The hippocampus (HPC) is a brain area in the medial temporal lobe involved in spatial navigation, as well as the formation of episodic memories. A subset of the principal cells of the HPC, known as place cells, are active in specific locations of an environment, called the place fields. Dorsal hippocampal area CA1 contains place fields that are known to change their firing during spatial tasks where animals learn the location of a reward, known as goal-oriented learning (GOL) – CA1 place fields shift toward rewarded locations. Previous studies suggest that this preferentially occurs at novel rewarded locations in a familiar environment, but the mechanism is unknown. The locus coeruleus (LC) is a neuromodulatory nucleus in the brainstem that projects throughout the brain and releases norepinephrine and a small amount of dopamine. Stimulating locus coeruleus-hippocampal area CA1 projections (LC-CA1) was recently shown to improve performance on spatial memory tasks. Since performance on the GOL task is correlated with the degree of overrepresentation of rewarded locations, we hypothesized that the LC-CA1 projection was involved in reward-related place field reorganization. Using in vivo two photon calcium imaging, we recorded the activity of the LC-CA1 projection during a head fixed GOL task with two phases – during the first phase, a water reward was presented in one location (RZ1), and in the second phase, it was moved to a novel location (RZ2). In the first phase of the task, the LC-CA1 axons were correlated with running, but in the second phase they showed an increase in activity preceding RZ2. To determine whether the LC-CA1 is involved in place field reorganization that normally occurs in RZ2, we optogenetically activated the projection just before RZ1, and saw a pronounced place field reorganization right before the reward. Conversely, inhibition of LC-CA1 at RZ2 attenuated place field reorganization at this site. Finally, LC-CA1 stimulation away from the reward did not lead to place field reorganization, indicating that the LC influences place field shifts in conjunction with other signals that are differentially active around rewards. A full account of the effects of neuromodulation should also include astrocytes, since they respond to neuromodulators with large calcium signals that may be able to affect the function of neurons. We also recorded HPC astrocyte calcium activity during different behavioral tasks. Astrocytes showed occasional large calcium signals, with some differences in synchronicity and activity levels between hippocampal layers and behavioral paradigms. Future studies should determine whether the LC-CA1 projection affects place fields directly by affecting neural activity, indirectly via astrocytes, or both.

Obesity, diabetes, hypertension, and heart disease are highly heritable conditions that in aggregate are the major causes of morbidity and mortality in the developed world and are growing problems in developing countries. To map the causal genes, we conducted a population screen for these conditions on the Pacific Island of Kosrae. Family history and genetic data were used to construct a pedigree for the island. Analysis of the pedigree showed highly significant heritability for the metabolic traits under study. DNA samples from 2,188 participants were genotyped with 405 microsatellite markers with an average intermarker distance of 11 cM. A protocol using LOKI, a Markov chain Monte Carlo sampling method, was developed to analyze the Kosraen pedigree for height, a model quantitative trait. Robust quantitative trait loci for height were found on 10q21 and 1p31. This protocol was used to map a set of metabolic traits, including plasma leptin to chromosome region 5q35; systolic blood pressure to 20p12; total cholesterol to 19p13, 12q24, and 16qter; hip circumference to 10q25 and 4q23; body mass index to 18p11 and 20q13; apolipoprotein B to 2p24-25; weight to 18q21; and fasting blood sugar to 1q31-1q43. Several of these same chromosomal regions have been identified in previous studies validating the use of LOKI. These studies add information about the genetics of the metabolic syndrome and establish an analytical approach for linkage analysis of complex pedigrees. These results also lay the foundation for whole genome scans with dense sets of SNPs aimed to identifying causal genes.

