気分障害 Mood Disorders
P3-2-202 初代培養ラット大脳皮質アストロサイトにおいて三環系抗うつ薬アミトリプチリンはMEK/ERKカスケードを介してBDNF exon mRNAの発現を調節する Amitriptyline increases BDNF exon mRNA expression through MEK/ERK activation in rat astrocytes ○中島一恵1, 金子将大1, 葛西美穂2, 梶谷直人1,3, 安部裕美1,3, 柴崎千代3,4, 森岡徳光1, 仲田義啓1, 竹林実3,4 ○Kazue Hisaoka-Nakashima1, Masahiro Kaneko1, Miho Kasai2, Naoto Kajitani1,3, Hiromi Abe1,3, Chiyo Shibasaki3,4, Norimitsu Morioka1, Yoshihiro Nakata1, Minoru Takebayashi3,4 広島大学大学院　医歯薬保健学研究院　薬効解析科学1, 広島大学　薬学部　薬効解析科学2, 国立病院機構呉医療センター　中国がんセンター　臨床研究部　精神神経科学研究室3, 国立病院機構呉医療センター　中国がんセンター　精神科4 Dept. Pharmacol., Grad. Sch. Biomed. Health Sci., Hiroshima Univ.1, Dept. Pharmacol., Sch. of Pharmacy, Hiroshima Univ.2, Inst. Clin. Res., Natl. Hosp. Org. Kure Med. Ctr.3, Dept. Psychiatry, Natl, Hosp. Org. Kure Med. Ctr.4 Recently, clinical and animal studies show that neuronal and glial plasticity are important for the therapeutic action of antidepressants. We reported that amitriptyline (a tricyclic antidepressant) acts on astrocytes and increases the expression of neurotrophic/growth factors, such as brain-derived neurotrophic factor (BDNF) (Kajitani et al., 2012). There is growing evidence that biosynthesis of BDNF by antidepressants may contribute to clinical effectiveness for depression. The rat BDNF gene produces 22 different transcripts, which composed of one alternatively spliced 5'UTR exon linked to a common downstream exon containing the coding region with two possible 3'UTR. Transcripts encoding the 5'exons 1, 2, 4, or 6 altogether represent 95% of the total BDNF mRNA in rat. In this study, we examined the effect of antidepressants on the levels of total BDNF mRNA and each exon mRNA (exon1, 2B, 2C, 4, 6), which are expressed in astrocytes, by real-time PCR in rat primary cultured cortical astrocytes. Treatment with amitriptyline significantly increased total, exon1, 4 and 6 BDNF mRNAs in a different time course, but not exon 2B and 2C. Furthermore, amitriptyline significantly increases BDNF protein. Different classes of antidepressant (clomipramine, fluvoxamine and duloxetine) also increase total BDNF mRNA, however each exon mRNAs are differentially regulated by them. The amitriptyline-induced total, exon4 and 6 BDNF mRNA expressions are significantly reduced by MEK inhibitors (U0126 and PD98059). Moreover, treatment with amitriptyline increases phosphorylation of ERK1/2. These results indicate that amitriptyline induces BDNF mRNA through MEK/ERK pathway, and individual class of antidepressant regulates BDNF mRNAs probably through a different recruitment of promoters in astrocytes. The astrocyte might play an important role for the antidepressant-induced BDNF expression in the brain.	P3-2-203 fMRIデータ機械学習は心理療法の治療反応を予測する Machine learning of fMRI data predicts treatment response to psychotherapy ○吉村晋平1, 清水優2, 岡本泰昌1, 土岐茂1, 高村真広1, 吉本潤一郎2, 銅谷賢治2, 山脇成人1 ○Shinpei Yoshimura1, Yu Shimizu2, Yasumasa Okamoto1, Shigeru Toki1, Masahiro Takamura1, Junichirou Yoshimoto2, Kenji Doya2, Shigeto Yamawaki1 広島大学大学院医歯薬保健学研究院1, 沖縄科学技術大学院大学神経計算ユニット2 Institute of Biomedical and Health Sciences, Hiroshima University1, Okinawa Institute of Science and Technology, Neural Computation Unit2 Objects: In general, psychotherapy such as cognitive behavioral therapy is an effective treatment for depression. However, for some patients psychotherapy remains unsuccessful. Hence, to reveal a biological factor to predict the treatment response to psychotherapy would be beneficial. We aim to reveal such a predictive factor by applying a machine learning method to fMRI data.Method: Depressive patients (N=29) participated in 12 weeks group psychotherapy sessions. Patients whose symptoms improved more than 50% were assigned to the treatment response (TR) group (n=15). Accordingly, patients who improved less than 50% were assigned to the non-treatment response (NR) group (n=14). Patients underwent fMRI while performing a personal relevance rate task using positive and negative affective words. The data was analyzed using SPM8. Two main contrasts were evaluated on individual level. One contrast reveals relevant brain areas during judgment of self-relevance with respect to positive words, the other self-relevance with respect to negative words. To predict treatment response from the fMRI data, we employed the L1-reguralized logistic regression algorithm in which the independent (input) variables are the activation levels in all voxels in two contrasts. The dependent (output) variable is 1 or 0 indicating TR or NR group, respectively. The regression weight for each voxel was regarded as a measure of contribution of the voxel to discriminate TR and NR groups.Results: The highest classification performance was obtained from brain activity in the negative words condition (sensitivity =86.7%; specificity=85.7%; accuracy=82.8%). However, we could not find any specific brain regions in which voxels with large classification contribution were concentrated.Discussion: We found that application of machine-learning to fMRI data is useful for the prediction of treatment response to psychotherapy.
