Thesis (Ph.D.)--Boston University / Research in rodents and computational modeling work suggest a critical role for the hippocampus in representing overlapping memories. This thesis tested predictions that the hippocampus is important in humans for remembering overlapping spatial events, and that flexible navigation of spatial routes is supported by key prefrontal and striatal structures operating in conjunction with the hippocampus. The three experiments described in this dissertation used functional magnetic resonance imaging (fMRI) in healthy young people to examine brain activity during context-dependent navigation of virtual maze environments. Experiment 1 tested whether humans recruit the hippocampus and orbitofrontal cortex to successfully retrieve well-learned overlapping spatial routes. Participants navigated familiar virtual maze environments during fMRI scanning. Brain activity for flexible retrieval of overlapping spatial memories was contrasted with activity for retrieval of distinct non-overlapping memories. Results demonstrate the hippocampus is more strongly recruited for planning and retrieval of overlapping routes than non-overlapping routes, and the orbitofrontal cortex is recruited specifically for context-dependent navigational decisions. Experiment 2 examined whether the hippocampus, orbitofrontal cortex, and striatum interact cooperatively to support flexible navigation of overlapping routes. Using a functional connectivity analysis of fMRI data, we compared interactions between these structures during virtual navigation of overlapping and non-overlapping mazes. Results demonstrate the hippocampus interacts with the caudate more strongly for navigating overlapping than non-overlapping routes. Both structures cooperate with the orbitofrontal cortex specifically during context-dependent decision points, suggesting the orbitofrontal cortex mediates translation of contextual information into the flexible selection of behavior. Experiment 3 examined whether the hippocampus and caudate contribute to forming context-dependent memories. fMRI activity for learning new virtual mazes which overlap with familiar routes was compared with activity for learning completely distinct routes. Results demonstrate both the hippocampus and caudate are preferentially recruited for learning mazes which overlap with existing route memories. Furthermore, both areas update their responses to familiar route memories which become context-dependent, suggesting complementary roles in both learning and updating overlapping representations. Together, these studies demonstrate that navigational decisions based on overlapping representations rely on a network incorporating hippocampal function with the evaluation and selection of behavior in the prefrontal cortex and striatum.

The capacity for memory is one of the most profound features of the mammalian brain, and the proper encoding and retrieval of information are the processes that form the basis of learning. The goal of this thesis is to further our understanding of the network-level mechanisms supporting learning and memory in the mammalian brain. The hippocampus has been long recognized to play a central role in learning and memory. Although being one of the most extensively studied structures in the brain, the precise circuit mechanisms underlying its function remain elusive. Principal cells in the hippocampus form complex representations of an animal's environment, but in stark contrast to the interneuron population -- and despite the apparent need for functional segregation -- these cells are largely considered a homogeneous population of coding units. Much work, however, has indicated that principal cells throughout the hippocampus, from the input node of the dentate gyrus to the output node of area CA1, differ developmentally, genetically, anatomically, and functionally. By employing in vivo two-photon calcium imaging in awake, behaving mice, we attempted to characterize the role of dened subpopulations of neurons in memory-related behaviors. In the first part of this thesis, we focus on the dentate gyrus input node of the hippocampus. Chapter 2 compares the functional properties of adult-born and mature granule cells. Chapter 3 expands on this work by comparing granule cells with mossy cells, another glutamatergic but relatively understudied cell type. The second part of this thesis focuses on the hippocampal output node, area CA1. In chapter 4, we characterize an inhibitory microcircuit that differentially targets the sublayers of area CA1. And in chapter 5, we directly compare the contributions of these sublayers to episodic and semantic memory.

