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京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第22297号 / 理博第4611号 / 新制||理||1661(附属図書館) / 京都大学大学院理学研究科生物科学専攻 / (主査)教授 高田 昌彦, 教授 中村 克樹, 教授 濱田 穣 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

In Parkinson's disease (PD), large parts of the brain transition into states of enhanced neural synchronization. These phase transitions have been associated with the death of dopaminergic neurons as well as with impaired motor function. In this thesis, we address the much-debated question of how parkinsonian synchronization depends on dopamine depletion in the basal ganglia (BG). To this end, we develop spiking neural network (SNN) models of BG circuits and study them via bifurcation analysis. First, we derive mean-field models that allow to account for various forms of short-term plasticity in SNNs. We show that such short-term plasticity mechanisms can lead to highly synchronous, periodic bursting dynamics and discuss the relevance of this bursting regime for PD. Second, we find that the external pallidum, an important part of the BG, cannot cause parkinsonian oscillations autonomously. However, our results suggest that the external pallidum may contribute to the emergence of cross-frequency coupling that has been reported for parkinsonian oscillations. Finally, we describe an open-source Python toolbox that we developed to implement and analyze mean-field models of neural dynamics. Together, this thesis provides insight into BG synchronization processes as well as the mathematical basis and software for future studies of neural synchronization.:1 Introduction 1.1 A complex systems perspective of the brain 1.2 Brain function and the phase transition to synchronized neural activity 1.3 Low-dimensional manifolds of synchronized neural activity 1.4 Phase transitions to synchronized neural activity in Parkinson’s disease 1.5 Thesis overview 2 Mathematical Models and Methods 2.1 A non-linear oscillator model of neural activity 2.2 Dynamical systems methods for the study of neural network models 2.3 Dynamics of a single QIF neuron 3 Low-Dimensional Dynamics in Spiking Neural Networks 3.1 Mean-field approaches in neuroscience 3.2 Dynamics of QIF networks with post-synaptic STP 3.3 Dynamics of QIF networks with spike-frequency adaptation 3.4 Mean-field dynamics of QIF networks with pre-synaptic STP 3.5 Discussion 4 Phase Transitions and Neural Synchronization in the External Pallidum 4.1 A new perspective on GPe structure and function 4.2 GPe model definition and analysis 4.3 Phase transitions in the GPe under static and periodic input 4.4 Discussion 5. Modeling of Neural Mean-Field Dynamics Via PyRates 5.1 Computational modeling in neuroscience 5.2 The Framework 5.3 Pre-implemented methods for neural modeling workflows 5.4 Results 5.5 Discussion 6. Conclusion and Outlook

Daily injections for basal insulin therapy are far from ideal resulting in hypo/hyperglycemic episodes associated with fatal complications in type-1 diabetes patients. The purpose of this study was to develop a thermosensitive copolymer-based in situ depot forming delivery system to provide controlled release of insulin for extended duration following a single subcutaneous injection, closely mimicking physiological basal insulin requirement. Size and nature of the incorporated therapeutic were observed to affect the release profile of insulin. Modification with zinc and chitosan preserved thermal, conformational, and chemical stability of insulin during the entire duration of storage (up to 9 months at 4 °C) and release (up to 3 months at 37 °C). In vivo, daily administration of long-acting insulin, glargine, resulted in fluctuating blood glucose levels between 91 – 443 mg/dL in type 1 diabetic rats. However, single administration of oleic acid-grafted-chitosan-zinc-insulin complexes incorporated in copolymer formulation demonstrated slow diffusion of insulin complexes maintaining peak-free basal insulin level of 21 mU/L for 91 days. Sustained release of basal insulin also correlated with efficient glycemic control (blood glucose <120 mg/dL), prevention of diabetic ketoacidosis and absence of cataract development, unlike other treatment groups. The suggested controlled basal insulin delivery system has the potential to significantly improve patient compliance by improving glycemic control and eliminating life-threatening diabetes complications. Furthermore, oleic acid-grafted-chitosan (CO) nanomicelles were investigated as a non-viral vector to deliver plasmid DNA encoding short hairpin RNA (shRNA) against pro-inflammatory cytokines to adipose tissue macrophages and adipocytes for the treatment of insulin resistance. Nanomicelles modified using mannose (COM) and adipose homing peptide (AHP) (COA) showed significantly higher uptake and transfection efficiency in inflamed macrophages- adipocytes co culture owing to glucose transporter-1 and prohibitin receptor mediated internalization, respectively. Ligand modified nanomicelles loaded with shRNA against tumor necrosis factor alpha (COM-TNFα) and monocyte chemoattractant protein-1 (COA-MCP1) demonstrated significant attenuation of pro-inflammatory cytokines and improved insulin sensitivity and glucose tolerance in obese-diabetic mice for six weeks post treatment with single dose of optimized formulation. Overall, chitosan nanomicelles mediated targeted gene therapy can help attenuate inflammation, the chief underlying cause of insulin resistance, thereby helping reverse the progression of diabetes. / National Institutes of Health (NIH) grant R15GM114701 / ND EPSCoR seed award FAR0030636

