Masahiko Mikuni

A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome)

Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet ß-cells and neurons.

Multichannel near-infrared spectroscopy in depression and schizophrenia: cognitive brain activation study

BACKGROUND Recent developments in near-infrared spectroscopy (NIRS) have enabled the noninvasive clarification of brain functions in psychiatric disorders with measurement of hemoglobin concentrations as cerebral blood volume. METHODS Ten patients with depression, 13 patients with schizophrenia, and 16 age- and gender-matched healthy control subjects participated in the study after giving consent. The relative concentrations of oxyhemoglobin [oxyHb] were measured with frontal and temporal probes every.1 sec during word fluency and unilateral finger tapping tasks, with two 24-channel NIRS machines. RESULTS The [oxyHb] increase patterns during the word fluency task varied among the three groups, although their task performances were similar: the depression group was characterized by a smaller [oxyHb] increase during the first half of the task period and the schizophrenic group by a small trough of [oxyHb] at the start of the task period and [oxyHb] re-increase in the posttask period. [OxyHb] increases during the finger-tapping task were rather larger in the patient groups than in the control group. CONCLUSIONS The characteristic time courses of [oxyHb] changes in the frontal lobe were elucidated for depression and schizophrenia. Near-infrared spectroscopy, with its noninvasiveness and high time resolution, can be a useful tool for research and clinical purposes in psychiatry.

Frontal lobe function in bipolar disorder: a multichannel near-infrared spectroscopy study.

Frontal lobe dysfunction has been implicated as one of the pathophysiological bases of bipolar disorder. Detailed time courses of brain activation in the bipolar disorder group were investigated using multichannel near-infrared spectroscopy (NIRS), a recently developed functional neuroimaging technology with a high time resolution, and were compared with those in the major depression and healthy control groups. Seventeen patients with bipolar disorder, 11 equally depressed patients with major depression, and 17 healthy controls participated in the study. Changes in oxy hemoglobin concentration ([oxy-Hb]) during cognitive and motor tasks were monitored using frontal and temporal probes of two sets of 24-channel NIRS machines. [oxy-Hb] increases in the bipolar disorder group were smaller than those in the healthy control group during the early period of a verbal fluency task, larger than those in the major depression and healthy control groups during the late period of this task, and were smaller than those in the major depression group during a finger-tapping task. Depressive symptoms and antidepressant dosages did not correlate with [oxy-Hb] changes in the two patient groups. Bipolar disorder and major depression were characterized by preserved but delayed and reduced frontal lobe activations, respectively, in the present high-time-resolution study by multichannel NIRS.

Periodic maternal deprivation alters stress response in adult offspring: potentiates the negative feedback regulation of restraint stress-induced adrenocortical response and reduces the frequencies of open field-induced behaviors.

The effects of periodic maternal deprivation (PMD) treatment on the adrenocortical stress response and on open-field behavior in adult offspring were investigated. Sprague-Dawley rat pups were deprived of mothers daily for 4.5 h during the first 3 weeks of life. PMD treatment resulted in lower corticosterone levels during restraint stress later in life. The result of dexamethasone suppression test indicated that PMD treatment caused a potentiation of the negative feedback function of adrenocortical response. These effects of PMD were not accompanied by an increased density of the hippocampal glucocorticoid receptor which has been reported to be induced in neonatal handling treatment (brief 15-min maternal deprivation). Serotonin (5-HT)-2 and beta-adrenergic binding sites were also examined in cerebral cortex and no change of binding capacities were induced by PMD treatment. In the open-field test, PMD treatment decreased the number of ambulations and rearings but did not affect a frequency of defecation. From these results, it is suggested that PMD treatment leads rats to be insensitive to environmental stimuli in adulthood.

