In the study of navigation, frequently it is assumed that navigation is accomplished using either an allocentric strategy based on a cognitive map, or an egocentric strategy based on stimulus response associations. Further, it is frequently assumed that individual navigators, or even entire genders, are only capable of navigating by one strategy or the other. The present study investigated whether individuals or genders were limited to a particular navigational strategy and whether both strategies might be learned or used at the same time. In the present study, undergraduate students were tested in a virtual Morris water maze that was modified to allow successful and efficient navigation using either an allocentric or an egocentric strategy. Learning trials on which the participants had to learn the location of the platform were alternated with probe trials on which participants would show which strategy they were using. At the end of testing, participants were given a series of tests to determine what knowledge they had acquired and which strategies they were capable of using. Results indicated that: a) most people preferred to navigate egocentrically in this maze, but some preferred to navigate allocentrically, b) people tended to use an egocentrically strategy first, but it was not a necessary step to learning to navigate allocentrically, c) people were better at their preferred strategy, d) people learned information about their non-preferred strategy, and e) those who preferred to navigate egocentrically could nevertheless learn to navigate allocentrically. Surprisingly, all of these results were true for both men and women, although women tended to prefer egocentric navigation at a higher rate than men, and men outperformed women when forced to navigate allocentrically. These results suggest it may be too simple to think of navigators as being capable of only a single navigational strategy or of learning only one strategy at a time. / Graduate

Research on the neural and cognitive basis of spatial navigation over the last 30 years has been largely guided by cognitive map theory and many of the studies have used a standardized procedure in a single task, the Morris Water Maze (MWM). Although this theory proposes that acquisition of place knowledge should be very rapid, little evidence has been provided to support this point. The present study investigates the possibility that a new procedure for measuring place knowledge in the MWM will show that place learning is faster than previously shown. In a virtual MWM with a fixed goal location, participants were given pairs of standard learning trials plus new explicit probe trials in which they were directed to go to where they found the goal on the immediately preceding trial. The distance between their estimate and the actual location was measured as “Place Error”. Results indicated that Place Errors were surprisingly small after just one learning trial and were equivalent for females and males. These findings provide new evidence for the fast learning proposed by cognitive map theory and demonstrate the value of this new method for measuring place learning. / Graduate

The ability of the spatial orientation of the reptiles is not fully researched yet. It is unknown if reptiles use only simple types of navigation, for example cue learning (one key mark), or more difficult types, for example allothetic navigation (combination of marks) or cognitive map (mental representation of the area). The main aim of this thesis was examine the possibility of the spatial orientation in lizard leopard gecko (Eublepharis macularius) in modificated Morris water maze (MWM). Design of the experiments was based on Parallel Map Theory, a theory which describes using spatial information from more navigation frames. The leopard gecko preferences of orientation frames were tested . That means the ability to combinate the spatial information from the bearing maps (one mark and gradient) and the sketch maps (local marks). This ability is prerequisite for creating the integrated map. The research was also focused on the significance of the simple cue learning strategy and cognitive more difficult allothetic navigation for the orientation of leopard gecko. Leopard geckos can use the combination of information from the navigation frames, which indicate the possibility of integrated map creation. Usage of navigation strategies is individual. Keywords: reptiles, leopard gecko, spatial...

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Cognitive Map Theory (O’Keefe & Nadel, 1978) posits that spatial behavior can reflect locale or taxon strategies. Only locale strategies depend on cognitive maps, and learning recruited by these strategies is unlike associative learning (e.g., Rescorla & Wagner, 1972; Mackintosh, 1975), which is prevalent in the taxon system. Associative learning phenomena like the blocking effect (Kamin, 1969) should therefore not occur during acquisition of cognitive maps. Contrary to this prediction, blocking effects have been demonstrated in spatial learning (e.g., Biegler & Morris, 1999; Chamizo, Sterio, & Mackintosh, 1985; Hamilton & Sutherland, 1999), and have been generally interpreted as evidence against cognitive map theory. Here we provide evidence suggesting that taxon and not locale strategies were promoted in these experiments, and we ask which factors determine whether taxon or locale strategies control spatial behavior in a computer-implementation of a widely used spatial task (Morris Water Maze; Morris, 1981). We isolated two factors relevant for spatial strategy choice in human spatial learning that are both related to the individual’s preexisting knowledge, namely conceptual knowledge about the distal cues, and knowledge about the task affordances. The blocking effect was used as an index for locale or taxon learning. We found that taxon strategies were more likely for abstract distal cues, while concrete cues promoted locale strategies – blocking was present for the former, but not the latter. When subjects were aware that the distal cues predicted locations, locale, and not taxon strategies were recruited, such that blocking was not observed. Spatial strategy choice appears to be largely driven by interindividual differences, and can therefore not be easily predicted a priori. Our findings cannot be explained by associative learning theories, but provide strong support for cognitive map theory and the position that multiple behavioral systems exist in the brain.

