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Alexithymia represents a deficit in identifying and expressing emotions, paucity of fantasies, and an externally oriented cognitive style. Currently, numerous studies document that alexithymia and several mental and somatic disorders are significantly related. Several findings also indicate that this association might be caused by alexithymia related dysregulation of neuroendocrine and immune functions. Together these findings indicate that stressors related to alexithymia could underlie the process of neuroendocrine and immune dysregulation that likely may present a significant risk, sustaining and mediating pathogenesis of several disorders and particulary psychosomatic illnesses. In this context, it is also known that several proinflammatory cytokines may play a role in pain generation and that alexithymia is significantly associated with pain symptoms in several pain disorders. Following these findings this study includes several new data developing current state of the art and showing some alexithymia specific changes in patients with neurological disorders. Main finding of this study shows that alexithymia and anxiety in their specific interactions are linked to increased levels of interleukine-8 (IL-8) in cerebrospinal fluid (CSF) in the group of patients with non-inflammatory neurological...

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The purpose of this thesis is to investigate and describe the effects of the Middle East policies of Turkey and the European Union on mutual relations between the two actors with particular focus on the Arab Spring and its repercussions on regional stability and international relations. The key components of Turkey's foreign policy are analyzed from the perspectives of EU-Turkey relations and political stances of Turkey and the European Union towards the Middle East. Analysis of Turkey's and the EU's responses to the uprisings and their impact on the situation in the region is an important part of the study. The conclusions of this study confirm that the strategic cooperation between the EU and Turkey and the necessity of compensating each other's relative weaknesses in order to achieve similar foreign policy goals in the concerned region after the Arab Spring led to a rapprochement between the two actors. However, a direct influence of this rapprochement on the negotiation process regarding the future Turkish membership in the EU has not yet been observed. Key words Turkey, the European Union, Turkey-EU relations, negotiation process, the Middle East, MENA, foreign politics, the Arab Spring…

Time-restricted eating is a fasting diet where the food intake is restricted to a short, typically eight-hour, window each day. It is associated with health benefits such as weight loss, improved sleep, protection against cognitive disorders, and improved cognitive function. The cognitive effects of time-restricted eating have primarily been explained by the production of ketogenesis – an alternative energy source produced when calories are restricted – and anti-inflammatory cytokines. The gut microbiota is the trillions of microorganisms inhabiting the intestinal tract and has also been associated with improved mental health through communication via the gut-brain axis. This review aims to investigate whether changes in the microbiota may mediate the effect of time-restricted eating on cognitive function. Studies investigating the effect of time-restricted eating on the microbiota were systematically reviewed. The results indicate that time-restricted eating may alter the microbiome composition and increase butyrate-producing bacteria. Butyrate is a short-chain fatty acid associated with the expression of genes involved in neural development and the reduction of neuroinflammation. Limited by the few studies reviewed, the results may indicate a possible link between time-restricted eating and cognitive function via the microbiota, although more research is needed.

Glucocorticoids are effective immunosuppressive and anti-inflammatory agents, but some aspects of stress appear to be proinflammatory. This study investigates this apparent paradox as it applies to stress exposure and the development of arthritis in a rat strain that has subnormal hypothalamic-pituitary-adrenal (HPA) responsiveness. Female Lewis rats were subjected to 1 week of rotating, psychological stressors for 5 h daily, beginning 7 days following inoculation with type [I collagen. The collagen-induced arthritis (CIA) group exposed lo stress showed reduced ankle width increase (p < 0.001) and decreased hindlimb severity scores (p < 0.001). At sacrifice, 2 days following stress termination, no differences in either measure remained and there was no difference in hind paw volume. However, the area of the tibia invaded by stroma, as quantitated by image analysis, was reduced in the stressed rats (p < 0.05). In animals exposed to stress, adrenal weights were increased (p < 0.005) and plasma corticosterone levels were elevated at sacrifice (p < 0.02). Both injected groups had significantly larger adrenal (p < 0.005) and lower thymus weights (p < 0.05) than did uninjected controls. Likewise, both CIA groups had reduced glucocorticoid receptor immunoreactivity in synovial membranes compared to controls (p < 0.001), suggesting that the Lewis rat's HPA deficiency may be intensified by glucocorticoid receptor downregulation during the induction of CIA. These data indicate that the responsiveness of the HPA axis to psychological stress in this strain is sufficient to alter disease progression.

