The experiments presented in this thesis were based on the evidence of previous research that suggests that the memory functions dependent on the integrity of the hippocampus and frontal lobes, namely declarative and working memory respectively, are sensitive to the effects of corticosteroids (stress hormones). The first experiment investigated the effects of acute changes of three different levels of cortisol (high vs. control vs.low) and time of day (am vs. pm) on working memory and the episodic and semantic components of declarative memory. This was carried out using a singleblind, mixed (3 x 2) design with three groups of young, healthy males (N = 20 per group). Whilst significant differences in salivary cortisol levels were observed, the results failed to demonstrate any significant differences in any aspect of memory performance as a function of corticosteroids. However, whilst the results also failed to demonstrate significant differences in either aspect of memory performance as a function of time of day, they did identify a significant positive relationship between morning cortisol levels in the control group and two measures of episodic memory in the morning; this suggests that, in the morning, these aspects of memory performance were facilitated by higher cortisol levels. They also identified a significant negative relationship between afternoon cortisol levels in the high cortisol group and one measure of semantic memory in the afternoon; this suggests that, in the afternoon, this aspect of memory performance was impaired by higher cortisol. The second experiment investigated the effects of acute changes in corticosteroids following activation of the different corticosteroid receptors on working memory and the episodic and semantic components of declarative memory. This was carried out using a repeated measures design with nine patients with Addison's disease. The results suggest that, whilst significant effects were not identified across all memory tasks, activation of the mineraIocorticoids appears essential during sensory storage (i.e., encoding) whereas activation of the glucorticoids appears essential during memory consolidation and retrieval. This supports previous research carried out in rats (Oitzl & De Kloet, 1992). The results also suggest that balanced activation of the mineralocorticoids and glucocorticoids is necessary for optimal memory function. The contributions made by both experiments are discussed

The purpose of this thesis was to delineate the neural underpinning of three types of declarative memory retrieval; autobiographical, episodic, and semantic. Autobiographical memory was defined as the conscious recollection of personally relevant events, episodic memory as the recall of stimuli presented in the laboratory, and semantic memory as the retrieval of factual information and general knowledge about the world. Young adults participated in an event-related fMRI study in which pictorial stimuli were presented as cues for retrieval. By manipulating retrieval demands, autobiographical, episodic, or semantic memories were extracted in response to the same stimulus. The objective of the subsequent analyses was threefold: firstly, to delineate regional activations common across the memory conditions, as well as neural activations unique to each memory type (“condition-specific”); secondly, to delineate a functional network common to all three memory conditions; and, thirdly, to delineate functional network(s) of brain regions that show condition-specific activity and to assess their overlap with the common functional network. The results of the first analysis showed regional activations common to all three types of memory retrieval in the bilateral inferior frontal gyrus, left middle frontal gyrus, right caudate nucleus, bilateral thalamus, left hippocampus, and left lingual gyrus. Condition-specific activations were also delineated, including medial frontal increases for autobiographical, right middle frontal increases for episodic, and right inferior temporal increases for semantic retrieval. The second set of analyses delineated a functional network common to the three conditions that comprised 21 functionally connected neural areas. The final set of analyses further explored the functional connectivity of those brain regions that showed condition-specific activations, yielding two functional networks – one involved semantic and autobiographical conditions, and the other involved episodic and autobiographical conditions. Despite their recruiting some brain regions unique to the content of retrieved memories, the two functional networks did overlap to a degree with the common functional network. Together, these findings lend support to the notion of a common network, which is hypothesized to give rise to different types of declarative memory retrieval (i.e., autobiographical, episodic, or semantic) along a contextual continuum (i.e., highly contextualized or highly decontextualized).

