Memory stabilization following encoding (synaptic consolidation) or memory reactivation (reconsolidation) requires gene expression and protein synthesis. Although consolidation and reconsolidation may be mediated by distinct molecular mechanisms, disrupting the function of the transcription factor CREB (cAMP responsive element binding protein) impairs both processes. We use a gain-of-function approach to show that CREB (and CREB-coactivator CRTC1) can facilitate both synaptic and systems consolidation and reconsolidation. We first examine whether acutely increasing CREB levels in the dorsal hippocampus is sufficient to enhance spatial memory formation in the watermaze. Locally and acutely increasing CREB in the dorsal hippocampus using viral vectors is sufficient to induce robust spatial memory in two conditions which do not normally support consolidation, weakly-trained wild-type (WT) mice and strongly-trained mutant mice with brain-wide disrupted CREB function. CRTCs (CREB regulated transcription co-activators) are a powerful co-activator of CREB, but their role in memory is virtually unexplored. We show, for the first time, that the novel CREB co-activator CRTC1 enhances memory consolidation. Locally increasing CRTC1 (or CREB) in the dorsal hippocampus of WT mice prior to weak context fear conditioning facilitates consolidation of precise context memory. Last, we show that CREB or CRTC1 facilitates precise and enduring memory consolidation and reconsolidation. Acute enhancement of hippocampal CREB or CRTC1 during initial synaptic consolidation can maintain precision of remote context memory, while increasing CREB or CRTC1 just prior to reactivation of a weak remote context memory enhances context memory reconsolidation. These gain-of-function manipulations indicate that increasing CRTC1 or CREB function is sufficient to enhance the strength of new, as well as reactivated established, memories without compromising memory specificity. Together with previous results, these findings indicate that CREB is both necessary and sufficient for hippocampal-dependent memory formation, and underline its pivotal role in the hippocampal molecular machinery underlying long-term memory consolidation and reconsolidation.

Memory stabilization following encoding (synaptic consolidation) or memory reactivation (reconsolidation) requires gene expression and protein synthesis. Although consolidation and reconsolidation may be mediated by distinct molecular mechanisms, disrupting the function of the transcription factor CREB (cAMP responsive element binding protein) impairs both processes. We use a gain-of-function approach to show that CREB (and CREB-coactivator CRTC1) can facilitate both synaptic and systems consolidation and reconsolidation. We first examine whether acutely increasing CREB levels in the dorsal hippocampus is sufficient to enhance spatial memory formation in the watermaze. Locally and acutely increasing CREB in the dorsal hippocampus using viral vectors is sufficient to induce robust spatial memory in two conditions which do not normally support consolidation, weakly-trained wild-type (WT) mice and strongly-trained mutant mice with brain-wide disrupted CREB function. CRTCs (CREB regulated transcription co-activators) are a powerful co-activator of CREB, but their role in memory is virtually unexplored. We show, for the first time, that the novel CREB co-activator CRTC1 enhances memory consolidation. Locally increasing CRTC1 (or CREB) in the dorsal hippocampus of WT mice prior to weak context fear conditioning facilitates consolidation of precise context memory. Last, we show that CREB or CRTC1 facilitates precise and enduring memory consolidation and reconsolidation. Acute enhancement of hippocampal CREB or CRTC1 during initial synaptic consolidation can maintain precision of remote context memory, while increasing CREB or CRTC1 just prior to reactivation of a weak remote context memory enhances context memory reconsolidation. These gain-of-function manipulations indicate that increasing CRTC1 or CREB function is sufficient to enhance the strength of new, as well as reactivated established, memories without compromising memory specificity. Together with previous results, these findings indicate that CREB is both necessary and sufficient for hippocampal-dependent memory formation, and underline its pivotal role in the hippocampal molecular machinery underlying long-term memory consolidation and reconsolidation.

No description available.

