Many young adult university students engage in frequent alcohol bingeing and have high depression scores, both of which are factors that can reduce hippocampal neurogenesis in rodents. Rodents with depleted neurogenesis exhibit selective deficits on high interference memory tasks including visual and spatial pattern separation. We predicted that young adult humans with high bingeing and depression scores would exhibit similarly impaired spatial pattern separation as a result of neurogenesis reductions. The relationships between alcohol bingeing, depression, and spatial pattern separation have, to this point, not been investigated in humans. We developed a novel computerized memory task for assessing spatial pattern separation in humans, loosely based on the “Concentration” memory card game. To further identify how sensitive this pattern separation function is to spatial separation between two stimuli, we developed the spatial separation recognition task (SSRT). We found that young adults with elevated depression and alcohol consumption scores exhibited impaired spatial pattern separation, in spite of intact performance on control tasks, consistent with a selective neurogenesis reduction. Further, this difference in performance seemed to be driven by performance at relatively larger separations. / Thesis / Master of Science (MSc)

Effective memory representations must be specific to prevent interference between episodes that may overlap in terms of place, time, or items present. Pattern separation, a computational process performed by the hippocampus overcomes this interference by establishing non-overlapping memory representations. This project explores pattern separation and how it is impacted by age and sleep. Experiment 1. Structures of the medial temporal lobe (MTL) are known to be involved in declarative memory processes. However, little is known about how age-related changes in MTL structures, white matter integrity, and functional connectivity affect pattern separation processes in the MTL. In the present study, we used magnetic resonance imaging (MRI) to measure the volumes of MTL regions of interest, including hippocampal subfields (dentate gyrus, CA3, CA1, and subiculum) in healthy older and younger adults. Additionally, we used diffusion tensor imaging to measure white matter integrity for both groups. Finally, we used functional MRI to acquire resting functional connectivity measures for both groups. We show that, along with age, the volume of left CA3/dentate gyrus predicts memory performance. Differences in fractional anisotropy and the strength of resting functional connections between the hippocampus and other cortical structures implicated in memory processing were not significant predictors of performance. As previous studies have only hinted, it seems that the size of left CA3/dentate gyrus contributes more to successful discrimination between similar mnemonic representations than other hippocampal sub-fields, MTL structures, and other neuroimaging correlates. Accordingly, the implications of aging and atrophy on lure discrimination capacities are discussed. Experiment 2. Although it is widely accepted that declarative memories are consolidated during sleep, the effects of sleep on pattern separation have yet to be elucidated. We used whole-brain, high-resolution functional neuroimaging to investigate the effects of sleep on a task that places high demands on pattern separation. Sleep had a selective effect on memory specificity and not general recognition memory. Activity in brain regions related to attention, visual acuity, and visual recall demonstrated an interaction between sleep and delay. Surprisingly, there was no effect of sleep on hippocampal activity using a group-level analysis. To further understand the role of the hippocampus on our task, we performed a representational similarity analysis. We investigated whether hippocampal activity associated with looking at novel stimuli correlated more with similar-looking (lure) stimuli or repeated stimuli. Results indicate that while a single night's sleep does not significantly impact hippocampal responses, the hippocampus does treat lure stimuli similarly as it does novel stimuli.

A healthy memory is essential to personal identity, completion of everyday tasks, and social acceptance. As factors such as age and illness threaten this key aspect of life, scientific and commercial attention has shifted to software, pharmaceuticals, and medical devices that help stave off inevitable memory decline. There is evidence suggesting that changes in lifestyle similarly work to improve memory. Mindfulness meditation, which is a practice rooted in the spiritual beliefs of Buddhism, has emerged as a promising technique to improve facets of cognition, including memory, as well as to change structures in the brain. Pattern separation is a key process of episodic memory that allows one to keep similar memories distinct. In this study, we evaluate the efficacy of a 4-week mindfulness training program on visual object pattern separation against an active creative writing control intervention and find that mindfulness meditation improves pattern separation and promotes changes in hippocampal brain structures.