The purpose of this thesis was to delineate the neural underpinning of three types of declarative memory retrieval; autobiographical, episodic, and semantic. Autobiographical memory was defined as the conscious recollection of personally relevant events, episodic memory as the recall of stimuli presented in the laboratory, and semantic memory as the retrieval of factual information and general knowledge about the world. Young adults participated in an event-related fMRI study in which pictorial stimuli were presented as cues for retrieval. By manipulating retrieval demands, autobiographical, episodic, or semantic memories were extracted in response to the same stimulus. The objective of the subsequent analyses was threefold: firstly, to delineate regional activations common across the memory conditions, as well as neural activations unique to each memory type (“condition-specific”); secondly, to delineate a functional network common to all three memory conditions; and, thirdly, to delineate functional network(s) of brain regions that show condition-specific activity and to assess their overlap with the common functional network. The results of the first analysis showed regional activations common to all three types of memory retrieval in the bilateral inferior frontal gyrus, left middle frontal gyrus, right caudate nucleus, bilateral thalamus, left hippocampus, and left lingual gyrus. Condition-specific activations were also delineated, including medial frontal increases for autobiographical, right middle frontal increases for episodic, and right inferior temporal increases for semantic retrieval. The second set of analyses delineated a functional network common to the three conditions that comprised 21 functionally connected neural areas. The final set of analyses further explored the functional connectivity of those brain regions that showed condition-specific activations, yielding two functional networks – one involved semantic and autobiographical conditions, and the other involved episodic and autobiographical conditions. Despite their recruiting some brain regions unique to the content of retrieved memories, the two functional networks did overlap to a degree with the common functional network. Together, these findings lend support to the notion of a common network, which is hypothesized to give rise to different types of declarative memory retrieval (i.e., autobiographical, episodic, or semantic) along a contextual continuum (i.e., highly contextualized or highly decontextualized).

Since the field-defining patient HM, consistent links have been made between a region of the brain called the hippocampus and memories that can be consciously declared - so called declarative memories. Declarative memories fall into two categories (1) episodic memories, memories that are highly detailed and re-experiential, and (2) semantic memories, fact-based memories for personal and public information but that have no sense of re-experiencing. It is believed that the intrinsic anatomy of the hippocampus supports episodic memory but not semantic memory. The hippocampus consists of five regions (cornu Ammonis, CA, 1-3, dentate gyrus, subiculum) with each purported to have a specific role in episodic memory acquisition and retrieval. However, controversy surrounds the temporal extent to which episodic memories rely on the hippocampus for retrieval: current consensus suggests the hippocampus supports these memories for five-10 years post-acquisition, but some suggest that it is required for retrieval across the lifetime. Voltage-gated potassium channel-complex antibody-mediated limbic encephalitis (VGKC-complex LE) is a recently described autoimmune disease that causes chronic hippocampal atrophy and mild amnesia on standardized neuropsychological assessment. Two subfields of the hippocampus - CA1 and CA3 - contain the antigenic targets of the disease but it is unknown if specific atrophy of these subfields underlies the hippocampal damage in humans. Here, the human hippocampal subfield volumes of VGKC-complex LE patients (n = 19, mean age: 64.0±2.55; range: 24-71) were investigated using ultra-high spatial resolution MRI at 7.0-Tesla. Assessment also included standardized neuropsychology to examine the impact of the pathology on hippocampal-dependent and -independent memory performance, as well as attention, language, executive function, and perception Declarative memory assessment measured semantic and episodic memory performance across the lifespan. Manual segmentation detected lesions to just CA3, with no volume loss noted elsewhere in the hippocampus or brain. Patients were impaired on hippocampal-dependent memory domains but not the hippocampal-independent and non-memory domains. Notably, episodic memory assessment revealed episodic amnesia across the lifetime except for their earliest memories. This counters the received convention that the hippocampus has a temporally limited role in episodic retrieval. Conversely, the performance of the VGKC-complex LE patients for semantic memory, including a new test developed herein, was comparable to controls across the lifespan. It was then shown that CA3 volume predicted episodic memory performance across the lifetime. Together, the results suggest that VGKC-complex LE provides a novel model of human hippocampal subfield pathology, with which to explore the roles of hippocampal subfields in episodic memory acquisition and retrieval.

