Gene-environment interactions between adult lead exposure and Apolipoprotein E4 on adult hippocampal neurogenesis and cognitive behavior in mice

Thesis (Ph.D.)--University of Washington, 2016-06

Finding the balance: Living with memory loss

Since the late 1980s, it has been increasingly recognized that the experiences of people with dementia have been omitted from research in the area of dementia and memory loss. More recently, it has been accepted that people with dementia have insight into their condition and, therefore, the ability to contribute to research. A qualitative research project was undertaken with nine participants to explore the experiences and coping strategies of people with dementia. Interviews were undertaken and the data analysed using thematic analysis. Three major themes emerged: coming to terms with memory loss, maintaining control and independence, and the impact of illness on relationships. Understanding the reality for people is essential given that representations of the catastrophic impact of dementia generate high levels of anxiety and depression. Implications for nurses' practice include the need for skilled, well-paced, sensitive and ongoing information about the condition, along with the need to recognize and support the active coping strategies of people with memory loss.

The BAR domain proteins: Molding membranes in fission, fusion, and phagy

The Bin1/amphiphysin/Rvs167 (BAR) domain proteins are a ubiquitous protein family. Genes encoding members of this family have not yet been found in the genomes of prokaryotes, but within eukaryotes, BAR domain proteins are found universally from unicellular eukaryotes such as yeast through to plants, insects, and vertebrates. BAR domain proteins share an N-terminal BAR domain with a high propensity to adopt alpha-helical structure and engage in coiled-coil interactions with other proteins. BAR domain proteins are implicated in processes as fundamental and diverse as fission of synaptic vesicles, cell polarity, endocytosis, regulation of the actin cytoskeleton, transcriptional repression, cell-cell fusion, signal transduction, apoptosis, secretory vesicle fusion, excitation-contraction coupling, learning and memory, tissue differentiation, ion flux across membranes, and tumor suppression. What has been lacking is a molecular understanding of the role of the BAR domain protein in each process. The three-dimensional structure of the BAR domain has now been determined and valuable insight has been gained in understanding the interactions of BAR domains with membranes. The cellular roles of BAR domain proteins, characterized over the past decade in cells as distinct as yeasts, neurons, and myocytes, can now be understood in terms of a fundamental molecular function of all BAR domain proteins: to sense membrane curvature, to bind GTPases, and to mold a diversity of cellular membranes.

Relationship between work performance and personality traits in Hong Kong organizational settings

Four hundred and thirty-seven employees from four Hong Kong organizations completed the Traditional Chinese versions of the Fifteen Factor Personality Questionnaire Plus (15FQ+) and the Cross-Cultural Personality Assessment Inventory (CPAI-2) (indigenous scales) and provided objective and memory-based recent performance appraisal scores. A number of significant bivariate correlations were found between personality and performance scores. Hierarchical multiple regression analyses revealed that a number of the scales from the 15FQ+ contributed to significantly predicting four of the performance competency dimensions, but that the CPAI-2 indigenous scales contributed no incremental validity in performance prediction over and above the 15FQ+. Results are discussed in the light of previous research and a call made for continued research to further develop and increase the reliability of the Chinese instruments used in the study and to enable generalization of the findings with confidence.

Organizational learning orientation profile and implications for strategic planning capacity

Theory development on the relationship between strategic planning and organizational performance has focussed on largely discrete examinations of dependent and independent variables. While the literature has examined the impact of organizational learning on strategic planning, no holistic empirical approaches have been employed in order to fully explore the inter-play between these important constructs. This paper addresses the cited limitations in both the strategic planning and organizational performance literatures by creating profiles of organizational learning and strategic planning capacity using a configuration theory-based approach. The organizational learning orientation profiles (OLOPs) created of prospector, disseminator, interpretative and memory, contribute to theory development regarding the relationship of strategic planning and organizational learning. The theory developed provides insights that have not been previously reported.

Why do doctored images distort memory?