Assessment of the Dexamethasone/CRH Test as a State-Dependent Marker for Hypothalamic-Pituitary-Adrenal (HPA) Axis Abnormalities in Major Depressive Episode: A Multicenter Study

There is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in depression. Growing evidence has suggested that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA axis abnormalities. We organized a multicenter study to assess the DEX/CRH test as a state-dependent marker for major depressive episode in the Japanese population. We conducted the DEX/CRH test in 61 inpatients with major depressive episode (Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV)) and 57 healthy subjects. In all, 35 patients were repeatedly assessed with the DEX/CRH test on admission and before discharge. The possible relationships between clinical variables and the DEX/CRH test were also examined. Significantly enhanced pituitary–adrenocortical responses to the DEX/CRH test were observed in patients on admission compared with controls. Such abnormalities in patients were significantly reduced after treatment, particularly in those who underwent electroconvulsive therapy (ECT) in addition to pharmacotherapy. Age and female gender were associated with enhanced hormonal responses to the DEX/CRH test. Severity of depression correlated with DEX/CRH test results, although this was explained, at least in part, by a positive correlation between age and severity in our patients. Medication per se was unrelated to DEX/CRH test results. These results suggest that the DEX/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities in major depressive episode during treatment. Restoration from HPA axis abnormalities occurred with clinical responses to treatment, particularly in depressed patients who underwent ECT.

Sex and age dependencies of cerebral blood volume changes during cognitive activation: a multichannel near-infrared spectroscopy study

In this study, we measured the change in cerebral hemoglobin concentrations during a cognitive task using multichannel near-infrared spectroscopy (NIRS), and investigated the relationship between regional cerebral blood volume and sex, age, and task performance. Thirty-nine healthy volunteers (24 males and 15 females; mean age, 33.0 years) participated after giving their informed consent and performed a word fluency task. The relative oxy-hemoglobin concentration ([oxy-Hb]) was measured using frontal and temporal probes with two sets of 24-channel NIRS machines. The effects of sex, age, and task performance on [oxy-Hb] changes were analyzed using analysis of covariance: with sex, age, and task performance as independent variables, and [oxy-Hb] changes as dependent variables, and years of education as covariates. The effects on [oxy-Hb] increase were significant in many channels in the frontal and temporal probes for sex, that is the most prominent effect, and in a few frontal channels for age: [oxy-Hb] increases were larger in males than in females, and in the young than in the middle-aged. The effects on [oxy-Hb] increase were not significant for task performance, but [oxy-Hb] increases in subjects with low performance tended to be larger than those in subjects with high performance. The results demonstrated that multichannel NIRS could detect cerebral activation during cognitive tasks and clarify sex- and age-dependent differences in such cerebral activation. Sex- and age-dependent differences in cerebral activation, as demonstrated in the present study, should be considered when interpreting cerebral blood volume, cerebral blood flow, and cerebral glucose metabolism data.

Effect of ACTH, adrenalectomy and the combination treatment on the density of 5-HT2 receptor binding sites in neocortex of rat forebrain and 5-HT2 receptor-mediated wet-dog shake behaviors

The effect of ACTH and/or adrenalectomy on serotonin (5-HT)2 receptor binding sites was evaluated in the neocortex of rat forebrain. One day after the adrenalectomy or sham operation, ACTH (50 µg/day) was injected subcutaneously into adult male SD rats for 10 consecutive days. Saturation analysis showed that subchronic ACTH treatment significantly increased the Bmax values for3H-ketanserin binding without any change in the Kd values. Moreover, this ACTH-induced increase in the Bmax values was prevented by adrenalectomy. The concentrations of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) measured by HPLC-ECD were not altered by these manipulations. Ten-day administration of corticosterone (20 and 50 mg/kg) also increased 5-HT2 receptor density in the neocortex of rat forebrain. 5-HT2 (and 5-HT1C) receptor agonist, (±)DOI-induced wet-dog shakes in ACTH and/or adrenalectomy-treated rats were also examined. Ten-day administration of ACTH enhanced (±)DOI-induced wet-dog shakes and this increase was prevented by adrenalectomy. These results indicate that subchronic adrenocorticotropinadrenal axis activation of rats increases both the number of 5-HT2 receptors in neocortex of forebrain and the wet-dog shake responses induced by (±)DOI.