The hippocampus is thought to be involved in memory formation and consolidation, with computational models proposing the process of pattern separation as a means for encoding overlapping memories. Previous research has used semantically related targets and lures to investigate hippocampal responses to mnemonic interference. Here, we attempted to define the response function of the hippocampus and its inputs during pattern separation by parametrically varying target-lure similarity in a continuous recognition task. We also investigated the effect of task demands (intentional versus incidental encoding) on pattern separation processes. We collected functional magnetic resonance imaging (fMRI) data while participants were shown a series of objects. In the intentional paradigm, participants identified objects as "new" (novel stimuli), "old" (exact repetitions), or "rotated" (previously seen objects that were subsequently rotated by varied degrees). In the incidental paradigm, participants were shown the same stimuli but identified objects as "toy" or "not toy". Activation in the hippocampus was best fit with a power function, consistent with predictions made by computational models of pattern separation processes in the hippocampus. The degree of pattern separation was driven by the information most relevant to the task—pattern separation was seen in the left hippocampus when semantic information was more important to the task and seen in the right hippocampus when spatial information was more important. We also present data illustrating that top-down processes modulate activity in the ventral visual processing stream.

Depression is associated with reduced declarative memory performance and decreased hippocampal volume. Depression has also been associated with decreased levels of adult neurogenesis in the dentate gyrus. Computational models propose that neurogenesis is critical for the computational process of pattern separation, whereby distinct memory representations are created for very similar stimuli and events. It has been proposed that depression negatively impacts pattern separation abilities; however, a link between depression and performance in pattern separation memory tasks has yet to be investigated. Accordingly, we designed a study to investigate the relationship between pattern separation performance and the severity of depression symptoms. Participants completed a recognition memory test with high pattern separation demands as well as a set of questionnaires to gauge their level of depression. We found a negative relationship between depression scores and pattern separation scores in support of the theory that depression is negatively related to pattern separation performance.