Bakgrund: Depression utgör tillsammans med ångestsyndrom 90 procent av sjukskrivningarna i Sverige i de fall där psykisk ohälsa är bakomliggande orsak. De två vanligaste fysioterapeutiska behandlingsformerna vid depression är fysisk aktivitet och basal kroppskännedom. Syfte: Syftet var att utifrån kvalitativa studier sammanställa hur personer med depression upplever fysisk aktivitet och träning respektive basal kroppskännedom. Material och metod: Sökningarna gjordes i Web of Science, Scopus, Cinahl, PubMed, PsycINFO och PsycARTICLES genom avancerade sökningar samt fritextsökningar. Fem studier inkluderades, fyra studier för fysisk aktivitet och träning och en studie för basal kroppskännedom. Resultat: Behandlingsmetoderna bidrog till mestadels positiva upplevelser hos deltagarna vilket skapade förkroppsligad erfarenhet och ökad kroppsmedvetenhet. Detta ledde till ökad energi och ökat deltagande i livet i stort. Deltagarna beskrev känslan av att behöva bryta sig igenom ett motstånd och att det krävdes ett engagemang för att kunna överkomma de barriärer som diagnosen innebär. Stödet utifrån belystes och fysioterapeuten ansågs inneha en viktig roll som professionellt stöd. Konklusion: Fysioterapeuter bör ha ett professionellt bemötande, bygga en förtroendeingivande terapeutisk relation, inneha ett personcentrerat vårdperspektiv och individanpassa behandlingen. Genom detta utvecklas förkroppsligad erfarenhet vilket ökar kroppsmedvetenhet och leder till strategier som förbättrar livssituationen för personer med depression. Materialet till denna litteraturstudie var begränsat och visar på att det behövs mer forskning inom områdena.

De nombreuses études s’intéressent aux comportements décisionnels et d’apprentissage ainsiqu’aux structures qui les sous-tendent. Il a été montré que le Cortex Préfrontal (CPF) ainsiqu’un réseau de structures sous-corticales, les Ganglions de la Base (GB), étaient impliquésdans ces processus. Néanmoins, le rôle respectif de chacun n’est pas définit. Deux hypothèsessont émises. La première stipule que les deux structures fonctionnent indépendamment. LesGB seraient impliqués dans les comportements habituatifs tandis que le CPF se chargerait descomportements planifiés. La seconde hypothèse considère que les deux structures collaborent: les GB contrôleraient un processus d'apprentissage à cinétique lente dans le CPF et sedésengageraient progressivement au fur et à mesure de l’apprentissage. Ceci reviendrait d'unecertaine façon à inverser les rôles : les GB seraient nécessaires aux processus de décision tantque le CPF n'aurait pas fini son apprentissage. Celui-ci fonctionnerait ensuite sur un modeautomatique. Le principal obstacle à l’étude respectif du rôle des GB et du CPF dans cesprocessus intervient dans les paradigmes expérimentaux qui ne dissocient pas la prise dedécision per se des processus d’apprentissage. Notre premier objectif a donc été d’élaborerune tâche expérimentale qui permette de différencier les phases d’apprentissage des phases deprise de décision. Nous avons ensuite supprimé l'influence des GB sur le cortex, en inhibantleur structure de sortie, le Globus Pallidus interne (GPi) par des injections intracérébrales demuscimol chez le primate non-humain effectuant une tâche comportementale : le "two armedbandit task". Nous montrons que les animaux sont toujours capables de prendre des décisionsaprès inhibition du GPi mais qu’ils sont incapables d’apprendre la valeur de nouvelles cibles.Ces résultats confirment que, chez le primate en tous les cas, les GB et le CPF sont bienimpliqués dans un processus collaboratif : l'intégrité de l'ensemble du circuit est nécessairepour l'apprentissage alors que le cortex seul peut suffire une fois que le choix se situe dans uncontexte habituel. / Many studies are interested in decision making and learning processes and in brainareas which are engaged in. Among them, the implication Prefrontal Cortex (PFC) and a subcortical structures’ network, the Basal Ganglia (BG) has been shown. Nevertheless, theprecise role of each structure has not yet been defined. There are two main hypotheses. Thefirst one holds that GB and PFC function independently. BG would support habitualbehaviors and PFC planned behaviors. The second hypothesis proposes that both structuresare collaborating: the basal ganglia drive a low kinetic learning process in the prefrontalcortex and become less and less engaged as the task is learned. It means reversing the roles:BG would be necessary for decision making processes as soon as PFC finishes its learning.This latter would then function as an automatic mode. The main problem which avoids us todisentangle the role of each structure is the experimental paradigms used which mix uplearning and decision making. Our first aim was to design an experimental task in which therewas learning phase and decision making phase per se. Then, we blocked basal gangliainfluence on PFC by inhibiting their exit structure, the Globus Pallidus internal, withintracerebral muscimol injections in non-human primates performing a “two-armed bandittask”. Our results show that monkeys are able to do decision making after GPi inhibition butthey are unable to learn new values. These results confirm that, in non-human primates, BGand PFC are well involved as co-workers in one process: integrity of all the circuit isnecessary for learning whereas only cortex is sufficient once the choice is in habitual context.