Language production is characterized by an unlimited expressive capacity and creative flexibility that allows speakers to rapidly generate novel and complex utterances. In turn, listeners interpret language "on-line", incrementally integrating diverse representations to create meaning in real-time. A challenge for theories of language has been to understand how speakers generate, integrate, and maintain representations in service of language use and processing and how this is accomplished in the brain. Much of this work has focused prefrontal cortex mechanisms such as "working memory". The goal of this dissertation is to understand the role of the hippocampal declarative memory system (HDMS) in language use and processing, specifically in referential processing and narrative construction. To test the role of the hippocampus in referential processing, healthy comparisons, brain damaged comparisons (BDC), individuals with bilateral hippocampal damage participated in an eyetracking experiment in which individuals viewed scenes and listened to short stories. The amount of time participants spent looking at the characters after a pronoun reference was recorded. Healthy comparisons and BDC participants preferentially targeted the first mentioned character while participants with hippocampal damage did not, suggesting that the hippocampus plays a role in maintaining and integrating information, even in short discourse history. In a second experiment, participants with bilateral hippocampal damage and healthy comparisons told narratives multiple times over the course of a month. The narratives were analyzed for the number of words, the number of episodic details, the number of semantic details, the number of editorials and the consistency of details over the multiple tellings. The patients with hippocampal damage told stories that were significantly shorter, more semanticized and less consistent from telling to telling than healthy comparisons. The final goal of this study was to understand the effects of unilateral hippocampal damage on language processing. Individuals with unilateral hippocampal damage participated in all of the previous experiments. It was predicted that individuals with left hippocampal damage would perform worse than individuals with right hippocampal damage, and their performance was significantly impaired across measures. This suggests that the left hippocampus may be particularly important for processing linguistic material outside of even verbal memory.

<p>Memories are not veridical representations of the environment. Rather, an individual's goals can influence how the surrounding environment is represented in long-term memory. The present dissertation aims to delineate the influence of reward and punishment motivation on human declarative memory encoding and its underlying neural circuitry. Chapter 1 provides a theoretical framework for investigating motivation's influence on declarative memory. This chapter will review the animal and human literatures on declarative memory encoding, reward and punishment motivation, and motivation's influence on learning and memory. Chapter 2 presents a study examining the behavioral effects of reward and punishment motivation on declarative memory encoding. Chapter 3 presents a study examining the neural circuitry underlying punishment-motivated declarative encoding using functional magnetic resonance imaging (fMRI), and compares these findings to previous studies of reward-motivated declarative encoding. Chapter 4 presents a study examining the influence of reward and punishment motivation on neural sensitivity to and declarative memory for unexpected events encountered during goal pursuit using fMRI. Finally, Chapter 5 synthesizes these results and proposes a model of how and why motivational valence has distinct influences on declarative memory encoding. Results indicated that behaviorally, reward motivation resulted in more enriched representations of the environment compared to punishment motivation. Neurally, these motivational states engaged distinct neuromodulatory systems and medial temporal lobe (MTL) targets during encoding. Specifically, results indicated that reward motivation supports interactions between the ventral tegmental area and the hippocampus, whereas, punishment motivation supports interactions between the amygdala and parahippocampal cortex. Together, these findings suggest that reward and punishment engage distinct systems of encoding and result in the storage of qualitatively different representations of the environment into long-term memory.</p> / Dissertation