Alzheimer’s disease is an insidious neurodegenerative disease that affects millions of people worldwide. Currently, there are no determinants that can accurately predict the onset cognitive decline in AD. This thesis investigates and defines changes in the lipidome that are linked to symptomatic onset and cognitive impairment in mouse models of AD. Using a targeted lipidomic approach employing high performance liquid chromatography electrospray ionization tandom mass spectrometry, direct biochemical assessments, and behavioural evaluation, I was able to (a) profile and quantify cortical and hippocampal glycerophosphocholine and glycerophosphoethanolamine metabolites and signaling molecules in the APPSwe/PS1dE9 and the N5 TgCRND8 murine models of AD and (b) associate changes in lipid metabolism with learning and memory impairment. I demonstrate that glycerophosphocholine metabolism in the cortex but not the hippocampus is altered at symptomatic onset in both mouse models. These same metabolic changes were seen in younger animals exposed to chronic intermittent hypoxia, an environmental risk factor that accelerates their phenoconversion. In fully impaired transgenic mice, I defined metabolic changes associated with disease progression. To further assess the impact of sex, another risk factor of Alzheimer’s disease cognitive decline, I characterized an AD model of sex-specific cognitive resistance. I demonstrated that transgenic males but not females exhibit behavioural indices of cognitive reserve when tested in the Morris Water Maze. Using this mouse line, I then investigated how measures of learning and memory associated with glycerophosphocholine and glycerophosphoethanolamine metabolism. I identified increases in critical glycerophosphoethanolamine metabolites linked to spatial learning and memory impairment in the cortex of N5 TgCNRD8 mice and demonstrated that these changes could be predicted by profiling the plasma glycerophosphoethanolamine lipidome. Taken together, this thesis links glycerophospholipid metabolism to the onset and progression of learning and memory impairment in experimental models of AD and provides the first evidence that changes in cortical lipid metabolism can be predicted by changes in the plasma lipidome.

2.5 million people sustain a traumatic brain injury (TBI) annually in the United States. Although there is potential for functional recovery following TBI, there is no definitive treatment to improve recovery after TBI. Our lab has shown that TBI enhances an endogenous neurogenic response in the subventricular zone and hippocampus. TBI-induced neural stem cells (NSCs) can integrate into regions such as the hippocampus and olfactory bulb. Although the mechanism behind TBI-enhanced neurogenesis remains unknown, the Notch signaling pathway has been implicated as a regulator in the maintenance and survival of NSCs. This thesis explores the effects of Notch pathway manipulation on functional recovery following TBI. We hypothesize that Notch signaling plays a critical role in recovery after TBI. Activation of this pathway via a Notch agonist (Notch1) will facilitate post-injury recovery while inhibition of this pathway via a Notch antagonist (recombinant Jagged-1 Fc) will deter post-injury recovery. Functional recovery was assessed within 30 days or 60 days post-injury in two different cohorts of animals. The behavior assays conducted in this study included motor, cognitive, and olfactory assessment. In the 30-day phase, Notch pathway manipulation following TBI did not affect functional performance. In the 60-day study, significant group differences were found. While the FPI+Vehicle animals exhibited a functional recovery in Morris water maze, injured animals with Notch inhibition failed to show this cognitive recovery, indicating the involvement of the Notch pathway in cognitive recovery at the chronic stage following TBI. Motor and olfaction were not significantly affected by Notch pathway manipulation.