El objetivo fue analizar si existen diferencias en los niveles de estrés percibidos por los padres de niños con problemas crónicos de salud, de acuerdo al tipo de locus de control (externo o interno). Los participantes fueron 113 padres que tienen hijos con problemas de salud crónicos, y, que aceptaron voluntariamente contestar los cuestionarios preparados y que son parte del cuadernillo de medida, siendo el 65.5% mujeres y el 34,5% hombres. A esta muestra se les aplicó la escala de Locus de Control de Rotter, adaptada en Perú por Brenlla y Vázquez (2010) y la escala de Estrés Percibido adaptada en Perú por Guzmán (2016). El análisis de los datos hallados, determina que el estrés de los padres no se diferencia significativamente por el tipo de locus de control que poseen, pero si se reportan diferencias de acuerdo al diagnóstico que tiene el hijo con enfermedad crónica y por la procedencia de los mismos. / The aim was to analyze whether there are differences in the levels of stress perceived by the parents of children with chronic health problems, according to the type of locus of control (external or internal). The participants were 113 parents who have children with chronic health problems, and who voluntarily agreed to answer the prepared questionnaires and that are part of the measurement booklet, 65.5% being women and 34,5% being men. The Rotter Locus of Control scale, adapted in Peru by Brenlla and Vázquez (2010) and the Perceived Stress scale adapted in Peru by Guzmán (2016), were applied to this sample. The analysis of the data found determines that parental stress is not significantly differentiated by the type of locus of control that it possesses, but differences are reported according to the diagnosis of the child with chronic disease and by the origin of the same. / Tesis

Online learners bring varied learning experiences depending on their different personal characteristics and traits. This descriptive and correlational study explored students\' online satisfaction in relation to their locus of control orientation and their personal characteristics including gender, age, ethnicity, and online learning experiences. Responses were collected from students in an online course at Virginia Tech. Descriptive statistics, Pearson correlations and Multiple Linear Regression methods were used to detect the correlations and analyze the relationships among different variables. Results of the study did not find correlations between students\' online satisfaction and their locus of control, as well as their personal characteristics. The results also showed that students\' locus of control and personal characteristics did not contribute to students\' online satisfaction. / Ph. D.

Sexual reproduction is an important process amongst eukaryotic organisms, with one function being to maintain genetic variation. The idea that complex eukaryotic species can persist for millions of years in the absence of sex defies fundamental evolutionary dogma, yet a group of organisms known as ancient asexuals were thought to have evolved clonally under deep evolutionary time. Prominent among these are the arbuscular mycorrhizal fungi (AMF), which are obligate plant symbionts that colonize the root cells of plants and extend their hyphae into the soil assisting the plant in acquiring key nutrients. Unlike most eukaryotes, AMF cells are multinucleate with thousands of nuclei moving through a continuous cytoplasm. Genomic analyses have identified a putative mating-type (MAT) locus within the nuclear genomes of model AMF Rhizophagus irregularis, a region that in other fungi dictates the process of sexual reproduction. Additional findings demonstrated that AMF strains carry one of two nuclear organizations. They can be either homokaryotic (AMF homokaryons), where all nuclei within the cytoplasm are virtually identical, or heterokaryotic (AMF dikaryons), where two MAT-locus variants co-exist within the cytoplasm. Despite a lack of observable traits indicative of sex, this homo/heterokaryotic dichotomy is reminiscent of the nuclear organization of sexual fungi. My research aims to build on these findings to investigate the actual role of the MAT-locus in driving AMF reproduction. To address this, I build my thesis into three main chapters. The first chapter reviews our current understanding of AMF genetics and what drives genome evolution in these organisms. The second chapter establishes a relatively easy, inexpensive, and reproducible approach to genotype known MAT variants of R. irregularis in natural and experimental conditions. The last chapter uses experimental crossings between strains to assess cytoplasmic compatibility and nuclear exchange. I demonstrate that dikaryotic spore progenies can be formed after co-culturing two distinct AMF homokaryotic strains. Further analyses of various genomic regions also reveal possible recombination in homokaryotic spore progenies from co-cultures. Overall, this research provides new experimental insights into the origin of genetic diversity in AMF. These findings open avenues to produce genetically new AMF strains in the lab using conventional crossing procedures and provide a glimpse of the mechanisms that generate AMF genetic diversity in the field.