The long-term memory system for what is conscious and can be verbalized – declarative memory- is often separated into memory for general facts and memory for personal events (Squire, 2009; Tulving, 2002). Personal semantics share elements of both semantic memory (i.e., they are facts that can be known) and episodic memory (i.e., they are self-related and idiosyncratic; Renoult, Davidson, Palombo, Moscovitch, & Levine, 2012). According to the taxonomy of personal semantics (Renoult et al., 2012), they vary in proximity to either semantic or episodic memory. Towards one end of the continuum, memory for autobiographical facts such as jobs and names of friends were hypothesized to be closer to general facts. Towards the other end of the continuum, repeated events are summaries of the core elements of similar events that happened more than once (e.g., getting coffee at a coffee shop), and they were hypothesized to be closer to episodic memory (i.e., the recollection of a unique event). Self-knowledge involves self-reflection about one’s own personality traits and preferences; it was thought to be the most distinct from semantic and episodic memory. However, little research had compared personal semantics to both semantic and episodic memory, or to one another, and these proposals needed to be tested experimentally. In this thesis, I compared the neural correlates of three types of personal semantics to semantic memory (study 1, 2, 3) and episodic memory (study 1, 2), and to one another (study 1) using functional magnetic resonance imaging (fMRI; study 1) and event related potentials (ERPs; study 2, 3). Moreover, I examined whether temporal orientation modified the personal semantics’ relationship to the typically atemporal semantic memory (study 2, 3) and to the typically past-oriented episodic memory (study 2). In study 1, general facts, autobiographical facts, repeated events, and unique events were compared using fMRI, in a follow-up to an ERP study (Renoult et al., 2016). In our analyses of the hippocampus (HPC) and posterior medial network (Ritchey, Libby, & Ranganath, 2015), general semantics and autobiographical facts were often not significantly different from one another (except for the left posterior HPC), and repeated events and unique events did not differ from one another in any comparison. I observed a small graded increase of brain activity from general facts to autobiographical facts to repeated events and unique events (with a significant linear trend) in the left posterior HPC. In contrast, no memory type differed in the anterior temporal network (Ritchey et al., 2015). In study 2 and 3, self-knowledge was operationalized as the knowledge of one’s own traits, and could concern past (study 2), present (study 2, 3) and future selves (study 2, 3). A neural correlate of recollection, the Late Positive Component (LPC), had a larger mean amplitude for thinking about the self than others (study 2, 3), and thinking about a past and/or future self than the present self (on average for study 2, and significant for study 3). The amplitude of the LPC for thinking about the past and future selves did not differ from an episodic recognition memory task (or present self-knowledge; study 2). Further, the temporal orientation effect was smaller and not significant when we compared thinking about the present and the future traits of others (study 3). The operationalization of the “other” as a close friend or a group of people did not modify this result (study 3). Together, in addition to Renoult et al. (2016), these findings suggest that: the neural correlates of autobiographical facts, repeated events, and self-knowledge do not overlap perfectly with semantic or episodic memory. Moreover, the temporal orientation of the knowledge is one factor that can influence the proximity of the neural correlates of personal semantics to either semantic or episodic memory.

Patients with schizophrenia are normally treated with one of several antipsychotic medications that differ from one another in the areas of the brain they affect including the dorsal striatum, a subcortical section of the forebrain, and the prefrontal cortex (PFC), located in the anterior part of the frontal lobes. Two different tests of implicit memory, the probabilistic classification learning (PCL) and the Iowa gambling task (IGT), have been shown to rely on the dorsal striatum and the PFC, respectively. Studies have previously shown that patients with schizophrenia treated with antipsychotics that affect the dorsal striatum (e.g., risperidone), have altered performance on the PCL, and those treated with antipsychotics that affect the PFC (e.g., clozapine), have altered performance on the IGT. We tested the hypothesis that patients with schizophrenia treated with olanzapine would have a poorer performance on the IGT, but not the PCL, when compared with controls. This study aimed to clarify conflicting results from prior experiments observing the effects of olanzapine on implicit memory in people with schizophrenia. We also hypothesized that performance of patients taking aripiprazole would be comparable to those taking risperidone, or an FGA; however, we were unable to recruit a sufficient amount of participants to test this hypothesis. Patients with schizophrenia, a mental disorder characterized by a breakdown in relation between thoughts, emotion, and behavior, treated with olanzapine were recruited through local psychiatric clinics or using a newspaper ad. Administration of the Brief Psychiatric Rating Scale (BPRS) and the Mini Mental State Examination (MMSE) preceded a brief questionnaire of demographic information. Participants were tested on the PCL and the IGT using a personal computer. Results revealed poorer performance on both the MMSE and BPRS for patients when compared with controls. Patients taking olanzapine were impaired in learning the PCL but not the IGT when compared with controls. Results suggest that olanzapine acts on the PFC to augment IGT performance but further studies are needed. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2013-07-23 15:09:21.55

Cette thèse s’inscrit dans la thématique de l’identification des bases neurobiologiques du déclin de la mémoire déclarative (MD) lié au vieillissement. Deux difficultés principales sont à noter : 1) la modélisation animale de la MD, mémoire typiquement humaine et 2) le manque d’intégration des différents niveaux d’analyse du fonctionnement cérébral. Nos travaux ont contribué à résoudre ces deux problèmes par le développement d’un modèle murin du déclin de MD lié au vieillissement, associé une approche d’imagerie fonctionnelle de l’expression de la protéine Fos. Une première série de résultats montre que la perturbation du système cholinergique au cours du vieillissement s’accompagne d’une modification de l’activité des systèmes de mémoire. Une deuxième série montre que le déficit de MD observé au cours du vieillissement est attribuable au dysfonctionnement d’un composant de la mémoire à court terme/de travail, le tampon épisodique, sous-tendu par le CA1 hippocampique. / Abstract

Existem crescentes evidências sobre a contribuição da liberação de noradrenalina (NA) central na consolidação das memórias. Teoricamente, o Núcleo do Trato Solitário (NTS) recebe informações e diversos estímulos periféricos, que são então projetados ao Núcleo Paragigantocelular (PGi). Este, por sua vez, utiliza neurotransmissores, predominantemente excitatórios, para influenciar a ativação do Locus Coeruleus (LC). Então, o LC envia projeções noradrenérgicas ao hipocampo e à amígdala, influenciando os processos mnemônicos. Aqui nós demonstramos que a inibição pelo muscimol do NTS, PGi ou LC até 3 horas após o treino na tarefa de reconhecimento de objetos (RO) impede a consolidação da memória medida 24 h após o treino. Adicionalmente, a infusão de timolol, um antagonista de receptores β-adrenérgicos, na região CA1 do hipocampo também impede a consolidação deste tipo de memória. A infusão de NA na região CA1 do hipocampo não altera a retenção da memória, mas, reverte o prejuízo causado pela inibição do NTS, PGi ou LC. A infusão de NMDA no LC após a inibição do NTS ou PGi também reverte essa amnésia. Concomitantemente, verificamos que a inibição NTS, PGi ou LC bloqueia o aumento da expressão do fator neurotrófico derivado do cérebro (BDNF, do inglês brain-derived neurotrophic factor) que ocorre 120 min após o treino na tarefa de reconhecimento de objetos na região CA1 do hipocampo. Também a infusão de NA na região CA1 do hipocampo após a inibição do NTS, PGi ou LC ou de NMDA no LC após a inibição do NTS ou PGi promovem novamente o aumento do BDNF120 min após o treino no RO. Com isso conclui-se que a ativação da via NTS-PGi-LC-Hipocampo é necessária para que ocorra consolidação da memória de RO, na qual desempenha um papel o BDNF hipocampal. / There is evidence of the contribution of brain noradrenaline release (NA) to memory consolidation. The Nucleus of the Solitary Tract (NTS) receives information originated by peripheral stimuli and projects to the Paragigantocellularis Nucleus (PGi), which influences the Locus Coeruleus (LC) through excitatory neurotransmitters. The LC sends noradrenergic projections to the hippocampus and amygdala, influencing the memory processes. Here we show that inhibition by muscimol of NTS, PGi or LC up to 3 h after object recognition training impairs the consolidation of the memory measured 24 h later. Additionally, the infusion of timolol in the CA1 region of hippocampus also inhibits consolidation of this type of memory. The infusion of NA into the CA1 region of hippocampus does not alter memory consolidation of this task, but reverts the deleterious effect of NTS, PGi or LC inhibition. The infusion of NMDA in LC after inhibition of NTS or PGi also reverts the amnesia. Concomitantly, the inhibition of NTS, PGi or LC blocks the increase of brain-derived neurotrophic factor (BDNF) expression in CA1 that occurs 120 min after training in the object recognition task. Further, the infusion of NA in CA1 after inhibition of NTS, PGi or LC; or of NMDA in LC after inhibition of NTS or PGi promotes the BDNF increase seen 120 min after object recognition training. Thus, it is concluded that the activation of NTSPGi- LC-Hippocampus pathway is necessary for consolidation of the object recognition memory, and hippocampal BDNF is involved in this process.