京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18144号 / 医博第3864号 / 新制||医||1002(附属図書館) / 31002 / 京都大学大学院医学研究科医学専攻 / (主査)教授 松原 和夫, 教授 髙橋 淳, 教授 福山 秀直 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19178号 / 医博第4020号 / 新制||医||1010(附属図書館) / 32170 / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 淳, 教授 渡邉 大, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20262号 / 医博第4221号 / 新制||医||1020(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 伊佐 正, 教授 松原 和夫, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第20284号 / 医科博第75号 / 新制||医科||5(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 宮本 享, 教授 林 康紀, 教授 井上 治久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20805号 / 医博第4305号 / 新制||医||1025(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 高橋 淳, 教授 古川 壽亮, 教授 小杉 眞司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(生命科学) / 甲第20820号 / 生博第389号 / 新制||生||51(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 米原 伸, 教授 垣塚 彰, 教授 HEJNA James / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

Parkinson’s Disease (PD) is a neurological movement disorder characterized by depletion of dopaminergic cell bodies in the substantia nigra pars compacta with subsequent loss of dopamine in the nigrostriatal pathway. PD is definitively diagnosed by the presence of intracytoplasmic inclusions in dopaminergic neurons. These inclusions are composed of a-synuclein aggregates, known as “Lewy bodies.” Lewy Bodies are known to be toxic to neurons leading to cell death. Individuals with PD most commonly manifest with bradykinesia (slowness in movement), tremors, and rigidity, but may also suffer orthostatic hypotension, dysphagia, anosmia, constipation, and sleep dysregulation. Mechanisms of PD pathogenesis may include defective protein handling, mitochondrial dysfunction, oxidative stress, and inflammation. Exposure to pesticides has long been implicated in the etiology of Parkinson’s Disease. An increasing number of epidemiological studies have linked the incidence of Parkinson’s Disease to environmental risk factors such as exposure to occupational pesticides and rural living where pesticides are known to leak into the soil and water systems far from their original area of use. The epidemiologic literature is lacking studies with large enough cohorts and accurate means to measure the exact pesticide exposure and duration of exposure. Given the extensive worldwide use of pesticides it is important to further study the associations between Parkinson’s disease and occupation exposures in larger populations.

Effective decision making depends on using memories of past experiences to inform choices in the present. This dissertation examines several ways in which memory is used in decision making, and further aims to establish that one way we adapt to the statistics of our environment is by modifying how we use our memories to guide behavior. In chapters one and two, I focus on how incremental trial-and-error learning and episodic memories of individual events may each contribute to choice. In chapter one, I ask how the brain may arbitrate rationally between these two systems to achieve a balance that maximizes reward. By manipulating the volatility of the environment to affect uncertainty, I show that participants rely on each system in the circumstances to which it is best suited. In chapter two, I then ask how decisions based on these memory systems each depend on striatal dopamine. By studying patients with Parkinson’s disease both on and off their medication, I find that a lack of dopamine alters only incremental learning, and that dopamine replacement remediates this deficit with few effects on the use of episodic memory. Finally, in chapter three, I examine a more difficult class of decisions that require individual memories to be used for planning future action. Using neuroimaging to decode memory access, I find that that the statistical structure of relationships between memories determines when they are used to support planning. Combined, these three chapters suggest that we are capable of flexibly employing multiple forms of memory, with distinct neural mechanisms, to guide a variety of choices.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder primarily affecting the aging population over the age of sixty. Characterized by the significant degeneration of dopaminergic (DAergic) neurons of the substantia nigra causing severe motor dysfunction. Although the exact pathogenesis of this disease is still unknown endoplasmic reticulum stress and mitochondrial dysfunction are believed to play a role. PD is diagnosed after severe DAergic neuron degeneration, and yet is still often misdiagnosed. There is a need for a definitive diagnostic test for the early detection of PD. Current therapies only relieve symptoms and do not stop disease progression. Neurotrophic factors (NTF) are naturally occurring proteins that promote the survival, differentiation and maintenance of neurons and present a promising candidate for the treatment of PD. Cerebral dopamine neurotrophic factor (CDNF) is a novel NTF that protects and rescues DAergic neurons. The present study investigated the role of DAergic activity and CDNF mRNA expression in C. elegans, as well as understanding how does PD affect the endogenous levels of CDNF protein and mRNA expression. We demonstrated that of the various dopamine (DA) synthesis and transport mutants tested, the impaired synthesis of DA from levodopa is linked to the up regulation of CDNF. Also, following unilateral 6-hydroxydopamine (6-OHDA) lesioning protein and mRNA expression of CDNF was not affected implicating ER stress as inducing a possible compensatory up regulation of CDNF, thus returning levels to normal. CDNF mRNA expression was determined to decline with age and possibly increase ones vulnerability to developing a neurodegenerative disorder. An increase mRNA expression of CDNF in the PD patient population was found to be specific to platelets. Stroke patients showed an increase in CDNF expression in whole blood. In conclusion, these findings highlight the importance of the relationship between CDNF and ER stress and warrants further investigation. / Thesis / Master of Science (MSc)

Melatonin has a neuroprotective function, which is mediated via its G-protein-coupled MT1 and MT2 receptors. When activated, various downstream pathways are triggered promoting cell protection and survival. By utilizing this function of melatonin, studies have shown positive effects in animal models of neurodegenerative disorders such as Parkinson’s disease (PD). In our previous studies, a physiological dose of melatonin was shown to have neuroprotective effects in the nigrostriatal pathway, as indicated by preservation of tyrosine hydroxylase (TH) immunoreactivity in a 6-hydroxydopamine (6-OHDA) model of PD. We also have reported that transplantation of MT1 receptor-expressing mouse neural stem cells (C17.2) along with melatonin treatment, preserved TH immunoreactivity in a similar PD model. Moreover, others have reported an increase in striatal melatonin levels in 6-OHDA-induced hemiparkinsonian rats. Based on these implications of a close relationship between the dopaminergic and melatonergic systems, we hypothesize that degeneration of dopaminergic neurons induced by 6-OHDA will affect the melatonergic system in the nigrostriatal pathway. In this study, 6-hydroxydopamine was unilaterally injected in the rat striatum or medial forebrain bundle. An apomorphine rotation test showed significant increases in net contralateral rotations (p<0.01) in lesioned animals as compared to sham. Also, a loss of TH immunoreactivity in the striatum and substantia nigra was seen in striatum lesioned groups, confirming lesion-induced degeneration of dopaminergic neurons in the nigrostriatal pathway. There were no significant differences in MT1 receptor protein expression in the striatum and substantia nigra, between all intrastriatal lesioned groups and the sham group. However, 6-OHDA lesions in the medial forebrain bundle caused a significant increase in MT1 receptor mRNA expression on the lesioned side (right) of the ventral midbrain as compared with the contralateral side. These results suggest that MT1 receptors are upregulated in the ventral midbrain following lesion-induced dopaminergic neurodegeneration, and may be involved in an endogenous neuroprotective mechanism. / Thesis / Master of Science (MSc)