A fundamental problem in ecology is determining what factors affect the distribution of organisms across a landscape. Landscapes are by their nature heterogeneous and different habitat types confer different fitness benefits and costs to organisms that inhabit them. Ecologists are now aware of the importance of examining multiple spatial scales when designing studies quantifying animal resource selection. Scale of analysis has been shown to be important, since ecological pressures relating to the establishment of a home range differ from those relating to the use of resources within the home range. Most studies that examine multiple spatial scales examine the effect of modifying extent. Here, I examine the role of grain, an underappreciated component of scale, on our interpretation of habitat selection patterns and functional response. The goal of this thesis was to examine how grain size affects the interpretation of animal resource selection and functional response across multiple habitats. The perceptual range of an individual is known to change with habitat, therefore I hypothesized that resource selection and functional response would be both grain- and habitat-dependent, and that resource selection functions computed using different grains for different resources would be more predictive than models computed using only a single grain. I used GPS-collared white-tailed deer (Odocoileus virginianus) to quantify resource selection functions at various grains and used generalized linear mixed effects modelling and multi-model inference techniques to examine how resource selection patterns changed with spatial scale across habitat types. I used selection ratios to examine functional response across grains. Model coefficients changed with grain and the strength of selection varied by habitat type. Multi-grain resource selection functions had lower AIC values and better cross-validation scores than single grain models. Functional response varied with scale and habitat type, displaying a unique relationship for each habitat. My results suggest that spatial memory and habitat-dependent perceptual range play an important role in resource selection. I conclude that the examination of multiple grains in the study of animal habitat selection and functional response represents a step forward in our ability to understand what drives the distribution and abundance of organisms.

Many studies have suggested a relationship between sex steroids and negative mental and mood changes in women. Allopregnanolone, a potent endogenous ligand of the GABA-A receptor and a metabolite of progesterone, is one of the most accused neuroactive steroids. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. In women, there are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone probably develops. We have evaluated the 3β-hydroxy pregnane steroid UC1011 as a functional antagonist to allopregnanolone-induced negative effects in rats. In vivo, we used the Morris Water Maze (MWM) test of learning and, in vitro, we studied chloride ion uptake into cortical and hippocampal membrane preparations. The steroid UC1011 reduces the allopregnanolone-induced learning impairment in the MWM and the increase in chloride ion uptake induced by allopregnanolone. To detect whether chronic tolerance develops to an allopregnanolone-induced condition, male rats were pretreated with allopregnanolone injections for three or seven days. These rats were then tested in the Morris Water Maze for five days and compared with relevant controls. Rats with seven days’ allopregnanolone pretreatment experienced improved performance compared with the acutely allopregnanolone-exposed group, reflecting chronic tolerance development. To study the GABA-A receptor changes in acute allopregnanolone tolerance, we used the silent second (SS) anaesthesia threshold method. At acute tolerance, 90 minutes of anaesthesia, the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the thalamus ventral-posteriomedial (VPM) nucleus were reduced. There was also a significant negative correlation between the increase in the allopregnanolone dose needed to maintain anaesthesia and the α4 mRNA in the VPM nucleus. We also investigated whether allopregnanolone tolerance was still present one or two days after the end of the anaesthesia-induced acute tolerance. Tolerance persisted to one day, but not two days, after the treatment and the α4 subunit mRNA expression in the VPM nucleus was negatively related to the allopregnanolone doses needed after one day. In conclusion, the current thesis shows that the substance UC1011 can reduce the allopregnanolone-induced negative effects in the water maze test. Chronic allopregnanolone tolerance can develop to the effects of allopregnanolone. Allopregnanolone tolerance persists one day after the induction of acute allopregnanolone tolerance. The GABA-A receptor α4 subunit in the thalamus might be involved in the development and persistence of acute tolerance to allopregnanolone.

Existing computational cognitive models of spatial memory often neglect difficulties posed by the real world, such as sensory noise, uncertainty, and high spatial complexity. On the other hand, robotics is unconcerned with understanding biological cognition. This thesis takes an interdisciplinary approach towards developing cognitively plausible spatial memory models able to function in realistic environments, despite sensory noise and spatial complexity. We hypothesized that Bayesian localization and error correction accounts for how brains might maintain accurate location estimates, despite sensory errors. We argued that these mechanisms are psychologically plausible (producing human-like behaviour) as well as neurally plausible (implementable in brains). To support our hypotheses, we reported modelling results of neural recordings from rats (acquired outside this PhD), constituting the first evidence for Bayesian inference in neurons representing spatial location, as well as modelling human behaviour data. In addition to dealing with uncertainty, spatial representations have to be stored and used efficiently in realistic environments, by using structured representations such as hierarchies (which facilitate efficient retrieval and route planning). Evidence suggests that human spatial memories are structured hierarchically, but the process responsible for these structures has not been known. We investigated features influencing them using data from experiments in real-world and virtual reality environments, and proposed a computational model able to predict them in advance (based on clustering in psychological space). We have extended a general cognitive architecture, LIDA (Learning Intelligent Distribution Agent), by these probabilistic models of how brains might estimate, correct, and structure representations of spatial locations. We demonstrated the ability of the resulting model to deal with the challenges of realistic environments by running it in high-fidelity robotic simulations, modelled after participants' actual cities. Our results show that the model can deal with noise, uncertainty and complexity, and that it can reproduce the spatial accuracies of human participants.

