In the field of imaging genetics, brain function and structure are used as intermediate phenotypes between genes and cognition/diseases to validate and extend findings from behavioral genetics. In this thesis, three of the strongest candidate genes for episodic memory, KIBRA, BDNF, and APOE, were examined in relation to memory performance and hippocampal/parahippocampal fMRI blood-oxygen level-dependent (BOLD) signal. A common T allele in the KIBRA gene was previously associated with superior memory, and increased hippocampal activation was observed in noncarriers of the T allele which was interpreted as reflecting compensatory recruitment. The results from the first study revealed that both memory performance and hippocampal activation at retrieval was higher in T allele carriers (study I). The BDNF 66Met and APOE ε4 alleles have previously been associated with poorer memory performance, but their relation to brain activation has been inconsistent with reports of both increased and decreased regional brain activation relative to noncarriers. Here, decreased hippocampal/parahippocampal activation was observed in carriers of BDNF 66Met (study II) as well as APOE ε4 (study III) during memory encoding. In addition, there was an additive gene-gene effect of APOE and BDNF on hippocampal and parahippocampal activation (study III). Collectively, the results from these studies on KIBRA, BDNF, and APOE converge on higher medial temporal lobe activation for carriers of a high-memory associated allele, relative to carriers of a low-memory associated allele. In addition, the observed additive effect of APOE and BDNF demonstrate that a larger amount of variance in BOLD signal change can be explained by considering the combined effect of more than one genetic polymorphism. These imaging genetics findings support and extend previous knowledge from behavioral genetics on the role of these memory-related genes.

Learning occurs not only when we encode information but also when we test our memory for this information at a later time. In three empirical studies, I investigated the individual and combined effects of interleaved testing (via repeated rounds of study and test practice) and encoding (via motor enactment) during learning on later cued-recall performance for action phrases. Such materials (e.g., “water the flowers”) contain a verb and a noun and approximate everyday memory that typically revolves around past and future actions. Study I demonstrated that both interleaved testing (vs. study only) and enactment (vs. verbal encoding) individually reduced the forgetting rate over a period of 1 week, but these effects were nonadditive. That is, the direct testing effect on the forgetting rate occurred for verbal, but not for enactive encoding; enactment reduced the forgetting rate for the study-only condition, but not for the study–test condition. A possible explanation of these findings is that both study techniques sufficiently elicit verb–noun relational processing that cannot be increased further by combining them. In Studies II and III, I replicated these testing-effect results and investigated whether they varied as a function of recall type (i.e., noun-cued recall of verbs and verb-cued recall of nouns). For verbal encoding (Study II), the direct testing effect was of similar size for both noun- and verb-cued recall. For enactive encoding, the direct testing effect was lacking irrespective of recall type. In addition, interleaved tests enhanced subsequent re-encoding of action phrases, leading to an accelerated learning. This indirect testing effect was increased for the noun-cued recall of verbs—for both verbal and enactive encoding. A possible explanation is that because nouns are semantically more stable, in that the meaning of nouns changes less over time and across different contexts, they are more recognizable. Hence, associated information (e.g., about the recall status) may be more available to the learner during restudy that, in turn, can initiate more effective re-encoding. The two different testing benefits (i.e., direct and indirect) may, partly, engage different mechanisms, as they were influenced differentially by the manipulations of encoding type and recall type. The findings presented in the thesis provide new knowledge regarding the combined effects of strategies and materials that influence memory. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1. Epub ahead of print. Paper 2: Manuscript. Paper 3: Manuscript.</p>

The current study investigated whether there were age-related differences in episodic feeling-of-knowing (FOK) accuracy and whether accuracy was influenced by when the FOK judgments were made. Younger and older participants were randomly assigned to 1 of 4 conditions that manipulated the timing of the FOK in relation to cued-recall and recognition. Age-related differences in FOK accuracy were not reliable either when the FOK was immediate or when it was delayed. Moreover, FOK accuracy was above chance for both age groups. Remember/Know (RK) judgments correlated reliably with FOKs for unrecalled words for both age groups and did not vary by FOK timing. Verbal ability, but not education, health, or perceptual speed, correlated with FOK accuracy. These results suggest that rather than a general age-related deficit in episodic FOK accuracy, the presence of age-related differences in resolution might be influenced by individual differences in such factors as verbal ability and frontal functioning.