Recognizing and understanding where and when events occurred is essential for normal learning and memory of life experiences. Disruptions in the normal processing of spatial and episodic memories can have devastating consequences; in particular, this is one component of the debilitating cognitive deficits of schizophrenia. We are just now beginning to understand the molecular changes in schizophrenia, but still very little is known about how neural circuit are disrupted that lead to behavioral and cognitive dysfunction. In my thesis I will attempt to address two primary questions; how does hippocampal circuitry support spatial-episodic memories, and what goes wrong when these circuits and memories are impaired? First, how precisely do hippocampal circuits support spatial and episodic learning? In 1885 Hermann Ebbinghaus published the first results of a quantitative study of the psychology of memory, showing the predictable forgetting of items over time. Since then, psychologists and cognitive scientists have investigated, described, and defined the precise nature of memory and the behaviors it drives. We eventually realized that memory is not a unitary function of the brain, but that it is dissociable at it’s broadest level into explicit, recollectable memories and the implicit memory of learned skills and abilities. We have now identified networks of brain regions that are essential for these functions. The first functional imaging of the human brain further advanced out understanding of the particular brain regions active during memory tasks and technological advances have allowed us to generate higher resolution functional maps of the brain. Moving to rodent models, we are now getting closer to the memory engram, the set of changes that occur in the brain that store an object, event, or association for future recall. In some particular instances, such as spatial and episodic memories, we already have a very good understanding. But, which particular cells store this information and how does that memory come to be? In my primary thesis project, I will show that the stabilization of firing patterns in principal cells in hippocampal area CA1 supports learning of a spatial reward task. More specifically, as task demands shift pyramidal cells in CA1 specifically encode the reward zone by firing when the mouse is at the correct location. Finally, by modeling the shift of pyramidal cell activity throughout learning, I show the way in which the population of cells shift their firing activity to encode the reward zone. Second, what goes wrong in the normal processing of information that leads to disrupted memory storage and recall? Deficits in spatial and episodic memory are two of the primary cognitive dysfunctions in schizophrenia. While, hallucinations and delusions are perhaps the most widely recognized, they are in part treatable with antipsychotics, while the cognitive and memory deficits are not as well understood, untreatable, and the greatest barrier to rehabilitation. Cognitive deficits observed in schizophrenia patients are, at their core, neuronal circuit disruptions, spanning multiple brain regions and cognitive domains. What can we learn about the circuits underlying these behavioral symptoms? What goes wrong in the brain that is driving these disruptions? I focused on one particular well-characterized brain region (the hippocampus) by recording the activity of hippocampal area CA1 principal cells in an etiologically-validated mouse model of schizophrenia while the mice are actively engaged in a spatial learning task. I identified specific features of the place cell population that are disrupted and predict behavioral deficits - the day-to-day firing stability of the neuronal population and the lack of over-representation of the reward zone. Overall, my work used head-fixed two-photon functional imaging of awake mice to chronically record the activity of distinct components of the hippocampal memory system: long-range inhibitory projections from the entorhinal cortex to hippocampal area CA1, adult-born granule cells in the dentate gyrus, and large heterogeneous populations of CA1 principal cells. I recorded activity during hippocampal-dependent learning and memory tasks in both schizophrenia-mutant and wildtype mice in order to directly probe hippocampal circuits involved in spatial learning. These experiments provided new evidence of the underlying cellular substrates of both healthy and diseased spatial memory processing.

