency, imagery and meaning have all been shown to augment short term recall performance. Two competing theories as to the causes of this long-term memory influence are outlined and tested in this thesis. The first approach is the order-encoding account, which ascribes the effect to the usage of resources at encoding, hypothesising that word lists which require less effort to process will benefit from increased levels of order encoding, in turn enhancing recall success. The alternative view, trace redintegration theory, suggests that order is automatically encoded phonologically, and that long-term information can only influence the interpretation of the resultant memory trace. The free recall experiments reported here attempted to determine the importance of order encoding as a facilitatory framework and to determine the locus of the effects of long-term information in free recall. Experiments 1 and 2 examined the effects of word frequency and semantic categorisation over a filled delay, and experiments 3 and 4 did the same for immediate recall. Free recall was improved by both long-term factors tested. Order information was not used over a short filled delay, but was evident in immediate recall. Furthermore, it was found that both long-term factors increased the amount of order information retained. Experiment 5 induced an order encoding effect over a filled delay, leaving a picture of short-term processes which are closely associated with long-term processes, and which fit conceptions of short-term memory being part of language processes rather better than either the encoding or the retrieval-based models. Experiments 6 and 7 aimed to determine to what extent phonological processes were responsible for the pattern of results observed. Articulatory suppression affected the encoding of order information where speech rate had no direct influence, suggesting that it is ease of lexical access which is the most important factor in the influence of long-term memory on immediate recall tasks. The evidence presented in this thesis does not offer complete support for either the retrieval-based account or the order encoding account of long-term influence. Instead, the evidence sits best with models that are based upon language-processing. The path urged for future research is to find ways in which this diffuse model can be better specified, and which can take account of the versatility of the human brain.

ROC Curves within the Framework of Neural Network Assembly Memory Model: Some Analytic Results

On the basis of convolutional (Hamming) version of recent Neural Network Assembly Memory Model (NNAMM) for intact two-layer autoassociative Hopfield network optimal receiver operating characteristics (ROCs) have been derived analytically. A method of taking into account explicitly a priori probabilities of alternative hypotheses on the structure of information initiating memory trace retrieval and modified ROCs (mROCs, a posteriori probabilities of correct recall vs. false alarm probability) are introduced. The comparison of empirical and calculated ROCs (or mROCs) demonstrates that they coincide quantitatively and in this way intensities of cues used in appropriate experiments may be estimated. It has been found that basic ROC properties which are one of experimental findings underpinning dual-process models of recognition memory can be explained within our one-factor NNAMM.

Effect of delay of first interview and repetition of interview on accuracy and confidence of recall of a flashbulb -type memory

Hearing of the news of the death of Diana, Princess of Wales, in a traffic accident, is taken as an analogue for being a percipient but uninvolved witness to a crime, or a witness to another person's sudden confession to some illegal act. This event (known in the literature as a “reception event”) has previously been hypothesized to cause one to form a special type of memory commonly known as a “flashbulb memory” (FB) (Brown and Kulik, 1977). FB's are hypothesized to be especially resilient against forgetting, highly detailed including peripheral details, clear, and inspiring great confidence in the individual for their accuracy. FB's are dependent for their formation upon surprise, emotional valence, and impact, or consequentiality to the witness of the initiating event. FB's are thought to be enhanced by frequent rehearsal. FB's are very important in the context of criminal investigation and litigation in that investigators and jurors usually place great store in witnesses, regardless of their actual accuracy, who claim to have a clear and complete recollection of an event, and who express this confidently. Therefore, the lives, or at least the freedom, of criminal defendants, and the fortunes of civil litigants hang on the testimony of witnesses professing to have FB's. ^ In this study, which includes a large and diverse sample (N = 305), participants were surveyed within 2–4 days after hearing of the fatal accident, and again at intervals of 2 and 4 weeks, 6, 12, and 18 months. Contrary to the FB hypothesis, I found that participants' FB's degraded over time beginning at least as early as two weeks post event. At about 12 months the memory trace stabilized, resisting further degradation. Repeated interviewing did not have any negative affect upon accuracy, contrary to concerns in the literature. Analysis by correlation and regression indicated no effect or predictive power for participant age, emotionality, confidence, or student status, as related to accuracy of recall; nor was participant confidence in accuracy predicted by emotional impact as hypothesized. Results also indicate that, contrary to the notions of investigators and jurors, witnesses become more inaccurate over time regardless of their confidence in their memories, even for highly emotional events. ^

A Mismatch-Based Model for Memory Reconsolidation and Extinction in Attractor Networks

OSAN, R. , TORT, A. B. L. , AMARAL, O. B. . A mismatch-based model for memory reconsolidation and extinction in attractor networks. Plos One, v. 6, p. e23113, 2011.

A Mismatch-Based Model for Memory Reconsolidation and Extinction in Attractor Networks

OSAN, R. , TORT, A. B. L. , AMARAL, O. B. . A mismatch-based model for memory reconsolidation and extinction in attractor networks. Plos One, v. 6, p. e23113, 2011.