In episodic recognition memory, differentiation is the assumption that a study item's pre-existing memory trace is updated when additional study for that item is provided. The differentiation models commonly suppose that episodic memory encoding conforms to this process. Although these models have received considerable support within the literature, results inconsistent with their predictions have also been found. The present paper examined conflicting findings that resulted from study list strength manipulations with rhyming word stimuli and semantically related stimuli. As part of the investigation into this discrepancy, 79 university students participated in a computer-based recognition memory task. In this task, word categories of varying length (short vs. long) and word type (rhyming vs. taxonomic) were presented either five times or once within a mixed study list. Following study, an old-new response paradigm was used to examine recognition memory performance. Results from both the rhyming and taxonomic category stimuli were largely consistent with the previous findings in the literature, indicating that word type does appear to influence recognition memory, even within a mixed study list. These findings are interpreted primarily in terms of word type similarity predictions made by one of the differentiation models. Other possible explanations are also discussed.

The aim of this thesis is to examine the underlying cognitive and neural processes at play during retrieval of temporal and contextual source information. This was assessed across three experimental chapters. In the first experimental chapter, Chapter 2, the neural loci of context associations were assessed. Rats trained on an odour-context association task were given lesions to either the Lateral Entorhinal Cortex (LEC) or sham lesions. After surgery, performance on the odour-context task was assessed. It was hypothesised that memory for previously learned odour-context associations would be impaired following LEC lesions but not sham lesions. The results supported this hypothesis, demonstrating impaired memory for the previously learned odour-context associations in the LEC lesion group compared to the Sham lesion. In Chapter 3, the underlying retrieval processes used to retrieve time and context in human memory was assessed across three experiments. It was hypothesised that time would be remembered accurately using both recollection and familiarity, while correct context memory should rely on recollection alone. Two out of the three experiments supported this hypothesis, demonstrating that temporal information can be retrieved using familiarity in certain instances. The final experimental Chapter 4 used fMRI to extend Chapter 3 and examine whether neural activity would be greater in regions associated with recollection during memory for context, while activity in familiarity-related regions would be higher during memory for time. Results revealed no support for these predictions with no regions linked to recollection showing greater context-related activity, and no regions previously linked to familiarity exhibiting increased activation as temporal information was retrieved. The results are discussed in relation to established recollection and familiarity frameworks and previous work examining the neural substrates supporting memory for time and context.

Contexte – Cette recherche analyse les liens entre la pathologie démentielle de type maladie d’Alzheimer (MA) et le Trouble Stress Post Traumatique (TSPT) et vérifie si un traitement du TSPT chez les sujets souffrant de MA peut améliorer l’efficience de la mémoire épisodique, des fonctions cognitives globales et de la qualité de vie des patients. Méthode – Après avoir passé en revue la littérature sur les liens existants entre TSPT et pathologies de type MA, nous proposons l’hypothèse que la détection et le traitement d’un TSPT chez les sujets souffrant de MA pourrait améliorer la mémoire épisodique verbale et la mémoire autobiographique épisodique avec des effets positifs sur l’évolution de la pathologie démentielle. Nous présentons une recherche longitudinale, analysant les données recueillies auprès de 20 sujets cibles (TSPT et MA) et de 20 sujets témoins (MA sans TSPT). Durant trois sessions successives (T0, T1 et T2) séparées par des intervalles de six mois, les différentes composantes de la mémoire épisodique ont été suivies à l’aide de tests spécifiques. L’évolution d’une MA a été vérifiée avec le Mini-Mental State Examination (MMSE). Pour le groupe cible, la présence du TSPT et la qualité de vie ont été testées et un traitement du TSPT a eu lieu entre T0 et