Orientadora: Profa. Dra. Juliana Militão Berbert / Dissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Matemática , 2017. / Neste trabalho, procuramos compreender um pouco mais sobre movimentação animal. Uma das formas de se estudar movimentação animal é a partir de modelos de equação de reação-difusão, na qual a parte reativa representa a dinâmica populacional e parte difusiva a dispersão aleatória da população. Existem mecanismos que influenciam essa dispersão como por exemplo, a memória espacial, que induz um movimento direcional na população. Assim, nosso modelo apresenta um termo de advecção induzida pela memória dos indivíduos a qual se recordam dos locais visitados recentemente e pretendem evitá-los, um termo de dispersão aleatória e um termo reativo, para o qual consideramos quatro funções de crescimento populacional são elas: (i) Exponencial; (ii) Logística; (iii) Efeito Allee Fraco e (iv) Efeito Allee Forte. Logo, nosso modelo é dado por um sistema de duas equações diferenciais acopladas não-lineares: uma que descreve a dinâmica da memória e outra para a população. Neste trabalho, apresentamos estudos analíticos da velocidade de onda viajante para as diferentes dinâmicas populacionais e os estudos numéricos das soluções do espaço unidimensional, estudamos o alcance populacional para compreendermos numericamente o efeito que os parâmetros considerados têm na dispersão dos indivíduos. Nossos resultados mostram que as velocidades de onda mínimas para o crescimento exponencial e logístico são iguais independente da presença de memória e que a dispersão populacional é dependente das taxas de memória, de crescimento, capacidade de suporte e limiar dessa população; ou seja, a combinação destes parâmetros alteram os comportamentos dispersivos da população, podendo ser sub-difusivo, difusivo ou super-difusivo. / The reaction-diffusion equation is one of the possible ways for modeling animal movement, where the reactive part stands for the population growth and the diffusive part for random dispersal of the population. There are some mechanisms that affect the movement, such as spatial memory, which results in a bias for one direction of dispersal. Thus a spatial memory can be modelled as an advective term on a population movement dynamics. Our model is composed of a coupled partial differential equation system with two equations, one for the population dynamics and the other for the memory density distribution. The population is modelled by a reaction-diffusion-advection equation where the diffusive term is the population random movement, the advective term is due to spatial memory and the reactive term is one of the following growth functions: (i) Exponential; (ii) Logistic; (iii) Weak Allee Effect and (iv) Strong Allee Effect. In the analytic studies of the system, we have obtained the travelling wave speed for each case above. We show that the travelling wave speeds of the exponential and logistic growth are the same with or without memory. In the numerical analysis, we have studied how the reach of the population is affected by different values of the parameters: memory, growth rate, carrying capacity and threshold. The combination of these parameters causes the population to have normal or anomalous diffusion: subdiffusion and supperdiffusion.