Doctored images can cause people to believe in and remember experiences that never occurred, yet the underlying mechanism(s) responsible are not well understood. How does compelling false evidence distort autobiographical memory? Subjects were filmed observing and copying a Research Assistant performing simple actions, then they returned 2 days later for a memory test. Before taking the test, subjects viewed video-clips of simple actions, including actions that they neither observed nor performed earlier. We varied the format of the video-clips between-subjects to tap into the source-monitoring mechanisms responsible for the 'doctored-evidence effect.' The distribution of belief and memory distortions across conditions suggests that at least two mechanisms are involved: doctored images create an illusion of familiarity, and also enhance the perceived credibility of false suggestions. These findings offer insight into how external evidence influences source-monitoring. © 2009 Elsevier Inc. All rights reserved.

Practical, Computation Efficient High-Order Neural Network for Rotation and Shift Invariant Pattern Recognition

In this paper, a modification for the high-order neural network (HONN) is presented. Third order networks are considered for achieving translation, rotation and scale invariant pattern recognition. They require however much storage and computation power for the task. The proposed modified HONN takes into account a priori knowledge of the binary patterns that have to be learned, achieving significant gain in computation time and memory requirements. This modification enables the efficient computation of HONNs for image fields of greater that 100 × 100 pixels without any loss of pattern information.

Astrocyte and neuronal plasticity in the somatosensory system

Changing the whisker complement on a rodent's snout can lead to two forms of experience-dependent plasticity (EDP) in the neurons of the barrel cortex, where whiskers are somatotopically represented. One form, termed coding plasticity, concerns changes in synaptic transmission and connectivity between neurons. This is thought to underlie learning and memory processes and so adaptation to a changing environment. The second, called homeostatic plasticity, serves to maintain a restricted dynamic range of neuronal activity thus preventing its saturation or total downregulation. Current explanatory models of cortical EDP are almost exclusively neurocentric. However, in recent years, increasing evidence has emerged on the role of astrocytes in brain function, including plasticity. Indeed, astrocytes appear as necessary partners of neurons at the core of the mechanisms of coding and homeostatic plasticity recorded in neurons. In addition to neuronal plasticity, several different forms of astrocytic plasticity have recently been discovered. They extend from changes in receptor expression and dynamic changes in morphology to alteration in gliotransmitter release. It is however unclear how astrocytic plasticity contributes to the neuronal EDP. Here, we review the known and possible roles for astrocytes in the barrel cortex, including its plasticity.

The MK2/3 cascade regulates AMPAR trafficking and cognitive flexibility

The interplay between long-term potentiation and long-term depression (LTD) is thought to be involved in learning and memory formation. One form of LTD expressed in the hippocampus is initiated by the activation of the group 1 metabotropic glutamate receptors (mGluRs). Importantly, mGluRs have been shown to be critical for acquisition of new memories and for reversal learning, processes that are thought to be crucial for cognitive flexibility. Here we provide evidence that MAPK-activated protein kinases 2 and 3 (MK2/3) regulate neuronal spine morphology, synaptic transmission and plasticity. Furthermore, mGluR-LTD is impaired in the hippocampus of MK2/3 double knockout (DKO) mice, an observation that is mirrored by deficits in endocytosis of GluA1 subunits. Consistent with compromised mGluR-LTD, MK2/3 DKO mice have distinctive deficits in hippocampal-dependent spatial reversal learning. These novel findings demonstrate that the MK2/3 cascade plays a strategic role in controlling synaptic plasticity and cognition. © 2014 Macmillan Publishers Limited. All rights reserved.

Age differences in associative and strategic processes in human conditional learning

Research indicates associative and strategic deficits mediate age related deficits in memory, whereas simple associative processes are independent of strategic processing and strategic processes mediate resistance to interference. The present study showed age-related deficits in a contingency learning task, although older participants' resistance to interference was not disproportionately affected. Recognition memory predicted discrimination, whereas general cognitive ability predicted resistance to interference, suggesting differentiation between associative and strategic processes in learning and memory, and age declines in associative processes. Older participants' generalisation of associative strength from existing to novel stimulus-response associations was consistent with elemental learning theories, whereas configural models predicted younger participants' responses. This is consistent with associative deficits and reliance on item-level representations in memory during later life. © 2011 Psychology Press Ltd.