Locus of control has been associated with health outcomes (Donham et al., 1983; Holder & Levi, 1988) as well as interactions with the health care field (Christensen et al., 1996) and has independently predicted health outcomes among victims of sexual trauma (Simoni & Ng, 2002). As such, it may help to explain adverse health outcomes associated with sexual trauma. The current study sought to examine the potential mediating factor that an individual’s locus of control may have on the relationship between history of sexual trauma and health outcomes/health care interactions. Locus of control was measured via the Levenson Locus of Control Scales (Levenson, 1981) which divides locus of control into three subscales: internal locus of control, powerful others, and chance. Among a sample of women aged 18-50 years old (N = 753), an internal locus of control significantly mediated the relationship between sexual trauma and health outcomes (somatic symptoms, self-rated health, depression, and anxiety) as well as the relationship between sexual trauma and health care interactions (an individual’s level of medical mistrust and medical nonadherence). While each external locus of control scale did significantly predict outcomes, they were not significant mediators. Findings indicate the importance of internal locus of control in understanding sexual trauma’s effect on health outcomes.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24280号 / 医博第4896号 / 新制||医||1061(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森田 智視, 教授 松田 道行, 教授 波多野 悦朗 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Post-traumatic stress disorder (PTSD) is a psychiatric condition caused by exposure to a traumatic event. Veterans are at especially high risk of PTSD. In Canada, in a survey conducted in 2016, 16% of Regular Force Veterans released during 1998-2015 reported having PTSD, which is at least two times higher than the estimated prevalence rate in the general population. Individuals with PTSD experience a range of debilitating symptoms, such as the intrusion of unwanted and distressing memories, persistent flashbacks, hypervigilance and nightmares. The neuropathophysiological mechanisms underlying symptoms of PTSD are not well understood, which remains a significant barrier to developing effective treatments. Hallmark PTSD symptoms such as hyperarousal and sleep disturbances may be related to dysregulation of noradrenaline (NA), a neurotransmitter produced in the locus coeruleus (LC) known to modulate cognition, arousal and sleep. This thesis examines the possible associations between dysregulation in rapid-eye-movement (REM) sleep and dysfunction in NA-containing neurons in the LC among veterans with PTSD. Twenty-two operationally deployed veterans with a history of PTSD were recruited through the Royal Ottawa Mental Health Centre in Ontario, Canada. A novel, non-invasive neuroimaging method, neuromelanin-sensitive magnetic resonance imaging (NM-MRI), was used to detect a by-product of NA called neuromelanin (NM) in the LC of each participant. Then a contrast-to-noise ratio (CNR) was calculated to obtain a marker of the NA function. The LC was segmented into three subdivisions to assess whether the association between NM and REM sleep may differ across regions of the LC. As hypothesized, we observed different associations between NM and REM sleep across regions of the LC. After controlling for antidepressant usage, there was (i) a moderate, negative, significant correlation between the percentage of REM sleep and rostral LCCNR, r(19) = -.476, p = .029, (ii) a weak positive non-significant correlation between the percentage of REM sleep and caudal LCCNR, r(19) = .33, p = .145, and (iii) no significant correlation between REM sleep percentage and LCCNR in the middle LC, r(19) = -.04, p = .876. This thesis is the first study to show that NM and REM sleep may be related in veterans with PTSD and that this relationship may vary across subdivisions of the LC. These results improve understanding of REM sleep among individuals with PTSD. The results may stimulate the investigation of novel pharmacotherapy focused on sleep disturbances in PTSD, the development of personalized treatments for PTSD, and the search for clinical biomarkers of PTSD based on brain function. The current study also made methodological contributions that may be applicable beyond the research on PTSD to the field of REM sleep and the NA system. Specifically, the current study showed the suitability of the NM-MRI method for examining the connections between NM and REM sleep, and it showed that segmenting the LC can lead to a more nuanced understanding of its role in the human body.

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