Se déplacer selon un but déterminé est une activité courante de la vie quotidienne. Des capacités cognitives variées sont associées aux déplacements, comme la navigation, la mémoire ou encore l’orientation spatiale. De nombreux patients cérébro-lésés ou atteints par une maladie neuro-dégénérative présentent des difficultés topographiques qui retentissent sur leur autonomie en vie quotidienne. Les outils de réalité virtuelle permettent d’évaluer la navigation et la mémoire spatiale à grande échelle, avec une bonne corrélation entre cette évaluation et celle qui serait réalisée dans un environnement réel. La réalité virtuelle permet également d’ajouter des stimuli à la tâche proposée. Ces stimuli additionnels peuvent être contextuels, c’est à dire reliés à la tâche à réaliser dans l’environnement virtuel, ou noncontextuels, soit sans lien avec la tâche à accomplir. Ce travail de thèse s’est attaché à évaluer l’impact de stimuli auditifs et visuels sur la navigation et la mémoire spatiale de patients cérébro-lésés ou présentant une maladie neuro-dégénérative, dans des expériences de réalité virtuelle. Les deux premiers volets de cette thèse ont étudié l’effet de stimuli auditifs contextuels ou non-contextuels lors d’une tâche de courses au sein du supermarché virtuel VAP-S. Le premier volet a montré que des stimuli auditifs contextuels de type effet sonar et énoncé du nom du produit facilitaient la navigation spatiale de patients cérébro-lésés impliqués dans cette tâche de courses. Le second volet a mis en évidence que des sons non-contextuels avec une importante saillance cognitive ou perceptuelle péjoraient la performance de navigation de patients ayant présenté un accident vasculaire cérébral. Les deux volets suivants de cette thèse ont étudié l’effet d’indiçages visuels ou auditifs dans une tâche de navigation spatialedans un quartier virtuel. Ainsi, le troisième volet de la thèse a démontré que des indices visuels comme des flèches directionnelles ou des points de repère sursignifiés facilitaient la navigation spatiale et certains aspects de mémoire spatiale de patients avec des troubles cognitifs légers (MCI) ou présentant une Maladie d’Alzheimer. Enfin, le quatrième volet a mis en évidence qu’un indiçage auditif par des bips indiquant la direction à chaque intersection améliorait la navigation spatiale de patients cérébro-lésés droits présentant une héminégligence visuelle et auditive controlatérale. Ces résultats suggèrent que des stimuli auditifs et visuels pourraient être utilisés lors de prises en charge rééducatives et réadaptatives de patients présentant des difficultés topographiques, ainsi qu’en vie quotidienne par le biais de la réalité augmentée afin de faciliter leurs déplacements. L’impact des stimuli chez les sujets sains et chez les cérébrolésés est différent et justifie une analyse spécifique de processus probablement distincts impliqués lors des déficits cognitifs. / Navigating in a familiar or unfamiliar environment is a frequent challenge for human beings. Many patients with brain injury suffer from topographical difficulties, which influences their autonomy in daily life. Virtual Reality Tools enable the evaluation of largescale spatial navigation and spatial memory, resembling a real environment. Virtual reality also permits to add stimuli to the software. These stimuli can be contextual, that is to say linked to the task that participants have to accomplish in the Virtual Environment, or non-contextual, i.e. with no link with the require task. This thesis investigates whether visual or auditory stimuli influence spatial navigation and memory in Virtual Environments of patients with brain injury or with a neurodegenerative disease. The first part of the thesis showed contextual auditory stimuli type a sonar effect and the names of products of the shopping list improved spatial navigation of brain-injured patients during a shopping task in the virtual supermarket VAP-S. The second part of this thesis highlighted that non-contextual auditory stimuli with a high perceptual or cognitive salience decreased spatial navigation performance of brain-injured patients during a shopping task in the VAP-S. The third part of this thesis showed that visual cues like directional arrows and salient landmarks improved spatial navigation and some aspects of spatial memory of patients with Alzheimer’s disease or Mild Cognitive Impairments during a navigation task in a virtual district. The last part of this thesis demonstrated that auditory cues, i.e. beeping sounds indicating the directions, increased spatial navigation in a virtual district of patients who have had a stroke with contra-lesional visual and auditory neglect. These results suggest that some visual and auditory stimuli could be helpful for spatial navigation and memory tasks in patients with brain injury of neuro-degenerative disease. It further offers new research avenues for neuro-rehabilitation, such as the use of augmented reality in real-life settings to support the navigational capabilities of these patients.