O lobo temporal mesial (LTM) é essencial para tarefas de memória e possui muitas conexões com diferentes áreas do cérebro. Pacientes com epilepsia do LTM, refratários ao tratamento medicamentoso, são candidatos à cirurgia para remoção do foco das crises. Portanto, antes da cirurgia, é essencial avaliar eventuais riscos de declínio das funções de memória, por meio de uma série de testes clínicos. Recentemente, abriu-se a possibilidade de estudar certos aspectos do funcionamento cerebral, de modo não invasivo, utilizando Imagens funcionais por Ressonância Magnética (fMRI). O objetivo deste trabalho foi desenvolver métodos que possibilitem a aplicação de protocolos de memória em estudos de fMRI, com vistas a pacientes com epilepsia. Para a manutenção da atenção durante os estudos de fMRI foi confeccionado um dispositivo infravermelho para registrar as respostas obtidas. Além disso, foi desenvolvido um programa (VOI Analyser) para a otimização das análises dos exames de fMRI. Tanto o dispositivo infravermelho como o programa foram amplamente utilizados em vários projetos de pesquisa permitindo o estudo de tarefas complexas. Neste estudo, a tarefa visava identificar as redes funcionais que participam do processo de codificação e recuperação de memória episódica utilizando tarefas visuais de identificação de cenas complexas. Foram estudados nesse estudo 12 voluntários assintomáticos e 7 pacientes com epilepsia do LTM. O estudo de grupo evidenciou o envolvimento de estruturas do LTM. A tarefa demonstrou ter um nível de dificuldade alta, em especial para pacientes, baseando-se na avaliação do tempo de resposta e nível de acertos. Além do estudo dos grupos, foi realizada uma análise por região de interesse (ROI), com ênfase no complexo amídala-hipocampo. Em seguida, o foco do estudo foi voltado para a assimetria hemisférica funcional, por meio do cálculo do índice de lateralização (IL). Além de rever os resultados obtidos pelo IL convencional, resultados preliminares levaram à proposta de um segundo índice corrigido, considerando a quantidade de voxels e a assimetria das ROI. A utilização do índice corrigido tornou a análise mais estável por diminuir a dependência do limiar estatístico considerado. A seguir, foi realizada uma subdivisão do hipocampo em porção anterior, central e posterior a qual indicou uma maior participação da região posterior na tarefa de codificação e da anterior na tarefa de recuperação, tanto entre os voluntários como em pacientes. / Medial temporal lobe (MTL) is essential for memory tasks and has many connections with different areas of the brain. Patients with MTL epilepsy refractory to medical treatment are candidates for surgery to remove the epileptiform tissue. Therefore, before surgery, it is essential to assess the risk of memory function decrease caused by the procedure, through a series of clinical trials. Recently, there is the possibility of studying certain aspects of brain functioning by using a non-invasive technique: functional Magnetic Resonance Imaging (fMRI). The aim of this work was to implement memory protocols in fMRI studies of epilepsy patients. For attention maintenance during the fMRI study an infrared device was built, in order to record the response times. In addition, a software was developed (VOI Analyser) to optimize the analysis of the fMRI examinations. Both have been widely used in several research projects enabling the study of complex tasks. In this study, the task was intended to identify the functional networks involved in the process of encoding and retrieving of episodic memory using a visual task involving complex scenes. 19 subjects were studied: 12 controls and 7 patients with refractory epilepsy. Group study showed the involvement of structures in MTL. The task has demonstrated a high level of difficulty, especially for patients, based on the analysis of response times and correct hits. In addition to the study of groups, an individual analysis was performed by region of interest (ROI), with emphasis on amigdala-hippocampus complex. Then, functional hemispheric asymmetry was studied, by means of the lateralization index (LI). In addition to the computation of conventional LI, an alternative LI was proposed, which considers voxels occupancy and ROI asymmetry. The use of such modified index tuned the analysis more stable by decreasing the dependence on considered statistical threshold. Moreover, LI was also computed on 3 portions of the hippocampus: anterior, middle and posterior. The results indicated a greater involvement of the posterior portion on the encoding task and anterior one in the recovery task, both for volunteers and patients.

People with schizophrenia are known to have difficulties with episodic memory (EM). The purpose of this investigation was to examine the relationship between theta-power and: i) behavioural measures of EM performance, ii) event- related potential (ERP) indices of recollection and, iii) measures of schizophrenia symptomatology. In doing so, the aim was to gain a better understanding of the basic neural mechanisms that contribute to successful EM performance, and how these may differ for people with schizophrenia. The present investigation adopted an endophenotypic approach and collected measures of schizotypy from student participants to minimise patient factors that can confound interpretations. Fifty- four participants were asked to complete a reality-monitoring exclusion EM paradigm whilst electroencephalogram (EEG) data were collected. Measures of theta-power and ERPs were time-locked to words presented during the retrieval phase. There was a significant positive correlation between theta-power over Fz between 600-1000ms post-stimulus presentation and estimates of recollection in the imagine condition as well as a significant negative correlation between these measures of theta-power for perceive items and ERP indices of recollection for imagine items. There was also a significant positive correlation between measures of frontal theta-power in the imagine condition and negative schizotypy. The epoch employed means it is likely these measures of theta- power reflect processes contributing to the content-specific retrieval of imagined items, and post-retrieval processes acting in service of differentiating imagined items in EM. Results are discussed in terms of suggestions for interventions and directions for future research.