Several studies suggest profound effects on mood and cognition by neuroactive steroids. Estrogen alone or in combination with antidepressant drugs affecting the serotonin system has been used to treat mood disorders. On the other hand, progesterone is related to negative effects on mood and memory. A major part of the progesterone effects on the brain can be mediated by its metabolite allopregnanolone, which is also de novo synthesized in the brain, and affects the GABAA receptors. It would be of great importance to find a substance that antagonize allopregnanolone adverse effects. To investigate how long term supplementation of estradiol and progesterone, resembling postmenopausal hormone replacement therapy, affects serotonin receptors in different brain areas important for mood and memory functions, we used ovariectomized female rats. After 2 weeks of supplementation with 17β-estradiol alone or in combination with progesterone, or placebo pellets, estradiol alone decreases but estradiol supplemented together with progesterone increases 5HT1A mRNA expression in the hippocampus. Estradiol decreases the 5HT2C receptor gene expression, while estradiol in combination with progesterone increases the 5HT2A mRNA expression in the ventral hippocampus. Thus, estradiol alone has opposite effects compared to the estradiol/progesterone combination. To detect if acute tolerance develops to allopregnanolone, an EEG method was used where male rats by continuous allopregnanolone infusion were kept on anesthesia level of the silent second (SS). After different time intervals (first SS, 30 min or 90 min of anesthesia) several GABAA receptor subunit mRNAs were measured for detecting if changed expression of any GABAA receptor subunits is involved in development of acute tolerance. There is development of acute tolerance to allopregnanolone and brain regions of importance are hippocampus, thalamus and hypothalamus. The GABAA receptor alpha4 subunit in thalamus and alpha2 subunit in the dorsal hippocampus are related to development of acute tolerance. For assessing allopregnanolone behavioral effects, we studied how this neurosteroid affects spatial learning in the Morris water maze task Allopregnanolone inhibits spatial learning short after the injection and shows a specific behavioral pattern with swimming close to the pool wall. The steroid UC1011 can inhibit the increase in chloride ion uptake induced by allopregnanolone. UC1011 decreases allopregnanoloneinduced impairment of spatial learning in the water maze, as well as the specific behavioral swim pattern. In conclusion, the present work demonstrates that neuroactive steroids affect the 5HT and GABA systems in a brain region specific way. GABAA receptor subunit changes in hippocampus and thalamus are related to acute allopregnanolone tolerance. Allopregnanolone induces cognitive deficits, like spatial learning impairment and UC1011 can inhibit allopregnanolone-induced effects in vitro and in vivo. Key words: Estradiol, progesterone, HRT, allopregnanolone, UC1011, serotonin receptor, GABAA receptor, mRNA, Morris water maze, silent second, tolerance.