La maladie d’Alzheimer (MA) se caractérise par une perte des fonctions cognitives liée à une dégénérescence neuronale induite par l’accumulation de peptides amyloïdes-β (Aβs) dans des régions vulnérables du cerveau comme l’hippocampe. Au niveau moléculaire, les peptides Aβs se lient préférentiellement à la densité post-synaptique des synapses excitatrices, espace au niveau duquel la protéine d’échafaudage PSD-95 organise l’ancrage des récepteurs NMDA (RNMDAs) et régule leur mobilité membranaire. A l’aide d’une stratégie intégrative qui favorise des niveaux d’analyse verticaux (du phénotype aux événements moléculaires) et qui combine un ensemble d’approches corrélatives et invasives chez des souris double transgéniques APPswe/PS1dE9 modèles de la MA, nous avons mis en évidence que les peptides Aβs déstabilisent l’organisation synaptique (altération de l’expression de la PSD-95) et augmentent le pool extrasynaptique de sous-unités GluN2B des RNMDAs dans l’hippocampe. Cette réorganisation se traduit par une perturbation des fonctions mnésiques. Par ailleurs, il a été montré que certaines oscillations de l’activité hippocampique, comme les « sharp-wave ripples » (SWRs) générées pendant les périodes de sommeil, jouent un rôle crucial dans la formation de la mémoire. De façon surprenante, l’accumulation des peptides Aβs semble épargner la dynamique d’expression des SWRs durant les comportements de routine. Afin d’examiner l’effet potentiel des Aβs sur les SWRs chez des animaux confrontés à des challenges cognitifs, nous avons soumis des souris adultes injectées intracérébralement avec une solution d’Aβs à un test de reconnaissance spatiale. Alors qu’elles sont capables de former une mémoire à court terme, les souris Aβs montrent un oubli plus rapide, suggérant qu’elles encodent avec succès, mais qu’elles sont incapables de stabiliser et de rappeler une information acquise antérieurement. En l’absence d’une demande cognitive préalable, les propriétés des SWRs ne sont pas altérées par les Aβs. En revanche, lorsqu’elles doivent résoudre un test cognitif, les pics de SWRs normalement observés après encodage ou reconnaissance chez les souris témoins sont abolis chez les souris Aβs, indiquant une perturbation du traitement hippocampique de l’information spatiale. Pris dans leur ensemble, ces résultats identifient deux nouveaux mécanismes délétères sous-tendant les déficits de mémoire spatiale associés à la MA. / Cognitive impairments in Alzheimer’s disease (AD) are thought to be related to degenerative synaptic changes caused by the accumulation of amyloid-β peptides (Aβs) in vulnerable brain regions such as the hippocampus. At the molecular level, Aβs bind preferentially to the postsynaptic density of neuronal excitatory synapses, where the scaffolding post-synaptic protein-95 (PSD-95) organizes NMDA receptor (NMDAR) location as well as its downstream signaling. By using an integrative strategy which favoured vertical levels of analyses (from phenotype to molecular events) and combined a set of interrelated correlative and invasive approaches in a double transgenic mouse model of AD (APPswe/PS1dE9 mice), we were successful in establishing that Aβs destabilize the synaptic organization (reduction of expression of PSD-95) and increase the extrasynaptic pool of GluN2B-containing NMDAR in the hippocampus, a reorganization which translates into impaired memory functions. It is also well-known that hippocampal sharp wave-ripples (SWRs) generated during sleep periods are crucial for memory formation but accumulation of soluble Aβs, surprisingly seems to spare SWR dynamics during routine behavior. To unravel a potential effect of Aβs on SWRs in cognitively-challenged animals, we submitted vehicle- and Aβ-injected mice to spatial recognition memory testing. While capable of forming short-term memory, Aβ mice exhibited faster forgetting, suggesting successful encoding but an inability to adequately stabilize and/or retrieve previously acquired information. Without prior cognitive requirements, similar properties of SWRs were observed in both groups. In contrast, when cognitively challenged, the post-encoding and -recognition peaks in SWR occurrence observed in controls were abolished in Aβ mice, indicating impaired hippocampal processing of spatial information. Altogether these results identify two new disruptive mechanisms for the spatial memory deficits associated with AD.

A computerized virtual version of the Morris water maze (vMWM) was used to assess human gender differences in spatial working memory. In Experiment 1, the release point and platform location was changed on every other trial for 20 trials. Men had significantly reduced acquisition latencies and more accurate heading errors on the first daily trial compared to women. In Experiment 2, the release point and platform location was changed every fourth trial for 20 trials. Men had significantly shorter acquisition latencies and path lengths than women. Experiment 3 was identical to Experiment 2, except that environmental cues were changed throughout testing. Men had significantly shorter acquisition latencies and path lengths than did the women. These studies are the first to demonstrate significant gender differences in a spatial working memory version of the vMWM.