T1.Résultats – La littérature scientifique souligne des similitudes entre le TSPT et la MA, avec un rôle clé de la mémoire épisodique. Nos résultats confirment que le traitement d’un TSPT chez les sujets souffrant de MA améliore significativement tous les indicateurs testés : rappel et reconnaissance de mots, rappel immédiat et différé, rappel d’événements de vie, fonctionnement cognitif global et qualité de vie.Discussion/Conclusion – Des données solides existent en faveur de la proposition d’une détection systématique et d’un traitement du TSPT chez les patients avec MA. Cette recherche suggère une voie prometteuse pour les soins de patients atteints de MA et souffrant d’un traumatisme psychique non résolu. / Purpose – This research aims to analyze the links between Alzheimer’s disease (AD) and Post-Traumatic Stress Disorder (PTSD) and to verify if a PTSD treatment can improve episodic memory, global cognitive functioning and quality of life in AD patients.Methods – We review the literature about the links between PTSD and AD, building on several theoretical models. We propose the hypothesis that the treatment of PTSD in AD can improve verbal episodic memory and autobiographical episodic memory with some positive effects on AD evolution. We present a longitudinal study in order to confirm the likely benefits of such an approach. There were 20 participants in the target group (AD and PTSD) and 20 participants in the control group (AD without PTSD). During three sessions (T0, T1 and T2) separated by an interval of six months, different components of episodic memory were assessed with specific tests. AD evolution was assessed with the Mini-Mental State Examination (MMSE). For the target group, PTSD presence and quality of life were also assessed, and treatment for PTSD was undertaken between T0 and T1 for the target group.Results/Findings – The analysis of scientific literature highlighted some clinical, cognitive and neurobiological similarities between AD and PTSD with a key-role of episodic memory. The results of the research indicate that PTSD treatment in AD participants improves significatively all assessed indicators: word recall, word recognition, immediate recall, delayed recall, personal recent events recall, personal lifetime events recall, global cognitive abilities (MMSE) and quality of life.Discussion/Conclusion – There are strong theoretical and practical reasons to search for an effective intervention for PTSD in AD patients. This study indicate a promising avenue for therapeutic care of AD patients with involved trauma.

Made available in DSpace on 2014-12-17T15:36:36Z (GMT). No. of bitstreams: 1 FlavioFB_TESE_partes_autorizadas.pdf: 1203438 bytes, checksum: 7fffdef6a1497cb97b87a0103365db00 (MD5) Previous issue date: 2011-01-20 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Episodic memory refers to the recollection of what, where and when a specific event occurred. Hippocampus is a key structure in this type of memory. Computational models suggest that the dentate gyrus (DG) and the CA3 hippocampal subregions are involved in pattern separation and the rapid acquisition of episodic memories, while CA1 is involved in memory consolidation. However there are few studies with animal models that access simultaneously the aspects &#8215;what-where-when . Recently, an object recognition episodic-like memory task in rodents was proposed. This task consists of two sample trials and a test phase. In sample trial one, the rat is exposed to four copies of an object. In sample trial two, one hour later, the rat is exposed to four copies of a different object. In the test phase, 1 h later, two copies of each of the objects previously used are presented. One copy of the object used in sample trial one is located in a different place, and therefore it is expected to be the most explored object.However, the short retention delay of the task narrows its applications. This study verifies if this task can be evoked after 24h and whether the pharmacological inactivation of the DG/CA3 and CA1 subregions could differentially impair the acquisition of the task described. Validation of the task with a longer interval (24h) was accomplished (animals showed spatiotemporal object discrimination and scopolamine (1 mg/kg, ip) injected pos-training impaired performance). Afterwards, the GABA agonist muscimol, (0,250 &#956;g/&#956;l; volume = 0,5 &#956;l) or saline were injected in the hippocampal subregions fifteen minutes before training. Pre-training inactivation of the DG/CA3 subregions impaired the spatial discrimination of the objects (&#8215;where ), while the temporal discrimination (&#8215;when ) was preserved. Rats treated with muscimol in the CA1 subregion explored all the objects equally well, irrespective of place or presentation time. Our results corroborate the computational models that postulate a role for DG/CA3 in spatial pattern separation, and a role for CA1 in the consolidation process of different mnemonic episodes / A mem?ria epis?dica refere-se ? capacidade de recordar quando e onde um determinado evento ocorreu. O hipocampo ? uma estrutura chave para esse sistema de mem?ria e diversos estudos te?ricos t?m sugerido que o giro denteado (GD) e CA3 est?o envolvidos na aquisi??o r?pida da mem?ria epis?dica, enquanto a sub-regi?o CA1 estaria envolvida na separa??o temporal de diferentes epis?dios. Contudo, h? poucos estudos em modelos animais com tarefas que acessem os aspectos &#8213;o que&#8214;, &#8213;quando&#8214; e &#8213;onde&#8214; simultaneamente. Recentemente, uma tarefa de reconhecimento de objetos em roedores que avalia a mem?ria similar a epis?dica foi desenvolvida. A tarefa consiste em duas sess?es de treino e uma de teste, cada uma com 5 minutos de dura??o. Na primeira sess?o de treino o rato ? colocado em uma arena familiar com quatro objetos id?nticos (A), ap?s uma hora o rato ? reexposto ao campo com outras c?pias (B). O teste ? realizado 1 h depois, e o animal ? apresentado a dois objetos da segunda e dois objetos da primeira exposi??o, sendo que um dos objetos A est? uma nova localiza??o no campo aberto. Espera-se que o objeto mais antigo e deslocado seja o mais explorado. O objetivo deste estudo foi avaliar o papel das sub-regi?es hipocampais na aquisi??o da mem?ria similar a epis?dica em ratos. Inicialmente, avaliamos a capacidade de ratos Wistar evocarem essa tarefa ap?s 24 h de reten??o, uma vez que a tarefa foi desenvolvida inicialmente com um intervalo de 1h. De fato, os animais conseguiram discriminar a localiza??o e a ordem de apresenta??o dos objetos ap?s um intervalo de 24h. Al?m disso, a administra??o de escopolamina (1 mg/kg, ip) imediatamente ap?s o treino prejudicou o desempenho dos animais, o que favoreceu a valida??o desse protocolo com esse intervalo de reten??o. Esse novo intervalo permitiu avaliar o efeito da inativa??o tempor?ria do giro denteado/CA3 e de CA1 na aquisi??o desta tarefa. Muscimol, um agonista gaba?rgico (0,250 &#956;g/&#956;l; volume = 0,5 &#956;l), ou solu??o salina no mesmo volume foram injetados nessas sub-regi?es quinze minutos antes da primeira sess?o de treino. A inativa??o pr?-treino do GD/CA3 prejudicou a discrimina??o espacial dos objetos, enquanto que a inativa??o de CA1 levou a explora??o igual dos objetos, independentemente da localiza??o ou ordem de apresenta??o. Estes resultados corroboram os modelos te?ricos, indicando um papel importante de GD/CA3 na aquisi??o r?pida de mem?rias epis?dicas, assim como na separa??o de padr?es espaciais, enquanto a sub-regi?oCA1 estaria relacionada com a consolida??o dos diferentes epis?dios

Introdução: independentemente do grau de incapacidade física, o declínio cognitivo tem sido considerado motivo de maior impacto em importantes aspectos da vida diária dos pacientes com Esclerose Múltipla (EM) como o gerenciamento de tarefas domésticas, participação na sociedade e manutenção do emprego. Alterações de Memória Episódica (ME) em pacientes com EM são comumente descritas na literatura, sendo observadas em 40% a 65% dos casos. Seu impacto já é observado em pacientes com Esclerose Múltipla Remitente-Recorrente (EMRR) incipiente e pode ser um indicador de pior prognóstico para evolução da doença. Adicionalmente, déficits na memória verbal bem como na velocidade de processamento de informação e função executiva predizem condição ocupacional dos portadores da doença. Há vários trabalhos transversais na literatura científica que visam investigar sobre alterações cognitivas encontradas nestes pacientes. Entretanto, os estudos longitudinais são escassos e estes têm revelado resultados inconclusivos e divergentes. Além disso, tanto nos estudos transversais quanto nos estudos longitudinais, não há preocupação em caracterizar de forma aprofundada o declínio da Memória Episódica Verbal (MEV) especificamente. Objetivo: neste estudo, investigamos a MEV de pacientes com EMRR e sua evolução através de avaliação longitudinal. Métodos: vinte e nove pacientes com EMRR foram submetidos a duas avaliações neuropsicológicas realizadas entre um intervalo de tempo médio de 4,5 anos. Vinte e seis controles saudáveis foram submetidos à uma única e idêntica avaliação neuropsicológica. Considerou-se nível de significância p < 0,05 para delinear diferenças estatísticas entre os grupos