Embryogenesis is one of the most delicate biological processes which requires precise control in various levels, including molecular distribution and gene expression, cellular orientation and specification, and tissue dynamics giving rise to proper morphology. The diverse animal morphology can be resulted from the difference during early embryonic cleavages. Spiral cleavage is a conserved embryonic patterning strategy used in the majority of the animal clade Spiralia. The specific cell positioning during cell division and quadrant-based clonal domain formation make the embryos with the blastomeres orientated in a spiral manner when viewing from the animal pole. Although spiral cleavage is conserved in many phyla, the detailed cellular, molecular and biophysical mechanisms for this left-right symmetry breaking event remain unclear. Here I studied the early development of the prototypic annelid spiral-cleaver Platynereis dumerilii, which performs two unequal embryonic cleavages followed by the first dextral spiral cleavages, and compared the mechanisms to other spiralians or to other cleavage types. First, I described the morphology of each cell cycle from the zygote until 64-cell stage by imaging the fluorescently labeled fixed embryos. Second, with mRNA injection, whole-embryo live-imaging with Selective Plane Illumination Microscopy (SPIM), and in silico cell tracking, I monitored these cleavages in 4-D, constructed the early cell lineages, and revealed the subtle asynchrony of the four quartets. Third, together with the spindle inclination angle measurement, I discovered the leading role of the D macromere during P. dumerilii spiral cleavage. I also confirmed that the dextral micromere orientation is neither affected by the eggshell nor the presence of all the neighbor macromeres, suggesting that this cellular property may be achieved by cell autonomous molecular mechanisms. In order to quantify the candidate cytoskeletal dynamics during spiral cleavage, I optimized the construction of the injected mRNAs and the injection protocol to achieve the highest translational level of the fluorescent protein within a given developmental time. Beside mRNA injection, I also established a protein expression and injection protocol for P. dumerilii protein injection in order to visualize the target gene as early as possible. Both techniques didn’t dramatically influence embryogenesis and allow for quantification of the protein dynamics. With these strategies, I discovered and measured the chiral counter rotational flow of cortical actomyosin in each spiral cleavage and revealed that it’s present in the first two spiral cleavages, especially of the macromeres. The biophysical force generated by actomyosin contributes in the cell deformation and spindle inclination, resulting in proper dextral micromere positioning, during the first spiral cleavage, confirmed by the chemical treatment to the P. dumerilii embryos. The asymmetric actomyosin distribution, nuclei migration, and the change of the cell axes during cytokinesis in the macromeres also suggests that the macromeres may play critical roles to lead spiral cleavage. This work is built on the knowledge of the spiral cleavage machinery and has extended it in multiple dimensions. The detailed phase-by-phase description of each cleavage increases the information of P. dumerilii embryogenesis. The established labeling and imaging techniques in this thesis are the important basis for investigation and comparisons of different spiralian development in the future. More broadly, the discovery of actomyosin dynamics shows conservation to the left-right symmetry breaking events of the animals which does not belong to Spiralia. These together bring insights to a global evolutionary speculation: a conserved mechanical force generation pathway, tuned by the upstream molecular signals, may be the key of the miscellaneous cleavage types, resulting in the astonishing variety of embryo patterning.

Major depressive disorder (MDD) is rapidly growing and one of the most common causes of disability and mortality worldwide. People with MDD often display brain changes such as adisrupted balance in neurotransmitters, impaired neurogenesis and neuroplasticity. Traditionally has MDD been treated with medications and talking therapies (psychotherapy). Studies have shown that just around 50 % of people with MDD get improvements from common traditional treatments.Therefore is there a great need for a better understanding of MDD and new treatments. There is now an emerging field of research that indicates that the gut microbiota plays a crucial role in disturbing normal brain functioning in MDD. This connection between the gut and the brain is called the gutbrain axis.The thesis aims to investigate if there is a connection between gut microbiota disruption and MDD and if gut microbiota restoration can be a potential effective future treatment for MDD. Key findings of the thesis were, studies show that people with MDD often display gut microbiota disruption and chronic low grade inflammation. Studies also indicate that this inflammation can cause the specific brain change often displayed in people with MDD. One of the most critical findings in the thesis was that gut brain treatments affect tryptophan metabolism, which affects the risk of MDD. The research area of the gut brain axis is still new and many more studies are needed,particularly in humans.

abstract: Of the 2.87 million traumatic brain injuries (TBI) sustained yearly in the United States, 75% are diffuse injuries. A single TBI can have acute and chronic influences on the neuroendocrine system leading to hypothalamic-pituitary-adrenal axis (HPA) dysregulation and increased affective disorders. Preliminary data indicate TBI causes neuroinflammation in the hippocampus, likely due to axonal damage, and in the paraventricular nucleus of the hypothalamus (PVN), where no axonal damage is apparent. Mechanisms regulating neuroinflammation in the PVN are unknown. Furthermore, chronic stress causes HPA dysregulation and glucocorticoid receptor (GR)-mediated neuroinflammation in the PVN. The goal of this project was to evaluate neuroinflammation in the HPA axis and determine if GR levels change at 7 days post-injury (DPI). Adult male and female Sprague Dawley rats were subjected to midline fluid percussion injury. At 7 DPI, half of each brain was post-fixed for immunohistochemistry (IBA-1) and half biopsied for gene/protein analysis. IBA-1 staining was analyzed for microglia activation via skeleton analysis in the hypothalamus and hippocampus. Extracted RNA and protein were used to quantify mRNA expression and protein levels for GRs. Data indicate increased microglia cell number and decreased endpoints/cell and process length in the PVN of males, but not females. In the dentate gyrus, both males and females have an increased microglia cell number after TBI, but there is also an interaction between sex and injury in microglia presentation, where males exhibit a more robust effect than females. Both sexes have significant decreases of endpoints/cell and process length. In both regions, GR protein levels decreased for injured males, but in the hippocampus, GR levels increased for injured females. Data indicate that diffuse TBI causes alterations in microglia morphology and GR levels in the hypothalamus and hippocampus at 7 DPI, providing a potential mechanism for HPA axis dysregulation at a sub-acute time point. / Dissertation/Thesis / Masters Thesis Biology 2019

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20613号 / 医博第4262号 / 新制||医||1023(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 小川 修, 教授 篠原 隆司, 教授 近藤 玄 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM