Thesis (M.S.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains vi, 78 p. : ill. Includes abstract. Includes bibliographical references (p. 55-64).

Thesis (Ph. D.) -- California Institute of Technology, 2010. / Title from home page (viewed 03/03/2010). Advisor and committee chair names found in the thesis' metadata record in the digital repository. Includes bibliographical references.

Synaptic dysfunction is a critical neuropathological feature prior to the formation of extracellular senile plaques and intracellular fibrillary tangles (NFTs) in Alzheimer’s disease (AD). The synapse loss and neurites impairment lead to synaptic dysfunction that can be induced by oligomeric Aβ. The administration of oligomeric Aβ reduced the pre-synaptic vesicle proteins and altered the cytoskeletal proteins. The synaptic vesicles (SVs) playing a crucial role to transport and recycle the SV proteins and neurotransmitters (NTs) in synaptic terminals. However, the uptake and release capabilities of SVs were also disrupted by oligomeric Aβ. The disruption of SVs recycling and neurites impairment attenuate neurotransmission that exacerbates the pathogenesis of AD. Therefore, any agents can maintain the SVs recycling and protect the neurites development that could be a therapeutic target for AD. Testosterone is a male sex steroid hormone, which is a potent therapeutic drug for neurodegenerative diseases. It has been found the neuroprotective effects for neuronal death, but the implication on synaptoprotection is still not clear. This study investigated the neuroprotective effects of testosterone from oligomeric Aβ-induced synaptic dysfunction in primary cultured hippocampal neurons. My study demonstrated that testosterone prevented Aβ-induced reduction of pre-synaptic proteins and shortening neurites. Also, testosterone could protect SVs recycling by increasing SVs unloading capability via estrogenic independent pathway. The findings reinforce the neuroprotective effects of testosterone. They are probably facilitating future development for using the concept of male sex hormone as therapy and the intervention of therapeutic drugs for AD patients. / published_or_final_version / Anatomy / Master / Master of Medical Sciences

Volumetric analysis (VA) in magnetic resonance imaging (MRI) has provided great comprehension of the neuroanatomical changes associated to normal cognition and progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD), the most common form of dementia. However, the use of VA has primarily focused in gray matter changes; the emergence of diffusion tensor imaging (DTI) has allowed a better understanding of the microstructural changes in both white and gray matters in MCI and AD patients, with numerous studies showing DTI to be more sensitive than VA in discriminating between MCI to AD. Diffusion kurtosis imaging (DKI), an extension of DTI, is speculated to be more sensitive in detecting changes due to differences in mathematical modeling, as it accounts for non-Gaussian diffusion in the brain. Studies using DKI suggested kurtosis parameters—axial, radial, and mean kurtoses—are able to provide further microstructural details in additional information to tensor and diffusion parameters, namely axial, radial, and mean diffusivities, and fractional anisotropy. In this study, DKI is compared to DTI and VA in an attempt to evaluate the sensitivities of each technique. DKI of all four cerebral lobes and VA of the hippocampus were performed in 30 patients, 18 diagnosed with AD and 12 with MCI. Mann-Whitney U test was performed to determine differences between MCI and AD, and correlations between diffusion parameters and hippocampal volume to mini-mental state examination (MMSE) scores as a biomarker of cognitive function were tested using Pearson’s R correlation test. MMSE scores were statistically different between sexes (p = 0.025) and between MCI and AD groups (p = 0.048), as well as positively correlated with age (p = 0.004). A marginal trend was observed in the hippocampal volume between MCI and AD (p = 0.077), and did not significantly correlate with MMSE. Several diffusivity and kurtosis parameters were significantly different between MCI and AD groups in the white and gray matters of the parietal and occipital lobes. Only tensor parameters had significant negative correlations with MMSE scores in within-group analyses of the two lobes. Correlational tests of white and gray matters of all four lobes to MMSE scores revealed more significant correlations between tensor parameters than kurtosis parameters. Findings from the present study provide further evidence that diffusion MRI is a more sensitive technique than VA in the discrimination between MCI and AD. Results from this study also corroborate with another DKI study exploring diffusivity in neuroanatomical regions predominately composed of white matter in AD progression. While DKI provides additional information on the microstructural changes of white matter and gray matter during disease progression in the brain, whether DKI is superior to DTI requires further research. Diffusion MRI appears to be more advantageous when comparing cognitive function on a continuum like MMSE scores than segregated groups. / published_or_final_version / Diagnostic Radiology / Master / Master of Medical Sciences

The amygdala, a small structure located deep bilaterally in the medial temporal lobe, is the key structure for the emotional processing and storage of memories associated with emotional events, especially fear. The structure has also been shown to enable humans and animals to detect and respond to environmental threats. Fear conditioning became the main model to examine the neural substrates of emotional learning in mammals and specifically in rats’. With the fear conditioning method, researchers can tests rats’, responses to aversive stimuli during the delivery of a cue and then measure how the responses change after learning of the association between the stimuli and the cue. After learning of the two stimuli, the delivery of a cue alone will prompt a fear response in the rats. The fear response can also be elicited by placing the rats in the same chamber in which the aversive stimuli has previously been experienced, which depends on both the amygdala and the hippocampus. Where the amygdala stores the memories of stimulus related to fear, the hippocampus seems to hold all the fear memories in relation to contextual information about the stimulus. The aim of this paper will be to make a comprehensive overview of internal neural processes of both the amygdala and hippocampus and the interaction between the two structures during fear conditioning, to see how the structures separately work to overlap emotion and memory processes.

Upon acquisition, memories undergo an initial stabilization, or consolidation, process after which they are generally resistant to interference. There is now an abundance of evidence that reactivation or retrieval of a consolidated memory opens up a window of time during which the memory can be strengthened, disrupted, or updated via a process of "reconsolidation". This dissertation is comprised of three experimental studies in rats aimed at investigating previously unexamined aspects of this dynamic memory process. The first study assessed whether spatial memories learned under positively-motivated conditions could be updated with new information following reactivation. Rats that learned a second spatial task in the same environmental context as a previously learned task intruded items from the second episode during recall of the first. This result suggests that the context reactivated the memory for the first task, triggering reconsolidation and updating of the memory. The second study used the memory updating effect obtained in the first study as a behavioral measure to investigate the effects of aging on reconsolidation. Unlike in the young rats, the context reminder did not lead to intrusions of the second learning episode during recall of the first. Older adult human participants in this study also showed a different pattern of results than what had been seen previously in young participants. Therefore, in humans as well as in rats, it appears that aging may lead to changes in spatial memory reconsolidation. The third study piloted an experiment to examine hippocampal network activity associated with the spatial memory reconsolidation task used in the first two studies. Preliminarily, we found that the context reminder manipulation was associated with more place field stability across some spatial tasks and that stability across certain tasks was positively related to our measure of memory updating. Additionally, we found evidence that the context reminder enhanced neural replay of some learning episodes. While preliminary, these results suggest that both place field stability and replay may play roles in this reconsolidation paradigm.

Patterns of hippocampal ensemble activity that occur during a spatial experience are reactivated during subsequent rest periods and slow wave sleep. Connections between active cells are thought to be strengthened, via long term potentiation (LTP), by repeated co-activation during experience, which suggests that the level of memory trace reactivation would increase proportionately with repetition. Alternatively, plasticity associated with memory formation, such as LTP-dependent place field expansion and the induction of activity-dependent immediate early gene, ARC, saturates after only a few laps, indicating that reactivation would plateau after a few repetitions. The length of the repeated sequence may also affect reactivation, since activation of a very short sequence can be repeated more frequently than a long sequence in a given time period. We studied how memory trace reactivation was affected by repetition and the length of the repeated sequence by observing the reactivated patterns of cell-pair correlations after a rat ran laps around a long circular track versus running more laps around a short track. On the shorter track, fewer cells had place fields, but they covered more of the track, resulting in generally stronger correlations among active cells. In addition, neuronal activity was recorded from dorsal and mid-ventral CA1. In mid-ventral CA1, there were fewer place fields in the environment but they were larger, with generally stronger correlations among active cells. The comparison between dorsal and mid-ventral regions is thus analogous to the comparison between the sequence of place fields on a long versus short track, respectively. Although there were more cells active in the dorsal region, but more potent correlations in the middle region, no differences in memory trace reactivation were found with respect to repetitions, track length or hippocampal region. This suggests that although spatial scaling increased along the dorsoventral axis of the hippocampus, reactivation is balanced, and possibly coherent across the hippocampal axis and it is relatively independent of sequence length or number of repetitions, at least when that number exceeds about 20.

Perirhinal cortical-dependent behavior and single-unit neuron activity in this brain region were compared between normal aged and young rats. Three different variants of the spontaneous object recognition task were used in these experiments, and the results confirmed previous reports that aged animals are impaired at stimulus recognition. The novel contribution of the present experiments was the identification that the behavioral deficit in the aged rats was due to the old animals treating novel objects as familiar, rather than to forgetting the previously experienced stimuli. This pattern of results in the old animals mirror data obtained from rats with perirhinal cortical lesions and promotes a hypothesis that this area of the brain serves a perceptual-mnemonic function. Additionally, multiple single-unit recordings were obtained from perirhinal cortical cells while young and aged rats traversed a track that contained several objects. Perirhinal neurons exhibited selective increases in their firing rates at object locations. We have called these areas of higher perirhinal cortical cell activity `object fields'. While both young and old rats expressed object fields, a lower proportion of perirhinal neurons showed this type of activity in the aged compared to the young rats. Although familiar and novel objects were placed on the track as part of a systematic design, there was no effect of novelty on the overall firing rates of perirhinal cortical neurons or the proportion of cells expressing object fields under these experimental conditions. These data suggest that the physiological correlate of stimulus recognition is not decrements in perirhinal cortical activity when a stimulus goes from novel to familiar. A final important observation made during these studies in young rats was that place fields in the middle hippocampal CA1 subregion are affected by placing objects in the track. Because this same manipulation increases perirhinal cortical activity, it could indicate that age-related changes in the perirhinal cortex might alter the function of other closely associated structures.

Stress is an important risk factor for the development of clinical depression, yet little is known about the neurobiological mechanisms by which stress might promote depressive symptomatology. The brain is particularly susceptible to the negative effects of stress, as high levels of stress hormones result in decreased hippocampal neurogenesis, slowed cell maturation, and decreased cell complexity. Although we already know that these neurobiological changes are associated with significant impairments in important psychological functions such as learning, memory and motivation, we know little about the molecular details of this stress-induced remodeling and how it contributes to the development of depression. Currently, one candidate molecule of particular interest is reelin, an extracellular matrix protein responsible for regulating neuronal maturation and synaptic plasticity in the adult brain. Interestingly, recent post- mortem analyses indicate that reelin expression is decreased in depressed patients. Similarly, preclinical research has shown that repeated glucocorticoid administration significantly reduces reelin expression in the adult hippocampus. Combined, these results suggest that reelin may be an important protein to examine in regards to the pathogenesis of depression as well as a potential therapeutic target for the treatment of this disorder. The goal of this dissertation is to provide a comprehensive examination of the influence repeated glucocorticoid administration has on reelin expression in the rat hippocampus, and how this relates to the pathogenesis of depression. In chapter 2 we examined how co-treatment with the stress hormone corticosterone (CORT), and the antidepressant imipramine, influence reelin expression in the proliferative region of the hippocampus. In addition we determined whether changes in reelin expression are associated with alterations in neurogenesis and behavioral measures of depression. Results revealed that imipramine prevents CORT-induced downregulation of reelin in the hippocampus, and that these changes parallel improvements in FST behavior, increased neurogenesis and enhanced maturation of immature granule cells. Importantly, these data provide further evidence of reelin’s role in depression and establish this protein as a target of antidepressant treatment. In chapter 3 we examined the effect of CORT on a number of interneuron markers that co-localize with reelin throughout the hippocampus to determine whether the populations of neurons that express reelin are lost or are no longer expressing this protein. Results of this study indicate that CORT influences a number of interneuron markers in a region-specific manner in the hippocampus, but does not cause these cell populations to die, suggesting that CORT exploits an intracellular mechanism to regulate reelin expression in the hippocampus. Finally, in chapter 4, the influence of CORT on MeCP2 and DNMT1, two markers associated with DNA methylation, was examined in the hippocampus to elucidate a potential intracellular mechanism for CORT-induced reelin deficits. Results of this study indicate that CORT has no influence on global protein levels of these markers, but significantly increases the number of MeCP2-expressing cells in the proliferative subgranular zone of the hippocampus, suggesting that there is an increase in the number of methylated cells in this region. While it cannot be conclude from this study that increased methylation causes reelin deficits, the fact that an increase in MeCP2 is seen in the exact region where reelin deficits are most pronounced suggest it is possible. Moreover, these findings are novel, and suggest a role for MeCP2, and more generally, DNA methylation, in the neurobiology of depression. Collectively, the results of this dissertation enhance our understanding of the functional consequences of altered hippocampal neuroplasticity on the development of depressive symptomatology, and the role that reelin may play in this process. They also provide further support for reelin as a novel therapeutic target for the treatment of major depression.

This study investigated the role of nicotinic acetylcholine receptors (nAChR) in object recognition and spatial recognition memory using the spontaneous object recognition (SOR) and object-location (OL) tasks, respectively. Experiments 1 to 4, did not yield any consistent facilitative effects of systemic nAChR activation with nicotine using 24- and 48-hr delays. Using a 72-hr delay, experiments 5 and 8 revealed that systemic pre-sample nicotine dose-dependently facilitated SOR and OL performance, respectively. Experiments 6-7 and 9-10 investigated the potential involvement of the perirhinal cortex (PRh) and hippocampus (HPC) in these systemic effects, with activation of nAChR in both of these brain regions producing facilitative effects on SOR and OL performance. These results not only demonstrate that nAChR facilitate performance on SOR and OL memory tasks, but suggest these effects are mediated by nAChR action in both PRh and HPC. This study indicates that, even though PRh and HPC are functionally distinct, they can interact to enhance performance on tasks for which they are not entirely necessary. / This research was supported by NSERC and CFI, operating grants to Dr. Boyer Winters.