abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects 5.4 million Americans. AD leads to memory loss, changes in behavior, and death. The key hallmarks of the disease are amyloid plaques and tau tangles, consisting of amyloid-β oligomers and hyperphosphorylated tau, respectively. Rho-associated, coiled-coil-containing protein kinase (ROCK) is an enzyme that plays important roles in neuronal cells including mediating actin organization and dendritic spine morphogenesis. The ROCK inhibitor Fasudil has been shown to increase learning and working memory in aged rats, but another ROCK inhibitor, Y27632, was shown to impair learning and memory. I am interested in exploring how these, and other ROCK inhibitors, may be acting mechanistically to result in very different outcomes in treated animals. Preliminary research on thirteen different ROCK inhibitors provides evidence that while Fasudil and a novel ROCK inhibitor, T343, decrease tau phosphorylation in vitro, Y27632 increases tau phosphorylation at a low dose and decreases at a high dose. Meanwhile, novel ROCK inhibitor T299 increases tau phosphorylation at a high dosage. Further, an in vivo study using triple transgenic AD mice provides evidence that Fasudil improves reference memory and fear memory in both transgenic and wild-type mice, while Y27632 impairs reference memory in transgenic mice. Fasudil also decreases tau phosphorylation and Aβ in vivo, while Y27632 significantly increases the p-tau to total tau ratio. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2017

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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Studies have shown that there is a strong correlation between aging and neurodegenerative diseases. Aging is considered the number one risk factor to develop neuropathologies such as memory loss, senile dementia, Alzheimer's disease (AD), and Parkinson's disease. Neurodegenerative diseases tend to start during adulthood, and aggravate over time, making them difficult to prevent and to treat. In the Unites States, demographic studies by U.S. Bureau of the Census have determined that our aging population of >65 years is expected to increase from the present 35 million to 78 million in 2030. This would result, not only to an increase of age-related chronic illness, and mental disability, but to a decrease of quality of life, and an elevation of medical cost. Thus, this dissertation has focused on investigating the molecular mechanisms during the process of aging and its correlation to chronic inflammation and cognitive impairments. The etiology of neurodegenerative diseases is not very well understood, but research has shown that the process of aging is a key factor, which involved oxidative stress, an over reactive microglia, and increased production of pro-inflammatory cytokines. All these factors are known to decrease cell proliferation, which limit neuroplasticity and they might lead the transition from normal aging to more severe cognitive dysfunction associated with neurodegenerative diseases. Previously, we have shown that natural compounds such as polyphenols from blueberry, and green tea, and amino acids like carnosine are high in antioxidant and anti-inflammatory activity that decreases the damaging effects of reactive oxygen species (ROS), in the blood, brain, and other tissues of the body. Therefore, we examined the hypothesis that the pro-inflammatory cytokine TNF-[U+F061] may be a critical factor that modulates classical conditioning behavior, the effects of NT-020 on adult neurogenesis, inflammatory markers of the CNS, and the effect of NT-020 on cognitive function as shown using spatial navigation task. The results show that in aged rats, endogenous production of pro-inflammatory cytokine TNF-α impairs the acquisition of learning and memory consolidation in the delay eyeblink classical conditioning task (EBC). It was shown that this effect can be replicated by infusing young rats with exogenous TNF-α prior to EBC. Using NT-020 as a dietary supplement for one month, it was found that NT-020 ameliorates the age-related impairments typically found in aged rats in the spatial navigation tasks Morris water maze and radial arm water maze. By looking at immunohistochemistry analysis, it was found a decreased number of OX6 MHC II positive cells, increased neurogenesis, and increased number of proliferating cells in the dentate gyrus (DG) of the hippocampus in the aged rats fed with NT-020 relative with their counterpart aged control. In the CNS, Inflammatory markers were analyzed, and it was found that aged rat fed with NT-020 supplemented diet has decrease levels of pro-inflammatory cytokines in compared with aged rats fed with NIH-31 control diet. In conclusion, TNF-α, a pro-inflammatory cytokine has shown to have a modulatory effect during classical conditioning. Moreover, NT-020 may promote a healthy CNS milieu, proliferation of neuronal progenitors, and maintenance of nature neurons in the aged rats and it might exert anti-inflammatory actions which promote a functional stem cell pool in the CNS of aged rats.

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.