La polarité cellulaire planaire (PCP) est une voie de signalisation conservée au fil de l’évolution et qui joue un rôle crucial dans l’établissement de la polarité des cellules et tissues en régulant la dynamique du cytosquelette. De nombreuses études ont démontré l’implication de la PCP dans les mécanismes développementaux importants comme la gastrulation ou la neurulation chez les mammifères, et la mutation des gènes centraux qui composent la PCP mène à de sévères malformations de nombreux organes, et par conséquent une mort néonatale. Van Gogh-like 2 (vangl2) est un des gènes centraux de la PCP et code pour une protéine transmembranaire de la voie de la PCP, et sa mutation conduit à une absence de fermeture de la gouttière neurale et la mort à la naissance chez les mammifères, y compris l'homme. Certaines études suggèrent que Vangl2 jouerait un rôle dans le guidage axonal, mais aussi l’arborisation dendritique des neurones de l’hippocampe et le nombre des épines dendritiques.Dans ce travail, je montre que Vangl2 est enrichi dans l’hippocampe adulte de souris, et plus précisément dans le gyrus denté (DG) et le stratum lucidum du CA3. De nombreuses études suggèrent que le réseau formé par ces sous-structures sous-tend des processus cognitifs spécifiques impliqués dans l’encodage et le rappel de la mémoire : le pattern separation et le pattern completion. Le pattern separation est un processus d’encodage d’informations similaires en représentations différentes, permettant la formation de souvenirs distincts malgré les similitudes entre les évènements. Le processus de pattern completion permet, à partir de stimuli partiels, de se remémorer un souvenir dans son intégralité. De récentes études suggèrent que la maturation des nouveaux neurones issus de la neurogenèse adulte dans le DG joue un rôle critique dans le maintien d'une balance qui existerait entre ces deux processus cognitifs. Bien que les mécanismes qui sous-tendent les deux processus soient encore mal compris, la connectivité du DG et du CA3 semble essentielle.J’ai ainsi formulé et testé l'hypothèse selon laquelle l'absence d'expression de Vangl2 affecterait ces processus mnésiques. Pour ceci, j'ai généré plusieurs mutants murins n'exprimant pas le gène vangl2 dans différentes régions du cerveau, que j'ai ensuite testé dans des paradigmes comportementaux requérant l’utilisation des processus de pattern separation et de pattern completion. Mes résultats suggèrent que Vangl2 dans le DG est essentiel dans le maintien d'une balance existante entre les deux processus, en régulant la maturation des neurones du DG. / Planar cell polarity (PCP) signaling is an evolutionary conserved pathway known to play a crucial role in the establishment of tissue polarity via a regulation of cytoskeleton dynamics. PCP signaling is essential during critical developmental stages, such as gastrulation or neurulation, to shape tissues and organs, and disruption of core PCP genes in mammals leads to severe malformations and neonatal death. Van Gogh-like 2 (vangl2) is one of the core PCP genes coding for a transmembrane protein, and its mutation leads to a failure of the neural tube closure in mammals, including humans. It has also been suggested that Vangl2 plays a role in axonal guidance, dendritic arborization of hippocampal neurons and dendritic spines number. I showed that Vangl2 protein is enriched in the hippocampus in the adult stage, precisely in the dentate gyrus (DG) and CA3 stratum lucidum subregions. These subregions have been proposed to sustain two cognitive processes involved in memory functions: pattern separation and pattern completion. Pattern separation allows the encoding of similar or overlapping inputs in distinct neuronal representations, allowing formation of new memory without interference of a previous similar encountered event. Pattern completion is described as the ability to guide the recall of an entire memory using partial sensory cues. Recent studies suggest a critical role for the maturation of adult-born granule neurons of the DG in the balance that may exist between pattern completion and pattern separation. Although the mechanisms of both cognitive processes are still debated, the connectivity between DG and CA3 appears to be essential. I thereby tested the hypothesis that in absence of Vangl2 in the brain, these two processes would be affected. I generated several conditional mutant mice in order to excise vangl2 gene in specific areas of the hippocampus, and tested them in behavioral paradigms requiring pattern separation or pattern completion processes. My data support my hypothesis that Vangl2 in the DG is essential for a balance between pattern separation and pattern completion, through the regulation of the maturation of DG neurons.

<p>It is commonly accepted that aerobic exercise increases hippocampal neurogenesis, learning and memory, as well as stress resiliency. However, human populations are widely variable in their inherent aerobic fitness as well as their capacity to show increased aerobic fitness following a period of regimented exercise. It is unclear whether these inherent or acquired components of aerobic fitness play a role in neurocognition. To isolate the potential role of inherent aerobic fitness, we exploited a rat model of high (HCR) and low (LCR) inherent aerobic capacity for running. At a baseline, HCR rats have two- to three-fold higher aerobic capacity than LCR rats. We found that HCR rats also had two- to three- fold more young neurons in the hippocampus than LCR rats as well as rats from the heterogeneous founder population. We then asked whether this enhanced neurogenesis translates to enhanced hippocampal cognition, as is typically seen in exercise-trained animals. Compared to LCR rats, HCR rats performed with high accuracy on tasks designed to test neurogenesis-dependent pattern separation ability by examining investigatory behavior between very similar objects or locations. To investigate whether an aerobic response to exercise is required for exercise-induced changes in neurogenesis and cognition, we utilized a rat model of high (HRT) and low (LRT) aerobic response to treadmill training. At a baseline, HRT and LRT rats have comparable aerobic capacity as measured by a standard treadmill fit test, yet after a standardized training regimen, HRT but not LRT rats robustly increase their aerobic capacity for running. We found that sedentary LRT and HRT rats had equivalent levels of hippocampal neurogenesis, but only HRT rats had an elevation in the number of young neurons in the hippocampus following training, which was positively correlated with accuracy on pattern separation tasks. Taken together, these data suggest that a significant elevation in aerobic capacity is necessary for exercise-induced hippocampal neurogenesis and hippocampal neurogenesis-dependent learning and memory. To investigate the potential for high aerobic capacity to be neuroprotective, doxorubicin chemotherapy was administered to LCR and HCR rats. While doxorubicin induces a progressive decrease in aerobic capacity as well as neurogenesis, HCR rats remain at higher levels on those measures compared to even saline-treated LCR rats. HCR and LCR rats that received exercise training throughout doxorubicin treatment demonstrated positive effects of exercise on aerobic capacity and neurogenesis, regardless of inherent aerobic capacity. Overall, these findings demonstrate that inherent and acquired components of aerobic fitness play a crucial role not only in the cardiorespiratory system but also the fitness of the brain.</p> / Dissertation

