The aim of this investigation was to determine whether i) affective touch has a role in mediating beneficial social influences on resilience to depression and ii) whether affective touch acts through specific skin CT afferents to enhance central serotonin function. To develop and validate the Touch Experiences and Attitudes Questionnaire (TEAQ), 117 items about experiences and attitudes to touch were completed online by 618 participants. Principal components analysis reduced this to 57 items and 6 factors. Three factors concerned touch experienced; in social situations (CST), in intimate relationships (CIT) and during childhood (ChT) and 3 factors concerned attitude to touch; in intimate relationships (AIT), with unfamiliar people (AUT) and in Skin Care (ASkC). The shortened TEAQ was completed by a second sample of 704 participants. Confirmatory factor analysis found the 6 factor structure to be a good fit of the data, suggesting the TEAQ to be valid and reliable. Participants completed some demographic questions and some questionnaires to determine their current psychiatric symptoms, social circumstances, recent life events, childhood adversity and personality alongside the TEAQ. Currently depressed participants had lower touch scores for all factors compared to healthy controls. Remitted depressed participants had significantly lower touch scores on all factors except CST, ASkC and AIT compared to healthy controls. A multiple regression analysis found neuroticism, satisfaction with social support, recent life events, CIT and childhood adversity (CHA) to be predictive of depression, whereas extraversion, number of social supports, ChT and CST, did not significantly predict depression score. Logistic regression analysis found ChT, CHA and neuroticism to predict vulnerability to depression, but not AIT or AUT. It was concluded that CIT was the most important aspect of affective touch for promoting resilience to depression. The CNS effects of pleasant and unpleasant touch were investigated using fMRI in healthy female volunteers. It has been hypothesised that a novel class of CT afferent fibres in hairy skin encodes affective touch. Therefore, CNS responses to pleasant stroking of the forearm with stroking of the fingers were compared. No differential CNS effects of forearm stroking over finger stroking were seen. Indeed, more brain regions were activated by pleasant brush stroking of the fingers which lack CT afferents. Pleasant brush responses in left inferior frontal gyrus were attenuated by tryptophan depletion. However, the midbrain raphe was activated by unpleasant brush stroking and de-activated by pleasant and this effect was abolished by tryptophan depletion. This study found little evidence that CT afferents in hairy skin have a specific role in affective touch and serotonin cells of the raphe appear engaged by unpleasant stimuli rather than pleasant. In conclusion, the results of the questionnaire study indicated touch (hugs, kisses, stroking) in intimate relationships may promote resilience to depression whereas touch with other social contacts does not, suggesting type of affective touch to be important. It is suggested that future studies of the role of current social support and of early adversity in depression should include assessments of the correlated dimension of affective touch. The fMRI study found little evidence for a specific peripheral touch receptor encoding pleasant affective touch. The median raphe nucleus was inhibited by pleasant touch and this is in keeping with the idea that that aversive stimuli activate serotonin projections to the forebrain but not that this is strengthened by affective touch. Further investigation is required to identify CNS mechanisms of affective touch.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第22836号 / 人健博第78号 / 新制||人健||6(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 高桑 徹也, 教授 木下 彩栄, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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Indiana University-Purdue University Indianapolis (IUPUI) / Chlamydia trachomatis is an obligate intracellular bacterial pathogen that can infect the eyes, genital tract, and disseminate to lymph nodes in humans. Many C. trachomatis infections are clinically asymptomatic and can become chronic if left untreated. When humans are infected with C. trachomatis, a cytokine that is produced is interferon-gamma (IFN-γ). In vitro, IFN-γ stimulates expression of the host enzyme indoleamine 2,3-dioxygenase. This enzyme converts free intracellular tryptophan to N-formylkynurenine. Tryptophan starvation induces C. trachomatis to enter a viable-but-nonculturable state termed persistence, which has been proposed to play a key role in chronic Chlamydial disease. To circumvent host induced tryptophan depletion, urogenital strains of C. trachomatis encode a functional tryptophan synthase (TS). TS synthesizes tryptophan from indole and serine, allowing Chlamydia to reactivate from persistence. Transcriptomic analysis revealed C. trachomatis differentially regulates hundreds of genes in response to tryptophan starvation. However, genes that mediate entry, survival, and reactivation from persistence remain largely unknown. Using a forward genetic screen, we identified six Susceptible to IFN-γ mediated Persistence (Sip) mutants that have diminished capacities to reactivate from persistence with indole. Mapping the deleterious persistence alleles in three of the Sip mutants revealed that only one of the mutants had a mutation in TS. The two other Sip mutants mapped had mutations in CTL0225, a putative integral membrane protein, and CTL0694, a putative oxidoreductase. Neither of these genes plays a known role in tryptophan synthesis. However, amino acid (AA) competitive inhibition assays suggest that CTL0225 may be involved in the transport of leucine, isoleucine, valine, cysteine, alanine, and serine. Additionally, metabolomics analysis indicates that all free amino acids are depleted in response to IFN-γ, making this amino acid transporter essential during persistence. Taken together we have identified two new chlamydial persistence genes that may play a role in chronic chlamydial disease.