Title: Basal metabolism and nutritional intervention for people with spinal cord injuries Objectives: The main objective of this work was empirical research of case evaluation studies (n = 3), where we analyzed: the relationship between energy expenditure (basal metabolism) and energy intake for people diagnosed with spinal cord injury (SCI). The secondary objective was to determine whether the changes in macronutrient distribution and daily energy intake would result in a decrease in body weight and body fat for individual probands. The pilot study in our work was focused on the overview of variable basal metabolism (BM) values for people with SCI. Methods: In our work, we used the method of indirect calorimetry to measure BM and together with the value of working metabolism we determined in the nutritional intervention (n. i.) the ideal energy intake for our probands. We observed primarily measurable changes in the amount of fat and muscle tissue. Results: We have found that, in keeping with the prescribed n. i. rules, all probands achieved to reduce their body weight. The average body weight loss for probands was 0.29 ± 0.02 kg per week. BM values in our pilot study were 15 to 61% lower for our probands (n = 15) and did not correlate with the height of SCI. Key words: spinal cord injury (SCI),...

Title: Basal metabolism and nutritional intervention for people with spinal cord injuries Objectives: The main objective of this work was empirical research of case evaluation studies (n = 3), where we analyzed: the relationship between energy expenditure (basal metabolism) and energy intake for people diagnosed with spinal cord injury (SCI). The secondary objective was to determine whether the changes in macronutrient distribution and daily energy intake would result in a decrease in body weight and body fat for individual probands. The pilot study in our work was focused on the overview of variable basal metabolism (BM) values for people with SCI. Methods: In our work, we used the method of indirect calorimetry to measure BM and together with the value of working metabolism we determined in the nutritional intervention (n. i.) the ideal energy intake for our probands. We observed primarily measurable changes in the amount of fat and muscle tissue. Results: We have found that, in keeping with the prescribed n. i. rules, all probands achieved to reduce their body weight. The average body weight loss for probands was 0.29 ± 0.02 kg per week. BM values in our pilot study were 15 to 61% lower for our probands (n = 15) and did not correlate with the height of SCI. Key words: spinal cord injury (SCI),...