Transition from community dwelling to retirement village in older adults:cognitive functioning and psychological health outcomes

Supported living and retirement villages are becoming a significant option for older adults with impairments, with independence concerns or for forward planning in older age, but evidence as to psychological benefits for residents is sparse. This study examined the hypothesis that the multi-component advantages of moving into a supported and physically and socially accessible “extra care” independent living environment will impact on psychological and functioning measures. Using an observational longitudinal design, 161 new residents were assessed initially and three months later, in comparison to 33 older adults staying in their original homes. Initial group differences were apparent but some reduced after three months. Residents showed improvement in depression, perceived health, aspects of cognitive function, and reduced functional limitations, while controls showed increased functional limitations (worsening). Ability to recall specific autobiographical memories, known to be related to social-problem solving, depression and functioning in social relationships, predicted change in communication limitations, and cognitive change predicted changes in recreational limitations. Change in anxiety and memory predicted change in depression. Findings suggest that older adults with independent living concerns who move to an independent but supported environment can show significant benefits in psychological outcomes and reduction in perceived impact of health on functional limitations in a short period. Targets for focussed rehabilitation are indicated, but findings also validate development of untargeted general supportive environments.

Benchmarking of distributed computing engines spark and GraphLab for big data analytics

In this paper we evaluate and compare two representativeand popular distributed processing engines for large scalebig data analytics, Spark and graph based engine GraphLab. Wedesign a benchmark suite including representative algorithmsand datasets to compare the performances of the computingengines, from performance aspects of running time, memory andCPU usage, network and I/O overhead. The benchmark suite istested on both local computer cluster and virtual machines oncloud. By varying the number of computers and memory weexamine the scalability of the computing engines with increasingcomputing resources (such as CPU and memory). We also runcross-evaluation of generic and graph based analytic algorithmsover graph processing and generic platforms to identify thepotential performance degradation if only one processing engineis available. It is observed that both computing engines showgood scalability with increase of computing resources. WhileGraphLab largely outperforms Spark for graph algorithms, ithas close running time performance as Spark for non-graphalgorithms. Additionally the running time with Spark for graphalgorithms over cloud virtual machines is observed to increaseby almost 100% compared to over local computer clusters.

Estrogen and lithium: Facilitating factors involved in brain cell signaling pathways

Learning and memory in adult females decline during menopause and estrogen replacement therapy is commonly prescribed during menopause. Post-menopausal women tend to suffer from depression and are prescribed antidepressants – in addition to hormone therapy. Estrogen replacement therapy is a topic that engenders debate since several studies contradict its efficacy as a palliative therapy for cognitive decline and neurodegenerative diseases. Signaling transduction pathways can alter brain cell activity, survival, and morphology by facilitating transcription factor DNA binding and protein production. The steroidal hormone estrogen and the anti-depressant drug lithium interact through these signaling transduction pathways facilitating transcription factor activation. The paucity of data on how combined hormones and antidepressants interact in regulating gene expression led me to hypothesize that in primary mixed brain cell cultures, combined 17β-estradiol (E2) and lithium chloride (LiCl) (E2/LiCl) will alter genetic expression of markers involved in synaptic plasticity and neuroprotection. Results from these studies indicated that a 48 h treatment of E2/LiCl reduced glutamate receptor subunit genetic expression, but increased neurotrophic factor and estrogen receptor genetic expression. Combined treatment also failed to protect brain cell cultures from glutamate excitotoxicity. If lithium facilitates protein signaling pathways mediated by estrogen, can lithium alone serve as a palliative treatment for post-menopause? This question led me to hypothesize that in estrogen-deficient mice, lithium alone will increase episodic memory (tested via object recognition), and enhance expression in the brain of factors involved in anti-apoptosis, learning and memory. I used bilaterally ovariectomized (bOVX) C57BL/6J mice treated with LiCl for one month. Results indicated that LiCl-treated bOVX mice increased performance in object recognition compared with non-treated bOVX. Increased performance in LiCl-treated bOVX mice coincided with augmented genetic and protein expression in the brain. Understanding the molecular pathways of estrogen will assist in identifying a palliative therapy for menopause-related dementia, and lithium may serve this purpose by acting as a selective estrogen-mediated signaling modulator.

The influence of gene environment interaction on the risk of cognitive impairment: Reducing sexual risk behaviors and alcohol use in HIV-infected adults

Memory deficits and executive dysfunction are highly prevalent among HIV-infected adults. These conditions can affect their quality of life, antiretroviral adherence, and HIV risk behaviors. Several factors have been suggested including the role of genetics in relation to HIV disease progression. This dissertation aimed to determine whether genetic differences in HIV-infected individuals were correlated with impaired memory, cognitive flexibility and executive function and whether cognitive decline moderated alcohol use and sexual transmission risk behaviors among HIV-infected alcohol abusers participating in an NIH-funded clinical trial comparing the efficacy of the adapted Holistic Health Recovery Program (HHRP-A) intervention to a Health Promotion Control (HPC) condition in reducing risk behaviors. ^ A total of 267 individuals were genotyped for polymorphisms in the dopamine and serotonin gene systems. Results yielded significant associations for TPH2, GALM, DRD2 and DRD4 genetic variants with impaired executive function, cognitive flexibility and memory. SNPs TPH2 rs4570625 and DRD2 rs6277 showed a risk association with executive function (odds ratio = 2.5, p = .02; 3.6, p = .001). GALM rs6741892 was associated with impaired memory (odds ratio = 1.9, p = .006). At the six-month follow-up, HHRP-A participants were less likely to report trading sex for food, drugs and money (20.0%) and unprotected insertive or receptive oral (11.6%) or vaginal and/or anal sex (3.2%) than HPC participants (49.4%, p^

Estrogen and Lithium: Facilitating Factors Involved in Brain Cell Signaling Pathways

Learning and memory in adult females decline during menopause and estrogen replacement therapy is commonly prescribed during menopause. Post-menopausal women tend to suffer from depression and are prescribed antidepressants – in addition to hormone therapy. Estrogen replacement therapy is a topic that engenders debate since several studies contradict its efficacy as a palliative therapy for cognitive decline and neurodegenerative diseases. Signaling transduction pathways can alter brain cell activity, survival, and morphology by facilitating transcription factor DNA binding and protein production. The steroidal hormone estrogen and the anti-depressant drug lithium interact through these signaling transduction pathways facilitating transcription factor activation. The paucity of data on how combined hormones and antidepressants interact in regulating gene expression led me to hypothesize that in primary mixed brain cell cultures, combined 17beta-estradiol (E2) and lithium chloride (LiCl) (E2/LiCl) will alter genetic expression of markers involved in synaptic plasticity and neuroprotection. Results from these studies indicated that a 48 h treatment of E2/LiCl reduced glutamate receptor subunit genetic expression, but increased neurotrophic factor and estrogen receptor genetic expression. Combined treatment also failed to protect brain cell cultures from glutamate excitotoxicity. If lithium facilitates protein signaling pathways mediated by estrogen, can lithium alone serve as a palliative treatment for post-menopause? This question led me to hypothesize that in estrogen-deficient mice, lithium alone will increase episodic memory (tested via object recognition), and enhance expression in the brain of factors involved in anti-apoptosis, learning and memory. I used bilaterally ovariectomized (bOVX) C57BL/6J mice treated with LiCl for one month. Results indicated that LiCl-treated bOVX mice increased performance in object recognition compared with non-treated bOVX. Increased performance in LiCl-treated bOVX mice coincided with augmented genetic and protein expression in the brain. Understanding the molecular pathways of estrogen will assist in identifying a palliative therapy for menopause-related dementia, and lithium may serve this purpose by acting as a selective estrogen-mediated signaling modulator.