Recent studies indicate that endogenously ligand-activated Aryl Hydrocarbon Receptor (AHR) plays an important role in normal and pathological processes, including the induction and progression of breast cancer. As the known number of AHR-mediated processes grows, so too does the importance of identifying endogenous AHR ligands that influence breast cancer progression. The following studies focus on two tryptophan metabolism pathway branches, the kynurenine (KYN) branch and the indoxyl sulfate (IS) branch, to determine if ER-/PR-/HER2- breast cancer cells can produce, or are exposed to, AHR ligands from these branches, how these ligands affect cell migration and, if produced, how their production is controlled. It is hypothesized that: 1) malignant cells produce, or derive from their microenvironment, AHR ligands through the KYN and/or IS pathways, 2) these metabolites drive AHR-dependent breast cancer migration, 3) environmental AHR ligands mimic the effects of endogenous ligands, 4) rate-limiting kynurenine pathway enzymes are responsible for endogenous AHR ligand production and their downstream effects, and 5) the AHR controls expression of a rate-limiting kynurenine pathway enzyme(s) in a positive feedback loop. ER-/PR-/HER2- mammary epithelial cells were assayed for production of AHR-activating tryptophan metabolites and for the kynurenine pathway enzymes tryptophan 2,3-dioxygenase (TDO) and indolamine 2,3-dioxygenase (IDO). The relationship between kynurenine and IS pathways, AHR activity, cell migration, and aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker associated with poor prognosis, was investigated using tryptophan metabolites, enzyme-specific gene knockdown or over-expression, qPCR, cell migration assays and ALDH1 activity assay. ER-/PR-/HER2- tumor cells produce KYN and its downstream metabolite xanthurenic acid (XA), at levels sufficient to activate the AHR. KYN, XA, and IS significantly accelerate migration in an AHR-dependent fashion, and at physiological doses, while environmental AHR ligands 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and benzo[a]pyrene (B[a]P) mimic this effect. IS induces ALDH1 activity. AHR knockdown or inhibition significantly reduces Tdo2 expression. Finally, gene expression dataset analyses reveal high Tdo2 levels in primary breast tumors, with the highest levels in ER-/PR-/Her2- and stage 4 tumors. These studies identify three tryptophan-derived AHR ligands that contribute to breast cancer progression and demonstrate a positive feedback loop, where AHR activity up-regulates Tdo2, which drives endogenous AHR ligand production.