Cancers of the human skin are divided into melanoma and non-melanoma. Being among the most commonly diagnosed cancer cases globally, non-melanoma skin cancers are comprised of basal and squamous cell carcinomas. In dermato-pathology, basal cell carcinomas (BCCs) are a frequently encountered diagnosis of skin cancer, and most cases are treated with surgical excisions. While sporadic BCC tumors appear primarily due to aging and ultra-violet exposure, the development of numerous BCCs from a young age is one of the main clinical signs in Gorlin syndrome patients. The critical driver of BCC tumor formation is the sonic hedgehog (SHH) pathway, a pivotal developmental signaling pathway that regulates organ development, cell proliferation, and tissue repair. The majority of all sporadic and syndromic BCCs exhibit mutations in two key components in this pathway, the tumor suppressor gene patched 1 (PTCH1) or the proto-oncogene smoothened (SMO), which result in aberrant pathway activation and continued transcription of SHH-dependent genes. In the last decade, SHH inhibitors have emerged as a novel treatment for advanced and metastatic BCCs. Systemic treatment with vismodegib, a potent SMO inhibitor, can effectively reduce BCC tumor burden in adult Gorlin syndrome patients. However, it is associated with chemotherapy-related adverse events, and treatment cessation results in cancer recurrence and formation of a subset of drug resistant BCCs. While aberrant SHH signaling is key, mechanisms that underlie epithelial–stromal crosstalk and reprograming of tumor metabolism can potentially converge with this pathway and promote BCC tumor development. In this study, we investigated the effects vismodegib on the morphology, behavior, and energy metabolism of human BCC cells and human dermal fibroblasts, in individual cultures as well as in co-cultures, that enabled the crosstalk between these two cell types. Computer-assisted bright-field microscopy was used to characterize cell morphology and behavior. Nuclear magnetic resonance (NMR) and metabolomics were used to determine the metabolic activity of these cells. We found that continuous crosstalk between the cells and different concentrations of vismodegib led to distinct changes in cell morphology and growth, as well as consumption of glucose, pyruvate, and glutamine and secretion of acetate, lactate, and glutamate by these cells. Deciphering tumor driver mechanisms that converge with SHH pathway and contribute to changes within the tumor microenvironment are important not only for better understanding of BCC pathobiology, but also for the development of new mechanism-based BCC therapies with improved clinical outcomes. / 2023-02-22T00:00:00Z

The urothelium is a crucial stratified epithelial barrier that protects the urinary tract. It consists of basal cells in the lower layers and intermediate and superficial cells in the luminal layer. These urothelial cells can be identified by their distinct gene expression patterns. Superficial cells are terminally differentiated, binucleated, post-mitotic cells that are responsible for the barrier function of the urothelium via the production of uroplakin proteins. Intermediate cells act as the progenitor cells for superficial cells during development, homeostasis, and after acute injury. Basal cells consist of two populations, K14-basal cells and K5-basal cells. K14- basal cells have been shown to be progenitors that can repopulate the urothelium after chronic injury and are the cells of origin that produce bladder cancer. Bladder cancer can be classified as basal subtype or luminal subtype. The basal subtype is generally immune infiltrated, aggressive, and invasive with a poor prognosis. The luminal subtype is generally immune poor, less aggressive, and non-invasive with a better prognosis compared to basal tumors. Pparg is a nuclear hormone receptor that has been described as a master regulator of adipogenesis and cellular differentiation that also carries out important anti-inflammatory functions (in part by antagonizing the NFKB pathway). Pparg is downregulated in basal subtype muscle invasive bladder cancer and amplified in luminal subtype bladder cancer. In vivo we find that Pparg is a master regulator of cell specification during urothelial development, homeostasis, regeneration, and cancer. When Pparg is ablated in the entire urothelium, Pparg KO mutants lack mature superficial cells and undergo squamous differentiation, with an expansion of the K14-basal cell population. These Pparg KO mutants also display persistent inflammation and squamous metaplasia after injury by urinary tract infection (UTI), due to unregulated NFKB signaling. However, the squamous differentiation in the Pparg KO mutants did not progress to bladder cancer. Constitutive activation of Pparg in basal cells using a novel VP16;Pparg transgenic mouse line crossed to an Krt5CreERT2 driver induces basal cells to undergo a luminal differentiation program towards post-mitotic S-cells during homeostasis. Not surprisingly, these cells did not progress to form bladder cancer on their own. Interestingly, expression of VP16;Pparg in basal cells only drives tumor formation when the basal cells are in an “activated state,” induced by 1 month of BBN treatment. In a BBN mouse model which produces basal subtype bladder cancer in wild type animals, expression of the VP16;Pparg transgene in activated basal cells drives the formation of luminal tumors with papillary morphology, suggesting that this transcription factor is a master regulator of urothelial luminal differentiation, as has been suggested from previous in vitro studies. Like their human counterparts, these VP16;Pparg luminal tumors are immune cold. Additionally, these VP16;Pparg luminal tumors have different domains; a top domain that is “luminal,” and a bottom domain that is “basal”, suggesting the luminal tumors produced by activation of Pparg are not homogenous and undergo a phenotypic shift that mimics what has previously been reported in patient-derived organoids. Understanding the molecular mechanism that drives luminal bladder cancer provides critical information in bettering our approach in diagnosing and treating MIBCs.