nas análises Mann Withney e Wilcoxon pareado. Resultados: não houve diferença estatística nos resultados dos testes de MEV entre a primeira e a segunda avaliação neuropsicológica realizada pelos pacientes. Houve discrepância estatística nos resultados dos testes de MEV entre o grupo de controles e grupo de pacientes no momento da avaliação inicial. Em contrapartida, no momento da segunda avaliação o grupo de pacientes não se diferenciou estatisticamente do grupo dos controles. Conclusões: a estabilização ou discreta melhora do desempenho dos pacientes com EMRR entre a avaliação inicial e o follow-up em testes de MEV, pode estar relacionada ao fato de que neste estudo foram incluídos predominantemente jovens adultos na amostra, com a forma clínica mais branda da doença. Possível processo de neuroplasticidade cerebral, ou mesmo inclusão de casos benignos da EM precisam ser considerados. Atrelado a isso, deve-se considerar que o breve período de follow-up pode não ter sido o suficiente para detectar possíveis déficits a longo prazo / Introduction: Regardless of the degree of physical disability, cognitive decline has been considered as having the greatest impact on important aspects of the daily life of Multiple Sclerosis (MS) patients, such as managing household tasks, participation in society and maintaining employment. Changes in Episodic Memory (EM) in MS patients are commonly described in the literature and are observed in 40% to 65% of cases. Its impact is already observed in patients with incipient Relapsing-Remitting Multiple Sclerosis (RRMS) and may be an indicator of a worse prognosis for disease progression. In addition, deficits in verbal memory as well as in the speed of information processing and executive function predict the occupational condition of the patients with the disease. There are several transversal works in the scientific literature that aim to investigate cognitive alterations found in these patients. However, longitudinal studies are scarce and these have revealed inconclusive and divergent results. Moreover, in both crosssectional studies and longitudinal studies, there is no concern to characterize in depth the decline of Verbal Episodic Memory (VEM) specifically. Objective: In this study, we investigated the VEM of patients with RRMS and its evolution through longitudinal evaluation. Methods: Twenty-nine patients with RRMS were submitted to two neuropsychological evaluations performed between a mean time interval of 4.5 years. Twenty-six healthy controls were submitted to a single and identical neuropsychological evaluation. A significance level of p < 0.05 was used to delineate statistical differences between the groups in the Mann Withney and Wilcoxon paired analyzes. Results: There was no statistical difference in the VEM results between the first and second neuropsychological evaluation performed by the patients. There was a statistical discrepancy in the VEM results between the control group and the patient group at the time of the initial evaluation. In contrast, at the time of the second evaluation, the group of patients did not differ statistically from the control group. Conclusions: The stabilization or discrete improvement in the performance of RRMS patients between the initial evaluation and the follow-up in the VEM trials may be related to the fact that in this study, predominantly young adults were included in the sample, with the mildest clinical form of the disease. Possible process of cerebral neuroplasticity, or even inclusion of benign cases of MS need to be considered. Coupled with this, one should consider that the brief follow-up period may not have been enough to detect possible long-term deficits

This report aims to explore if pattern recognition and pattern separation tasks performance degenerate with age. This as there are studies by Brickman et al. (2014) that suggest that these tasks are being performed by the hippocampus in particular, the dentate gyrus part. The tasks used in this report were replicated from a study in which it was assumed that they tested this parts. As both the hippocampus and the dentate gyrus supposedly degenerate with age, the tasks tested this degeneration by looking if the participant’s performance on the tasks changed with age. The performance on the pattern separation task did not change with age while the pattern recognition task did. This preservation of pattern separation might mean that the pattern separation tasks does not measure the dentate gyrus. It might also mean that the hippocampus might not degenerate as previously assumed or that the pattern separation task really test the hippocampus.