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Suicidal behavior has to be considered as a multifactorial phenomenon, which can be analyzed in a classifying-phenomenological manner. We have examined the relation of parasuicide typology to whole blood concentrations of serotonin, HVA, and tryptophan in 58 patients classified into 4 groups of parasuicide typology compared to 22 nonsuicidal depressed patients and 20 healthy subjects. Suicidal patients classified as impetuous, desperate and ambivalent types had significantly reduced whole blood 5-HT levels in comparison with the appealing type as well as nonsuicidal subjects. No differences were detected in the HVA content, but whole blood tryptophan concentrations were significantly reduced in impetuous suicidal patients and depressed patients compared to healthy subjects. This study provides evidence for reduced whole blood serotonin content based on different types of parasuicide. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Serotonin (5-Hydroxytryptamin, 5-HT) ist ein wichtiger Neurotransmitter im Zentralnervensystem (ZNS). Seine Biosynthese erfolgt unter Beteiligung des Enzyms Tryptophanhydroxylase 2 (TPH2). Polymorphismen im TPH2 Gen beim Menschen sind Risikofaktoren bei der Entstehung von Depressionen und Angstverhalten. Die gängigsten Antidepressiva und Anxiolytika wirken auf das Serotonin System. Unklar ist, ob das komplette oder teilweise Fehlen von Serotonin im Gehirn zu Entwicklungsstörungen und neurochemischen oder psychologischen Veränderungen führt. In dieser Arbeit werden Mauslinien mit unterschiedlichen TPH2 Aktivitäten im ZNS verglichen und der Einfluss verringerter 5-HT Konzentrationen auf Entwicklung und Verhalten der Tiere untersucht. Zentrales Serotonin ist nur für die postnatale Entwicklung notwendig. Das verzögerte Wachstum von Tph2-/- Tieren ist nicht auf eine Störung der Hypothalamus-Hypophysen-Nebennieren-Achse oder auf metabolische Veränderungen zurückzuführen, sondern kann aus verringerter Vokalisation im Ultraschallbereich resultieren. Tph2-/- Mäuse wurden mit generierten Mausmodellen mit niedriger TPH2 Aktivität vergleichen. Die Ergebnisse zeigen, dass 20% weniger zentrales Serotonin nicht ausreichen, um Depression oder Angst-Verhalten herbeizuführen. Möglicherweise greifen kompensatorische Mechanismen wie ein verringerter Serotoninmetabolismus oder eine gesteigerte 5-HT1A-Rezeptorsensitivität. Der komplette Verlust von Serotonin im Gehirn führt zu einem starken depressiven und weniger ängstlich Verhalten, mit erhöhter Aggression - ohne Veränderung in Aktivität, Geruchsinn, Gedächnis und adulter Neurogenese. Fluoxetine Behandlung von Tph2-defizienten Mäusen zeigte einen Serotonin-unabhängigen Effekt dieses Antodepressivums auf Angst-Verhalten und Depression. Fluoxeine reduzieren den Serotoningehalt im Gehirn von Mäusen mit geringen TPH2-Aktivität, was zeigt, dass TPH-Aktivität die Effizienz von Serotonin beeinflussenAntidepressiva bestimmen, / Serotonin (5-HT) is a major neurotransmitter in the brain biosynthesis of which is initiated by tryptophan hydroxylase 2 (TPH2). Polymorphisms in the TPH2 gene are suggested as risk factors associated with depression and anxiety in humans. Furthermore, the most frequently prescribed antidepressants and anxiolytics target the serotonergic system. However, the question whether a complete ablation or partial reduction in brain serotonin leads to the developmental, neurochemical, or psychological abnormalities remains unresolved. In this study, I took advantage of mouse lines with various degree of decrease in TPH2 activity in order to dissect the impact of 5-HT loss on development, brain neurochemistry and behavior. Using Tph2-deficient mice I showed that central serotonin is essential for normal postnatal, but not prenatal development. Growth retardation of Tph2-/- mice was not a result of a disruption of the hypothalamo-pituitary-adrenal axis, metabolic abnormalities, or impaired thermoregulation, but could result from reduced ultrasonic vocalization. I tested Tph2-/- mice along with other newly generated mouse models with partial TPH2 reduction, and showed that 20% reduction in central serotonin is not enough to cause changes in anxiety- and depression-like behaviors most likely due to compensatory mechanisms including reduced serotonin metabolism and increased 5-HT1A receptor sensitivity. However, complete loss of central serotonin leads to a depression-like phenotype, reduced anxiety-like behavior, and exaggerated aggression, but no differences in activity, olfaction, memory, and adult neurogenesis. Fluoxetine treatment of Tph2-/- mice revealed serotonin-independent action of this antidepressant on anxiety- and depression-like behavior. Furthermore, fluoxetine drastically reduced the brain 5-HT content in mice with low TPH2 activity indicating that TPH2 activity may determine the efficiency of antidepressants targeting the serotonergic system.