Introdução: O aprendizado intencional/incidental pode influenciar a memória. A persistência deste efeito avaliado ao longo do tempo foi pouco estudada até o momento. Objetivos: Avaliar a persistência da memória comparando as aprendizagens intencional e incidental. Métodos: A amostra (120 sujeitos funcionalmente independentes, com idade variando de 18 a 81 anos), foi subdividida em dois grupos (experimental - condição ‘intenção de aprender’ - e controle). Uma abordagem ecológica foi utilizada para a avaliação do aprendizado incidental. As avaliações foram realizadas dois e sete dias após a codificação. Resultados: A intenção de aprender e a aquisição incidental (a partir de experiências de vida diária) melhoraram a recuperação da memória no dia dois, mas não sete dias após a codificação. Conclusão: Estes achados sugerem que o estado motivacional (espontâneo ou induzido) que modula o sistema da atenção deve ser importante para a melhora na recuperação das informações aprendidas. / Background: The intentional/incidental learning can influence memory. The persistence of this effect assessed over time has been little studied up to date. Objectives: To evaluate the persistence of memory comparing intentional and incidental learning conditions. Method: The sample (120 functionally independent subjects, age ranging from 18 to 81 years old), was subdivided into two groups (experimental - intention to learn condition - and control). An ecological approach was applied for the incidental learning condition. The assessments were performed two and seven days after the encoding. Results: The intention to learn and the incidental acquisition (from daily life experiences) improved performance two but not seven days after the encoding. Conclusions: These findings suggest that motivational state (spontaneous or induced) which module the system of attention may be important for the improvement in the retrieval of the information learned.

Many items encoded into episodic memory are highly similar – seeing a stranger’s car may result in a memory representation which overlaps in many features with the memory of your friend’s car. To avoid falsely recognising the novel but similar car, it is important for the representations to be distinguished in memory. Even in healthy young adults failures of this mnemonic discrimination lead relatively often to false recognition, and such errors become substantially more frequent in older age. Whether an item’s representation is discriminated from similar memory representations depends critically on how it is encoded. However, the precise encoding mechanisms involved remain poorly understood. Establishing the determinants of successful mnemonic discrimination is essential for future research into strategies or interventions to prevent recognition errors, particularly in the context of age-related decline. A fuller understanding of age-related decline in mnemonic discrimination can also inform basic models of memory. This thesis evaluated the contribution of encoding processes to mnemonic discrimination both in young adults and in ageing, within the framework of two prominent accounts of recognition memory, the pattern separation account (Wilson et al., 2006) and Fuzzy Trace Theory (FTT; Brainerd & Reyna, 2002). Firstly, a functional magnetic resonance imaging study in young adults found evidence for differences in regions engaged at encoding of images according to the accuracy of later mnemonic discrimination, consistent with both pattern separation and FTT. Evidence of functional overlap between regions showing activity consistent with pattern separation, and activity associated with later accurate recognition was consistent with a role of cortical pattern separation in successful encoding, but there was no direct evidence that cortical pattern separation contributed to mnemonic discrimination. This first evidence of cortical pattern separation in humans was supported by findings that in the majority of pattern separation regions, response functions to stimuli varied in their similarity to previous items were consistent with predictions of computational models. Regional variation in the dimension(s) of similarity (conceptual/perceptual) driving pattern separation was indicative of variation in the type of mnemonic interference minimised by cortical pattern separation. Further evidence of encoding contributions to mnemonic discrimination was provided by an event-related potential study in young and older adults. Older adults showed less distinct waveforms than young adults at encoding of items whose similar lures were later correctly rejected compared to those falsely recognised, supporting the proposal that age-related encoding impairments contribute to the decline in mnemonic discrimination. Finally, a set of behavioural studies found that older adults’ mnemonic discrimination deficit is increased by conceptual similarity, supporting previous findings and consistent with FTT’s account of greater emphasis by older adults on gist processing. However, older adults required greater reduction in perceptual or conceptual similarity in order to successfully reject lures, as uniquely predicted by the pattern separation account. Together, the findings support the notion that encoding processes contribute directly to mnemonic discrimination and its age-related decline. An integrated view of the pattern separation account and FTT is discussed and developed in relation to the current findings.