La facilitación del aprendizaje y la memoria por la autoestimulación eléctrica intracraneal (AEIC) se ha observado principalmente en tareas de memoria implícita, como la evitación activa de dos sentidos, en ratas. En este trabajo pretendemos investigar si la AEIC post-entrenamiento, además de facilitar el aprendizaje y la formación de la memoria en paradigmas de memoria implícita, puede facilitar también el aprendizaje y la formación de la memoria en un paradigma de memoria espacial explícita o relacional, hipocampo-dependiente, en el Laberinto Acuático de Morris (LAM), en ratas Wistar. Dado que nuestra investigación previa ha puesto de manifiesto que el efecto de la AEIC para facilitar el aprendizaje y la memoria podría ser sensible a la capacidad básica o inicial de los sujetos para aprender las tareas, en el presente trabajo hemos realizado 4 experimentos consecutivos con ratas Wistar que han sido diseñados para dificultar progresivamente el aprendizaje en el LAM reduciendo, en cada siguiente experimento, la cantidad de ensayos de entrenamiento administrados. En cada experimento, los sujetos se dividieron en dos grupos, grupo AEIC y grupo Control y realizaron, en función del experimento, 8, 5, 3 o 1 ensayo diario. Inmediatamente después de cada sesión de entrenamiento los sujetos del grupo AEIC recibieron el tratamiento de AEIC (2000 trenes de corriente reforzante y estimulante a través de un electrodo crónicamente implantado en el hipotálamo lateral derecho de los sujetos) mientras que los sujetos Control no recibieron tratamiento alguno. Los ensayos tenían una duración de 2 minutos y se iniciaban desde una posición que variaba de uno a otro. Los animales debían nadar en la piscina hasta localizar una plataforma escondida que estaba señalizada por una pelota de playa colocada en la periferia de la piscina en el cuadrante derecho adyacente a la plataforma (experimento 1) o en el cuadrante opuesto al de la plataforma (experimentos 2, 3 y 4). Durante el entrenamiento en esta tarea de plataforma-escondida, registramos la latencia de nado y otras variables como la velocidad media de nado, el tiempo en paredes y la distancia total nadada de cada sujeto. Tres días después de la última sesión de entrenamiento, los sujetos realizaron el ensayo de prueba que consistió en dejar nadar al animal durante 60 segundos con la pelota presente pero sin la plataforma. En este ensayo de prueba registramos la media de tiempo que cada sujeto pasó en cada cuadrante así como las trayectorias de nado. A lo largo de las sesiones de entrenamiento observamos una fuerte y consistente facilitación de la ejecución en el LAM en aquellas ratas que habían recibido el tratamiento de autoestimulación tras un único ensayo de adquisición, es decir, cuando el aprendizaje fue más difícil (experimento 4). En este mismo experimento, durante el ensayo de prueba, los sujetos AEIC nadaron significativamente más tiempo en el cuadrante donde debería haberse encontrado la plataforma que en el resto de zonas de la piscina. Esta facilitación también se observó en la última sesión y en el ensayo de prueba de aquellas ratas que habían realizado tres ensayos por sesión (experimento 3). No obstante, no observamos diferencias entre los sujetos tratados y los controles cuando realizaron 8 o 5 ensayos diarios por sesión (experimentos 1 y 2 respectivamente). Estos hallazgos apoyan y confirman resultados previos de nuestro laboratorio en los que, como hemos comentado anteriormente, observamos que la capacidad de la AEIC post-entrenamiento para facilitar la consolidación de la memoria ha sido y es mayor en sujetos con bajos niveles iniciales de condicionamiento y claramente prueban que este tratamiento es capaz de facilitar la memoria explícita, relacional o hipocampo dependiente. / Learning and memory improvement by post-training intracranial self-stimulation has been observed mostly in implicit tasks, such as active avoidance, in rats. Here we wanted to know whether post-training self-stimulation is also able to facilitate a spatial hippocampus-dependent task in the Morris water maze. Four experiments were run with Wistar rats. In each of them subjects were given at least 5 acquisition sessions, one daily, consisting of two-minute trials. Starting from a variable position, rats had to swim in a pool until they located a hidden platform signalled by a cue located on its opposite site. Each daily session was followed by an immediate treatment of intracranial self-stimulation. Control subjects did not receive the self-stimulation treatment and were placed in their home cage. In the three successive experiments, independent groups of rats were given five, three and one trial per session, respectively. Temporal latencies and trajectories to locate the platform were measured for each subject. Three days after the last acquisition session, the animals were placed again in the pool, for 60 sec, but without the platform and the time spent in each quadrant and the swim trajectories were registered for each subject. A strong and consistent improvement of performance was observed in the self-stimulated rats when they were given only one trial per session, i.e. when learning was more difficult. These findings agree with our previous data showing the capacity of post-training self-stimulation to improve memory especially in rats with low conditioning levels (little training), and clearly prove that post-training self-stimulation can also improve explicit or relational memory.

Fructose consumption has increased exponentially during the past four decades. The physiological effects of a high fructose diet include obesity and insulin resistance. In animal models, the effects of a high fructose diet on fat distribution are inconclusive in that some studies find increases in body mass and lipids while others find no effect. Recent findings indicate that a high fructose diet causes hippocampal insulin resistance in hamsters, raising the possibility that the diet causes impairments in cognition. The following experiments tested the hypotheses that a high fructose diet alters fat distribution rather than total body mass and impairs hippocampal-dependent memory. Results indicated that the high fructose diet did not affect fat distribution, but did increase plasma triacylglycerides. Interestingly, the diet also impaired spatial reference memory in the Morris water maze, and this effect was correlated with plasma triacylglycerides. These results indicate that a high fructose diet impairs brain function.