HPA axis dysfunction in unmedicated major depressive disorder and its normalization by pharmacotherapy correlates with alteration of neural activity in prefrontal cortex and limbic/paralimbic regions

Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis is one of the most prominent neurobiological findings in major depressive disorder (MDD). The relationship of regional brain metabolism to HPA axis dysfunction in depressed patients, however, is still unclear. In this study, to examine the clinical pharmacotherapeutic effects on HPA axis function and brain metabolism in MDD patients, we performed the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test on 24 antidepressant-free patients with MDD a few days after positron emission tomography (PET) with a radiotracer, [(18)F]-fluorodeoxyglucose (FDG). Moreover, 10 patients who responded to pharmacotherapy were re-tested. 75% of unmedicated MDD patients exhibited a heightened cortisol response to the DEX/CRH test, and thus were defined as non-suppressors. Non-suppressors showed a marked hypometabolism in the medial prefrontal cortex as compared with suppressors. After successful pharmacotherapy, enhanced cortisol responsiveness normalized. Prior to treatment of the unmedicated MDD, a significant hypometabolism in various frontal regions and a significant hypermetabolism in the right hippocampus and parahippocampal gyrus were observed compared with controls. Metabolic activity in treatment responders showed a normalizing pattern in almost all the areas that had been characterized by metabolic abnormality at baseline except for the medial prefrontal cortex. These results indicate that depressed patients remitted with antidepressant treatment were accompanied by resolution of HPA dysregulation and alteration of regional glucose metabolism in the prefrontal cortical, limbic and paralimbic regions.

Prenatal dexamethasone exposure alters brain monoamine metabolism and adrenocortical response in rat offspring.

In this study, it has been clearly demonstrated that prenatal dexamethasone treatment (Dex; 0.05 mg/kg on gestational days 17, 18, and 19) resulted in the significant reductions of 5-hydroxytryptamine (5-HT) turnover in four brain regions, including the neocortex, hippocampus, hypothalamus, and midbrain + pons-medulla (M + P-M) but not in the striatum in the offspring at 3 and 14 wk of life, as well as dopamine turnover in the hypothalamus. [3H]paroxetine binding densities were increased in the hypothalamus and M + P-M at 14 wk of life, which corresponded to increased 5-HT contents in both regions. On the other hand, significantly lower norepinephrine contents in the neocortex and hippocampus were observed in the Dex group compared with the control group at 14 wk of life. In addition, the exposure to new environmental condition elevated blood corticosterone levels and enhanced behavioral activities to a greater extent in the Dex group than in controls at 7 wk of life, suggesting that elevated glucocorticoid levels during the pregnancy mimicked prenatal mild stress, producing developmental alterations in brain monoamine metabolism, endocrine response, and behavior in adult offspring.In this study, it has been clearly demonstrated that prenatal dexamethasone treatment (Dex; 0.05 mg/kg on gestational days 17, 18, and 19) resulted in the significant reductions of 5-hydroxytryptamine (5-HT) turnover in four brain regions, including the neocortex, hippocampus, hypothalamus, and midbrain + pons-medulla (M+P-M) but not in the striatum in the offspring at 3 and 14 wk of life, as well as dopamine turnover in the hypothalamus. [3H]paroxetine binding densities were increased in the hypothalamus and M+P-M at 14 wk of life, which corresponded to increased 5-HT contents in both regions. On the other hand, significantly lower norepinephrine contents in the neocortex and hippocampus were observed in the Dex group compared with the control group at 14 wk of life. In addition, the exposure to new environmental condition elevated blood corticosterone levels and enhanced behavioral activities to a greater extent in the Dex group than in controls at 7 wk of life, suggesting that elevated glucocorticoid levels during the pregnancy mimicked prenatal mild stress, producing developmental alterations in brain monoamine metabolism, endocrine response, and behavior in adult offspring.

Serotonin but not norepinephrine-induced calcium mobilization of platelets is enhanced in affective disorders

Intracellular calcium concentrations ([Ca++]i) in blood platelets from 11 depressed patients and 11 healthy controls were investigated. The resting [Ca++]i of platelets from depressed patients was 69.4±2.9 nM while that from controls was 74.6±4.0 nM. Serotonin (5-HT), at a concentration of 10 µM, increased [Ca++]i by 129.2±3.9 nM in platelets from depressed patients, which was significantly greater than that found in platelets from control subjects (105.2±6.0 nM). Norepinephrine (NE) 100 µM increased [Ca++]i by 46.1±7.1 nM in platelets from depressed patients, and by 38.6±6.1 nM in platelets from controls, respectively. These results indicate that 5-HT2 receptor function in platelets of depressed patients is enhanced, and support the hypothesis of hypersensitivity of 5-HT2 receptors in affective disorders.