<p>There is a body of research on the effect of physical activity oncognition in the old adult population. Less research areconducted on adolescents. The aim for this study is to find out ifadolescents long-term memory is affected by physical activity.144 pupils were asked to rate their physical activity each week.Thereafter their long- term memory was tested through tests onepisodic- and semantic memory. The results showed that thosewho are physically active more than 4 hours had a better scoreon part of the semantic test but no effect was found in theepisodic test. This result indicates that physical activity not onlyaffects working memory, as was shown by previous research butalso has an effect in parts of the semantic long-term memory.</p>

The purpose of the study was to examine the effectiveness of autobiographical memories to support the improvement of episodic memory (i.e., word recall) in patients with mild- stage Alzheimer’s Disease (AD) and healthy older adults. Participants included 20 healthy young-old adults (M Age = 70.90; M MMSE = 28.70), 20 healthy old-old adults (M Age = 79.75; M MMSE = 28.05), and 15 patients with mild-stage AD or mixed dementia (M Age = 74.73; M MMSE = 22.47). Participants were presented with three lists of 30 words, each administered under a different support condition: (1) no cognitive support,(2) autobiographical memory support, and (3) semantic support. In the autobiographical memory support condition, participants associated each to-be- remembered word with a personal memory that was then shortened to a word cue for use in subsequent memory testing. In the semantic support condition, participants associated each to-be-remembered word with a one-word descriptor. Memory was assessed with three recall conditions: immediate free recall, cued recall, and recognition. It was expected that autobiographical memory cues would be more effective than general semantic cues in improving number of words recalled in patients with mild-stage AD and healthy older adults. The results indicated that healthy older adults and patients with mild- stage AD benefited from both forms of cognitive support. Although the young-old group recalled more words in the autobiographical than in the semantic support condition across the three recall conditions, the differences were not significant. The old-old group recalled more words in the autobiographical than in the semantic support condition on tests of immediate free recall. In contrast, the mild AD group recalled more words in the autobiographical than in the semantic support condition on tests of cued recall and recognition. A limitation was the ceiling effect for recognition performance in the young- old and old-old group. Consistent with previous studies, the results indicate that patients with mild-stage AD can benefit from cognitive support to improve episodic memory if support is provided at encoding and retrieval. The results suggest that autobiographical memory cues may be effective for improving everyday memory performance in healthy older adults and patients with mild-stage AD. / Counselling Psychology

Women outperform men in face recognition and are especially good at recognizing other females’ faces. This may be caused by a larger female interest in faces. The aims of this study were to investigate if women were more interested in female faces and if depth of friendship was related to face recognition. Forty-one women and 16 men completed two face recognition tasks: one in which the faces shown earlier had been presented one at a time, and one where they had been shown two and two. The Network of Relationships Inventory was used to assess depth of friendships. As hypothesized, but not statistically significant, women tended to recognize more female faces when faces were presented two and two. No relationships were found between depth of friendships and face recognition. The results gave some support for the previously untested hypothesis that interest has importance in women’s recognition of female faces.