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.

There is still a great deal that is unknown about various depressive conditions, though it is a very common affliction and cause of disability throughout the world. Not only do the underlying mechanisms of various types of depression remain uncertain, but the mystery of how different treatment options work and who will respond to them also persists. The aim of this study was to identify potential non-invasive biomarkers, to predict responsiveness to electroconvulsive therapy. Two hypotheses were investigated in this study. The first was that patient improvement from baseline on the neurocognitive, computer based pattern separation task prior to the third ECT treatment will correlate with a clinical antidepressant response. The second was that increased prefrontal slowing relative to baseline will correlate with a decrease in depressive symptoms. As a first step to validate this approach, a healthy control group performed both the pattern separation and EEG tasks once per week over the course of three weeks. Patient participants completed both tasks before their first ECT treatment, prior to their third treatment, and prior to their last treatment. A spectral analysis of EEG data was then conducted. Results indicated good test-retest reliability for the pattern separation task and EEG measurements across all three trials in the healthy control group. Results from patient data are inconclusive, but indicates that there is a change from baseline to subsequent trials for at least the EEG measurements. However, a larger sample size is needed to determine this. The limited results from this small patient sample suggest that these measurements may have clinical value in refining ECT treatment, and merit further study.

Cognitive performance declines in depression and increases with physical activity. These changes may in part be due to changes in the level of neurogenesis (the generation and survival of adult-born neurons), which decreases with depression and increases with physical activity. Pattern separation (the formation of distinct neural representations of incoming information through orthogonalizing similar patterns of activation) has also been linked to neurogenesis. This project explores pattern separation within these two populations through three experiments.Experiment 1. Previous research has found impaired pattern separation among individuals with higher depression scores, but who have not been diagnosed with Major Depressive Disorder (MDD). This experiment sought to expand these findings and evaluated behavioral differences during the performance of a continuous recognition pattern separation task among women with MDD and age- and education-matched controls. It was hypothesized that clinically depressed participants would have lower pattern separation scores and would be more likely to incorrectly identify lure stimuli as "old". Contrary to this prediction, clinically depressed participants had higher pattern separation scores, while controls were more likely to misidentify lure items as "old".Experiment 2. While there are many known benefits of regular physical activity, the majority of individuals in the United States do not engage in the recommended levels of fitness training. Furthermore, there have only been a limited number of studies evaluating the effect physical activity may have on cognitive abilities and neurological components and none have evaluated what effect the recommended levels of fitness may have on these areas. The second experiment evaluated differences between individuals with varying levels of physical activity using functional magnetic resonance imaging (fMRI) during the performance of a continuous recognition pattern separation task. It was hypothesized that participants with self-reported higher levels of physical activity would have greater activation in the CA3/dentate gyrus subregions of the hippocampus than those with lower fitness levels and sedentary individuals. Surprisingly, there were no activation differences across groups. Experiment 3. The final experiment explored diffusion tensor imaging (DTI) differences in physical activity levels with the same sample used in Experiment 2. It was hypothesized that participants with self-reported higher levels of physical activity would have indications of increased white matter integrity compared to those with lower fitness levels and sedentary individuals. There were significant differences across groups in DTI measures of white matter integrity (axial diffusivity or AD) in bilateral cingulum, the left temporal middle gyrus, and the right uncinate fasciculus.