[in Japanese]

View full abstract

Ghrelin, an endogenous ligand for growth-hormone secretagogue receptor (GHS-R), was recently identified in the stomach with structural resemblance to motilin. Ghrelin induces a state of positive energy balance and body weight gain by promoting food intake, decreasing energy expenditure and stimulating GH secretion. The expression and secretion are increased by fasting and are decreased by feeding. In addition, diet-induced weight loss increases plasma ghrelin level in humans. Moreover, ghrelin influences anxiety, memory retention, cardiac performance, gut motility, glucose metabolism and adipose tissue. These observations suggest that gastric peptide ghrelin and the receptors may be potential therapeutic targets for various diseases.

View full abstract

It is well documented that daily restraint stress (6 hrs per day) for 3 weeks appllied to rats causes atrophy of apical dendrites of hippocampal CA 3 neurons and decreased neurogenesis of granule cells in the dentate gyrus. BDNF plays a crucial role in hippocampal function by promoting cell survival and maintaining dendritic morphology. However, it is still controversial whether BDNF synthesis is affected by chronic stress. We investigated BDNF mRNA levels in the hippocampus, together with plasma glucocortiocid (GC) levels, GC receptors in the hippocampus/hypothalamus and 5-HT synthesis in the raphe nuclei, in animals chronically stressed for 1-3 weeks, using in situ hybridization, immunohistochmistry and denstiometric analyses of these data. Plasma GC and serotonergic projections from the raphe nuclei are considered to play major roles in reducing BDNF synthesis in the hippocampus. In these animals, BDNF mRNA levels were significantly decreased in the CA 3 and dentate gyrus at the end of 6 hrs of restraint, but the ability of restraint to reduce BDNF synthesis seemed less robust compared to that seen in acute stress models. HPA axis response to stress in these animals assessed by plasma GC levels was delayed and sustained, which may affect the regulation of BDNF synthesis in the hippocampus. The finding that GC receptor immunoreactive neurons in the paraventricular hypothalamic nucleus were increased at the end of 1 week may partly explain the altered HPA axis response in these animals. Immunoreactivity for 5-HT synthesizing enzyme, tryptophan hydroxylase, was increased in the median raphe nucleus, neurons of which mainly project to the hippocampus, but not in the dorsal raphe nucleus, in animals stressed for 2-3 weeks. Thus, repetitive stress may influence a variety of neural and endocrine systems. Stress-induced reduction of BDNF synthesis in the hippocampus was less prominent, but still significant in repetitively stressed animals, which may contribute, at least partly, to the neuronal atrophy, neuronal death and resultant reduction of hippocampal volume observed both in animals and humans suffering chronic stress and/or depression.

View full abstract

[in Japanese]

View full abstract

Objectives:The aim of this study to investigate the aggressiveness and the anxiety behavior of male mice exposed to an estrogenic endocrine disrupting chemical, and used immunohistochemistry to assess the mechanism underlying the changes in behavior. Methods:We administered bisphenol A orally at the dose of 2 ng/g body weight to pregnant ICR mice, and evaluated by activity testing the aggressiveness and anxiety of the male newborn mice (Bis-A mice) from 4 to 12 weeks of age. Furthermore, we examined the staining intensity of the estrogen receptors (ER) α and β in the DRN of brains from Bis-A mice and control mice at 4 and 12 weeks of age. Results:The contact time (interest of resident in intruder mice) of the Bis-A mice in the aggressiveness test was high (p<0.05) at 12 weeks of age (sexually mature stage) . The degree of anxiety was not different when compared to the control group. The expression of ER α and β in the DRN at 4 weeks and 12 weeks of age had increased compared to the control (p<0.04). Discussion:Bis-A mice showed increased expression of ER in the DRN, which is rich in serotonergic cells. It was suggested that in the sexually mature stage when sex steroid secretion becomes active, testosterone metabolites have greater effects on ER in the Bis-A mice, which may lead to the increased contact time in the aggressiveness test. Summary:Mice exposed to estrogen-like compounds during fetal life have increased ER α and β expression in the DRN from 4 weeks of age and have any ettect on the increasing of contact time in the activity test at the sexually mature stage.

View full abstract

To determine the role of 5-HT_<2C> receptors in regulation of behavior and energy metabolism, we evaluated food intake, physical activity, body weight, and energy metabolism in 5-HT_<2C> receptor mutant mice. Young adult mutants display hyperphagia which is not associated with changes in plasma insulin and leptin levels. Administration of leptin inhibited the hyperphagia in young mutants, indicating that the hyperphagia in 5-HT_<2C> receptor mutants does not result from disturbances of leptin signaling. Older mutants cause obesity associated with a partial leptin resistance and decreases in β3-adrenergic receptor mRNA levels in white adipose tissue. In addition, 5-HT_<2C> receptor mutants display hyperpactivity. Despite hyperactivity, obesity develops by reduced energy cost of physical activity in mutants. These findings indicate that 5-HT_<2C> receptors play an inhibitory role in regulation of food intake and physical activity. A perturbation of 5-HT_<2C> receptor signaling could cause leptin-independent hyperphagia and hyperpactivity that lead to a late onset of obesity.

View full abstract

Depressive patients have many difficulties in not only emotion but also behavior. To clear the brain mechanism of emotion and behavior, will greatly contribute to the elucidation of pathophysiology in depression. On the other hand, it gives a useful suggestion for understanding brain to clarify the pathophysiology in depression which is regarded as a model of disability of emotion and behavior. At the first stage of elucidation of pathophysiology in depression, we have done fMRI studies used by well known neuropsychological tasks (i. e. Verbal fluency test and GO/NOGO test). At the secondary stage, we have studied created tasks that is related to clinical depressive symptoms using fMRI. In this article, we present our neuroimaging studies by fMRI about the brain mechanism of emotion and behavior toward elucidatin of pathophysiology in depression.

View full abstract

Objectives:This research attempts to examine illness narrative as health resource in psychosomatic medical treatment. In clinical process, illness narratives in which explanatory models are implicated show considerable plasticity reflecting doctor-patient relationships. We argue for relevance of Narrative-Based Medicine, through detailed analysis of this plasticity in illness narratives. Subjects and Method:Illness narratives were collected from 20 outpatients at a clinic in Tokyo. From March 2000 to August 2000, we conducted non-structured interview in order to examine illness narratives qualitatively from an anthropological point of view. Results:We found that these illness narratives should be considered as health resources for every patient to cope with various stress-factors in their daily life. We hypothesized four-stage model of clinical process according to the observation on transition of doctor-patient relationship and changing contents of a patient's illness narratives. At the beginning of illness symptom, all patients suffer deeply from not being able to express their mind-body discrepancy verbally. At the first stage, they visit medical facility to seek an orthodox explanatory model of medical science. In the second stage, they begin to ask personal explanatory model of the doctor in charge. Finally, they become able to narrate their illness experience fluently, since they have developed a definition of their health conditions while maintaining mind-body discrepancy in certain degree. In the third stage, patients become an expert of "illness experience", while medical doctors remain as a specialist of "disease". Conclusion:It is clear that to continue narrating illness experience has important meaning and function for a patient's health care. In the third stage, some patients become enable to narrate their feelings and sensations particular to their bodily experience. At the same time, medical doctor respects their knowledge of bodily experience and shows proper attitude as audience in their illness narrative.

View full abstract