Age-related inhibitory effects were investigated during spatial memory performance. In Experiment 1, 15 young (M = 20 years) and 16 old adults (M = 70 years) completed two spatial tasks (i.e., Block Suppression Test, Corsi Block Tapping Test) that differed in need for inhibitory processing. Accuracy differences within each task revealed age-related differences in spatial working memory and between task differences revealed that older adults had difficulty ignoring irrelevant items. Experiment 2 (10 young, 10 old adults) examined whether the distractibility of irrelevant items in the inhibition task (i.e. BST) accounted for the age-related inhibitory effects. Findings were largely consistent with the initial experiment indicating that inhibitory function was affected by adult aging.

Both model-driven and data-driven approaches can be used to analyse fMRI data on group level but they have their respective advantages and disadvantages. A model-driven approach such as the GLM requires prior knowledge of the BOLD contrast while offering a simple way of performing inference. In contrast, ICA is a data-driven approach that instead takes full advantage of the data but in which it is harder to make meaningful inference. A method for combining GLM and ICA on group level utilising their respective strengths is therefore tested. The performance of the method highly relies on ICA’s ability to estimate accurate sources. Violation of ICA’s assumptions can potentially affect this ability and this aspect is investigated to get a broader understanding. The method is tested on both simulated and real fMRI data consisting of subjects with schizophrenia and healthy controls. The simulation shows high power but a higher false positive rate than expected. The method is able to find the brain regions that are typically active during a spatial working memory task, such as the posterior parietal cortex and the dorsolateral prefrontal cortex. It is further found that ICA performs especially poorly when the sources are uniformly distributed on the unit sphere.

Animals learn from past experience to guide future behavior and improve survival. This ability relies in part on specific episodic memories of past events encoded by neuronal activity and stored by updated connectivity between neurons. The unique architecture and activity of the hippocampus and related cortical regions are crucial for supporting these episodic memories. Hippocampal models propose the need for a pattern separation function to disambiguate similar memories and a pattern completion function to recall the full breadth of an experience from a partial cue. Past work suggests that neuronal activity in the dentate gyrus (DG) of hippocampus contributes to memory-guided navigation and plays a role in pattern separation. We tested the role of specific DG neuronal ensembles (i.e. engrams) in supporting the pattern separation function and altering downstream neural activity and, ultimately, behavior. To that end, we used an activity-dependent labeling paradigm to identify and manipulate engram ensembles during navigational and contextual fear conditioning (CFC) tasks. The results of our first experiment revealed that the DG partially disambiguates specific maze trajectories while still exhibiting greater overlap than chance levels. These findings suggest that the DG contributes to memory-guided navigation by both pattern separation and completion. Our second experiment manipulated nonspecific memory-related DG populations to assess the functional role of these cells in task generalization across contexts and ongoing spatial working memory. Optogenetic activation of these ensembles disrupted performance accuracy and exhibited a time-dependent impairment effect suggesting a role of the DG in task generalization between contexts. The final experiments investigated the physiological ramifications of artificial memory ensemble reactivation during ongoing navigation behavior. We recorded local field potential (LFP) and single unit responses in mouse DG and CA1 during artificial reactivation of a DG-mediated CFC memory engram. Stimulation of the DG entrained LFP and individual cell spiking in a subpopulation of CA1 pyramidal cells. Their spatial information was disrupted by stimulation despite stable navigational representation before and after the manipulation. Further, the presence of stimulation could be reliably decoded by the firing rate of the network, suggesting that engram reactivation forced the CA1 to adopt a repeatable state, perhaps to support behavioral expression of memories. In summary, my dissertation work presents empirical and theoretical evidence for the role of the dentate gyrus as a single node of an extended separation/completion circuit distributed anatomically and temporally as a neural mechanism supporting episodic memory.

Det finns individuella skillnader i människors medvetenhet om var de befinner sig och om hur deras omgivningar ser ut, särskilt efter att de har förflyttat sig. För att beskriva detta används allmänt begreppet lokalsinne, som kan definieras: ”förmågan att orientera sig och hitta rätt”. Studiens syfte var att undersöka om det finns samband mellan hur människor skattar sitt lokalsinne och deras faktiska förmåga att bearbeta visuell information. Trettiosju deltagare genomförde självskattning av lokalsinne, ett test som mätte kapacitet i visuo-spatialt arbetsminne och ett test som mätte mental rotationsförmåga. Resultaten från studien visar att mental rotationsförmåga har samband med i självskattat lokalsinne och kapaciteten i visuo-spatialt arbetsminne. Av det här drogs slutsatsen att mental rotationsförmåga är en integrerad del av individers navigationsförmåga. / There are individual differences in people's awareness of where they are and what their surroundings look like, especially after they have physically moved around in their surroundings.To describe this, the concept sense of direction is generally used, which can be defined as: "the ability to orient oneself and find the right way". The purpose of this study was to investigate whether there is a relationship between how people estimate their sense of location and their actual ability to process visual information. Thirty-seven participants completed self-assessment of local sense, a test measuring capacity in visuo-spatial working memory and a test measuring mental rotation ability. The results of the study show that mental rotation ability is related to self-rated local sense and visuo-spatial working memory capacity. From this it was concluded that mental rotation ability is an integral part of individuals' navigation ability.

In adults, sex and steroid hormone differences have been observed in several cognitive domains, most notably in the domains of spatial processing, language, and manual dexterity. Age-related cognitive differences have also been observed throughout the lifespan, with many improvements occurring during childhood. While cognition improves with age, other factors (i.e., sex, pubertal status, and steroid hormone levels) may also influence development. The present study compared performance on a visuo-spatial working memory (VSWM) task and three simple articulation (ART) tasks. Pubertal status and hormone levels, at time of testing, were measured. Sex, pubertal status, and hormone differences were observed. This study is one of the first to provide evidence of such differences in typically developing adolescents.

Ionotropic glutamate AMPA-type receptors mediate fast excitatory neurotransmission in the central nervous system and are essential for synaptic plasticity. Expression of the receptor subunits varies with cell type, stage of development and brain region. Subunit composition determines functional properties of the receptor, including gating kinetics and synaptic trafficking. The research aimed to selectively disrupt the GluA1 subunit abundantly expressed in the hippocampus of the wild-type mouse, so as to examine its role in learning and memory. Site-directed monoclonal antibodies were engineered to target the extracellular amino-terminal domain of GluA1 for subunit-selective manipulation. The antibody-binding region was selected for heterogeneity and accessibility based on the amino acid sequences and crystal structures solved for the AMPA receptor subunits. Immunisations of peptide antigen in mice generated serum antibodies that recognise the equivalent epitope on the fully folded GluA1 subunit. The antigen-binding Fab fragment of the monoclonal anti-GluA1 antibody was cloned from hydridoma mRNA and purified from large-scale transient expression in mammalian cells. Biophysical characterisations of anti-GluA1 Fab immunoglobulin showed high specificity and affinity for the target subunit. Acute bilateral intrahippocampal administration of anti-GluA1 Fab protein into awake, behaving wild-type mice produced dissociations in spatial memory performance that resembled GluA1-/- knockout mice. Impaired short-term spatial working memory but intact long-term spatial reference memory observed with anti-GluA1 Fab infusions suggested that the immunoglobulin reagent exerted an acute, reversible, localised, GluA1-specific antagonism in the brain. The findings argue for a critical involvement of the hippocampal GluA1 subunit in certain short-term memory processes, but not in other distinct long-term memory processes. Temporal resolution of the antibody-mediated disruption revealed novel fractionations of short-term memory performance never before observed in the GluA1-/- knockout mice, demonstrating the strength of the monoclonal anti-GluA1 antibodies as an investigative tool.

La consommation de cannabis chez les adolescents et les jeunes adultes constitue un facteur de risque de développement de symptômes psychotiques. L’objectif de cette thèse était d’étudier les conséquences à l’âge adulte d’une exposition chronique aux cannabinoïdes pendant l’adolescence. Nous avons réalisé ces études chez le Rat et démontré que l’administration chronique d’un agoniste des récepteurs cannabinoïdes, le CP55, 940, durant l’adolescence (JPN 29 à 50) entraîne à l’âge adulte des déficits significatifs et durables de la mémoire à court terme et de la mémoire de travail spatiale. Le même traitement administré à l’âge adulte (JPN 70 à 91) n’entraîne pas de déficits cognitifs à long terme. L’apport de ces travaux et leur originalité a été de contribuer à la compréhension des mécanismes sous-jacents au développement de ces déficits cognitifs. Nous avons mis en évidence, chez ces rats à l’âge adulte, une diminution significative de l’amplitude de la PLT induite sur le circuit reliant l’hippocampe au cortex préfrontal, fortement impliqué dans les processus de mémoire et dans la physiopathologie de la schizophrénie. Ce déficit de PLT a été mis en relation avec des modifications de la morphologie des neurones pyramidaux de la couche II/III du cortex préfrontal et de certains marqueurs de la plasticité synaptique. Ces résultats confirment que l'adolescence est une période critique et vulnérable aux effets délétères des cannabinoïdes sur les processus cognitifs. L’étude des bases neurobiologiques de ces effets, en particulier en ce qui concerne les altérations des circuits préfrontaux, devrait améliorer notre compréhension des mécanismes de l'émergence de la psychose et conduire à de nouvelles stratégies thérapeutiques et de prévention. / Cannabis use among adolescents and young adults is a risk factor for developing psychotic symptoms. The aim of this thesis was to study the consequences at different levels (behavioral, functional and structural in adulthood) of chronic exposure to synthetic cannabinoids during adolescence in the rat. We showed that chronic administration of a cannabinoid receptor agonist, CP 55940, during adolescence (PND 29-50) in rats leads to significant long-term deleterious effects in short-term memory and in spatial working memory in adulthood. The same treatment administered in adulthood (PND 70-91) does not cause long-term cognitive deficits. We further demonstrated that cannabinoid during adolescence leads in adults to a significant decrease in the expression of LTP induced in hippocampal to prefrontal cortex synapses, a circuit directly involved in memory processes and in the pathophysiology of schizophrenia. This alteration could be associated with changes in the morphology of pyramidal neurons in layer II / III of PFC and/or in the density of synaptic markers that we also identified in these cannabinoid-treated rats. These findings demonstrate that adolescence is a critical and vulnerable period to the deleterious effects of cannabinoids on cognitive processes. The neurobiological basis for this effect, especially with regard to alterations to prefrontal circuitry, which we partially provide should improve our understanding of the emergence of psychosis and lead to new therapeutic strategies and prevention.

認知功能的提升是當今神經科學領域中的研究重點之一，但其神經機制尚有待釐清。本研究利用一種用於改善阿茲海默症臨床的非競爭型N-甲基-D-天門冬胺酸受體拮抗劑memantine，檢測其對於大白鼠在不同時距相關操作式制約行為及空間工作記憶行為之影響效果。實驗一為針對時間屬性的操作式制約行為實驗，運用大白鼠的區辯性增強低頻反應作業（DRL 10秒行為）與固定時距作業（FI 30秒行為）之行為作業，並操弄連續訓練與間歇訓練的兩種不同模式，測試memantine對前述四組受試的操作式制約行為在表現、消除與自發恢復等三階段之劑量反應。實驗二利用配對性延遲T迷津作業區分出不等基準線(表現好與表現差)之受試，再加以藥理實驗，測試memantine對於前述兩組受試之劑量反應。實驗一結果顯示，受試在兩種不同訓練模式下經十五次習得訓練後，在兩種操作式壓桿行為的壓桿反應相關指標中都有明顯的差異，這證實不同的行為訓練模式會導致學習後的表現有差異之別。memantine藥理實驗結果顯示，此藥對於上述四組受試的操作式行為之三階段的影響效果，會因為不同訓練模式與不同作業而異。實驗二結果顯示，memantine提高空間工作記憶的正確率在表現不好的組別有很顯著的藥效，這證實memantine對於空間式工作記憶行為的影響，也會因學習基準線的不同水平而異。在行為實驗後所進行的蛋白質表現量檢測中，memantine（5 mg/kg）只對五個測試腦區中的背側紋狀體中ERK1磷酸化程度有明顯上升的影響，而其對ERK2及CREB的磷酸化在所有腦組織中皆沒有顯著的影響。綜合以上結果，memantine影響時間與空間屬性的相關行為之藥理效果，會依行為的不同習得歷程(或行為背景經驗)及基準線表現程度而異，而此項行為藥理效果，可能與紋狀體中ERK1的磷酸化有關。 / The neural basis of cognitive enhancement is one of the intriguing topics in neuroscience research; however, the underlying neural mechanisms remain to be elucidated. This study examined the effects of memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist which is used to treat Alzheimer’s disease in clinic, on operant behaviors and spatial working memory. In Experiment 1, using the differential reinforcement for low-rate-response 10 sec (DRL 10s) and the fixed-interval 30 sec (FI 30s) operant tasks, and with the manipulation of two different training regimens (continuous vs. intermittent) in the acquisition phase, the effects of memantine were evaluated in three stages of behavioral tests including the performance (right after the end of 15-day acquisition), the extinction, and the spontaneous recovery (after the extinction). In Experiment 2, memantine were tested in the subjects with different level of baseline performance (good vs. bad) on the distinctive patterns of operant responding in four different groups which received DRL 10s and FI 30s with different training regimens; indicating that behavioral task and training background are critical to the operant performance of temporal operant behaviors. Such behavioral outcomes led the dissociable effects of memantine appeared in between the four groups as tested in all three different stages. The results of Experiment 2 showed a profound improvement of the correct responses rate on spatial working memory in the low-baseline group as compared to the higher-baseline group. With a pretreatment of memantine (5 mg/kg), brain tissues in five selected areas were collected for western blot assays of ERK 1, ERK 2, and CREB. The results only revealed a significant increase of ERK 1 phosphorylation in the dorsal striatum. Together, the effects of memantine to improve cognition-associated processes in the temporal operant behaviors and the baseline of performance, and the present observation of cognition-enhancing effects of memantine may be resulted by the ERK 1 phosphorylation in the dorsal striatum.