Alzheimer’s disease (AD) is a neurodegenerative disorder, characterised by severe memory loss and the accumulation of amyloid-beta (Aβ) and tau pathology within neocortex and medial temporal lobe (MTL) structures. Episodic memory impairment is a defining feature of early AD. The hippocampal formation (HF), a major network involved in both memory formation and retrieval is one of the first areas affected by AD pathology. However, the aetiology of AD is unknown; specifically how Aβ and tau pathologies cause memory impairment and how the physiological function of HF is affected. In this thesis, the 3xTgAD mouse was used as a high fidelity model of human AD pathological progression to study the function of HF during early (intracellular Aβ) and more progressive (extracellular plaque and hyperphosphorylated tau pathology) AD stages, referred to as ‘young’ and ‘old’ respectively. Specifically we: i) applied the hippocampal-dependent What-Where-Which (WWWhich) task to study the onset and progression of episodic-like memory decline (previously uncharacterised in the 3xTgAD mouse); ii) examined allocentric spatial memory in radial arm water maze (RAWM) and spontaneous alternation (SA) behaviour in T-Maze to discern whether cognitive differences exist between spontaneous and negatively reinforced tasks (the latter could be influenced by an exaggerated stress response); and iii) performed electrophysiological recordings in vivo from the HF of urethane-anaesthetised 3xTgAD and control mice to study basic synaptic connectivity, short-term synaptic plasticity and neuronal reverberation across the CA1-DG axis using a multi-site electrode. Our results showed an early and specific deficit for WWWhich episodic-like memory in the 3xTgAD model, with a decline in performance witnessed in mice as young as 3 months. In contrast, 3xTgAD component memory comprising single or dual associations of ‘What’, ‘Where’, ‘Which’ and ‘When’ remained intact suggesting the episodic impairment was due to dysfunction during the association of three component information streams within hippocampus (Chapters 3 and 4). 3xTgAD mice were equally impaired for allocentric spatial memory in RAWM and in their SA behaviour, suggesting no inherent advantage of examining cognition in paradigms which elicit behavioural distress (Chapter 5). We witnessed the development of subtle synaptic abnormalities in young 3xTgAD mice in the form of enhanced short-term paired pulse facilitation in CA1 and DG, however, a paucity of response facilitation in CA1 in response to train stimulation. In contrast, we saw intact basic synaptic function (fibre integrity and synaptic connectivity) in 3xTgAD mice of both young and old ages, suggesting gross hippocampal circuitry remained in place (Chapter 6). Finally, we saw an effect of normal ageing on cognition in the WWWhich and spatial tasks (Chapters 4 and 5), and a decline in neuronal reverberation with age in control and 3xTgAD mice. Dysfunction in these two parameters (behavioural and electrophysiological) coincided with the onset of intracellular Aβ accumulation within HF in 3xTgAD mice. This suggests a role of intracellular Aβ in impairing the physiological function of HF in AD which translates as cognitive decline in hippocampal-dependent forms of memory. Episodic memory was found to be especially sensitive to AD-related pathology and impairment, thus the WWWhich task may be applied to faithfully study the onset of cognitive decline in other AD mouse models. Further examination of the relative contribution of Aβ to hippocampal dysfunction in the 3xTgAD model is required.