Inúmeros estudos têm demonstrado que a desnutrição protéica e/ou protéico-calórica, quando introduzida durante os estágios iniciais de desenvolvimento, produz diversas alterações neuroquímicas, neurofisiológicas e/ou funcionais no sistema nervoso central, além de comprometimentos físicos e atrasos no desenvolvimento cognitivo. O presente trabalho teve como objetivo investigar os efeitos de quatro técnicas de desnutrição precoce sobre os processos de aprendizagem e memória espacial (operacional e de referência) em ratos adultos testados em duas tarefas de aprendizagem em dois modelos de labirintos aquáticos. Os animais foram agrupados em seis diferentes condições de acordo com o tratamento durante a fase de lactação: grupo controle (C1), ninhadas alimentadas com dieta normoproteica ad libtum; grupo desnutrido protéico (DP), ninhadas alimentadas com dieta hipoprotéica ad libtum; grupo desnutrido protéico-calórico (DPC), ninhadas alimentadas com dieta normoproteica, restrita a 50% da quantidade consumida por uma ninhada controle de mesma idade; grupo desnutrido de grandes ninhadas (DGN) ninhadas com um número de filhotes duas vezes maior que as demais, alimentadas com dieta normoproteica ad libtum; grupo desnutrido por separação temporária (DS) ninhadas separadas das mães por 12 horas diárias, alimentadas com dieta normoproteica ad libtum; grupo controle para a condição DS (C2), ninhadas alimentadas com dieta normoproteica ad libtum. As ninhadas dos grupos C, CS, DP, DPC e DS foram compostas por oito filhotes cada. As ninhadas CS foram separadas de suas mães e mantidas com outra rata fêmea adulta, não lactante, por 12 horas diárias. Após o desmame, todos os grupos foram alimentados com ração comercial para roedores. Todos os grupos desnutridos apresentaram prejuízos de aprendizagem e/ou memória na tarefa do labirinto aquático de Morris. Na tarefa do labirinto radial aquático, apenas ratos DP apresentaram diferenças de desempenho comparados aos ratos C, entretanto essas diferenças apareceram apenas em duas sessões iniciais e não foram persistentes. Os efeitos deletérios da desnutrição precoce sobre os processos de aprendizagem e memória, avaliados na idade adulta, foram sutis e específicos para cada técnica de desnutrição utilizada, em contraste aos acentuados déficits observados no desenvolvimento físico dos filhotes. Nossos resultados indicam que a desnutrição precoce foi capaz de ocasionar déficits de memória operacional e de referência na tarefa de aprendizagem espacial do labirinto de Morris, dependente, preponderantemente, de estratégias de mapeamento espacial para sua resolução, entretanto não foram observados os mesmos efeitos na tarefa espacial do labirinto radial aquático solucionável também por estratégias de guiamento e orientação egocêntricas. / Numerous studies have shown that protein and/or protein-calorie malnutrition, when introduced during the early stages of development, produces several neurochemical, neurophysiological and / or functional changes in central nervous system, in addition to physical impairments and delays in cognitive development. The effects of different early malnutrition techniques on learning and spatial memory processes in adult rats were evaluated in two water maze tasks. Animals were grouped into six different conditions according to treatment during lactation phase: control group (C1), litters fed a normal protein diet ad libitum; protein malnourished group (PM), litters fed a low protein diet ad libitum; protein-calorie malnourished group (PCM), litters fed with 50% of the amount of diet ingested by C; malnutrition-induced by an increase in the number of pups in the litters (LLM - twice the number of pups in C litters) fed a normal protein diet ad libitum; malnutrition induced by removal the pups from their dams half the day (RM), litters fed a normal protein diet ad libitum; control group for RM condition (C2), litters fed a normal protein diet ad libitum. C, CR, PM, PCM and RM litters were composed by eight pups each. RM litters were removed from their dams and kept 12 hours daily with a non-lactating female rat. After weaning, all groups were fed a lab chow. All malnourished groups showed learning and memory impairments in the Morris maze task. Nevertheless, only PM rats showed different performance in Radial-arm water maze. Compared to controls, PM rats had fewer working memory errors and spent less time to complete the second and fourth sessions, however no enduring differences between C and PM were observed along the sessions. Malnutrition insults on learning and memory in adulthood were tenuous and specific for each malnutrition technique, despite the pronounced physical damages. Our results suggest that early malnutrition leads to working and reference memory impairments in place-strategies dependent spatial task in the Morris maze but not in a spatial learning task in the Radial-arm water maze solvable by guidance and egocentric strategies either.

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.