P3-2-204 うつ病患者における言語流暢性課題遂行時の脳活動減衰―音韻性および意味性課題を用いた検討 Attenuated brain activation in major depressive patients during two types of verbal fluency tasks ○高村真広1, 岡本泰昌1, 土岐茂1, 山本哲也1, 高石佳幸1, 吉村晋平1, 中尾敬1, 山脇成人1 ○Masahiro Takamura1, Yasumasa Okamoto1, Shigeru Toki1, Tetsuya Yamamoto1, Yoshiyuki Takaishi1, Shinpei Yoshimura1, Takashi Nakao1, Shigeto Yamawaki1 広大院・医歯薬保健・精神神経医科学1 Dept Psychiatry and Neurosciences, Hiroshima Univ, Hiroshima, Japan1 BACKGROUND: In major depressive disorder (MDD), prefrontal dysfunction is commonly observed. This prefrontal functional abnormality is thought to be related to symptoms of MDD such as low executive function. Several previous studies examined this prefrontal dysfunction using the verbal fluency task. Most of these studies used the phonological (letter) fluency task, and only a few used the semantic (category) fluency task. In this study, we examined MDD patients' altered brain functioning during both types of verbal fluency tasks. METHODS: Nineteen patients with major depression and 19 healthy controls participated in this study. They performed two types of covert, paced verbal fluency tasks in an MRI scanner (GE Signa HDxt 3.0T). During verbal fluency task, participants were asked to imagine a word and to press a response button when a cue was presented. In phonological task, letter cues (a Japanese syllable, e.g. "te") were presented. In semantic task, category word cues (e.g. "animal") were presented. RESULTS: Direct comparisons between patients and controls by two-sample t-test (uncorrected p-value < 0.001; cluster size > 40 voxels) revealed attenuated brain activation in depressive patients at several regions. In phonological task, attenuations were found at left DLPFC, left anterior cingulate cortex, and right precuneus. In semantic task, bilateral DLPFC, left precuneus, and thalamus were less activated in patients. DISCUSSION: In the present study, MDD patients exhibited attenuated brain activation in both types of verbal fluency tasks. Compared to the phonological task, the semantic task demonstrated large differences between groups. This result suggests the brain circuit altered in MDD patients involves semantic retrieval process.	P3-2-205 抗うつ薬とアルコールがもたらす末梢血血小板からの脳由来神経栄養因子遊離の変化 Alcohol and antidepressants alter BDNF release from platelet in the peripheral blood ○石井貴男1, 鵜飼渉1, 渡邊公彦1, 木川昌康1, 橋本恵理1, 齋藤利和1 ○Takao Ishii1, Wataru Ukai1, Kimihiko Watanabe1, Yoshiyasu Kigawa1, Eri Hashimoto1, Toshikazu Saito1 札幌医科大学　神経精神医学講座1 Dept Neuropsychiatry, Sapporo Medical University, Sapporo1 It has been elucidated that the alteration in neural circuits is the key mechanism of various clinical conditions of psychiatric diseases including alcohol related disorders and mood disorders. The neurogenic and neurotrophic effects of psychotropics are considered to contribute to the prevention of morphological and functional brain change induced by those psychiatric diseases. In recent years, protective role of brain-derived neurotrophic factor (BDNF) for the brain volume deficit in depression has been also demonstrated. Previously, we have investigated the effect of psychotropic agents such as antidepressants and BDNF on the neurogenetic change induced by alcohol and endoplasmic reticulum (ER) stress. We also have shown that the alterations of trophic factor signaling and transcription factors, CREB and NRSF/REST play an important role in the effects of these psychotropic agents.In addition, there are some reports demonstrated that serum BDNF level in depressive patients is lower than control subjects, and antidepressant treatment increases its serum levels in responder. However, its mechanism and biological meaning in the pathophysiology of depression have not yet understood. In this study, we investigated that antidepressants increased the platelet BDNF release through TrkB signaling and other cellular signaling. We also demonstrated that serum BDNF was also increased by the intravenous treatment of antidepressant. Furthermore, ethanol suppressed the antidepressant-induced platelet BDNF release. These results suggested that alterations of trophic factor functions not only in the brain but also in the peripheral blood possibly underlies the pathogenetic mechanism of neurogenesis dysfunction in alcohol-induced brain damage and other psychiatric disorders, those might be the key role of psychotropic drugs for their clinical efficacies.
P3-2-206 HCNP前駆体蛋白は双極性障害に関連する可能性がある Hippocampal Cholinergic Neurostimulating Peptide Precursor as a potential candidate gene responsible for bipolar disorder ○水野将行1, 加藤大輔1, 金森哲子1, 望月秀樹2, 小鹿幸生1, 松川則之1 ○Masayuki Mizuno1, Daisuke Kato1, Tetsuko Kanamori1, Hideki Mochizuki2, Kosei Ojika1, Noriyuki Matsukawa1 名古屋市立大学大学院医学研究科　神経内科学1, 大阪大学大学院医学系研究科　神経内科学2 Dept Neurol, Nagoya City Univ, Nagoya1, Dept Neurol, Osaka Univ, Osaka2 Hippocampal cholinergic neurostimulating peptide (HCNP) induces the synthesis of acetylcholine in the medial septal nucleus in vitro and in vivo. The precursor, HCNP-pp, is a multifunctional protein that participates in a number of important signaling pathways, including those of MAPK/extracellular signal regulated kinase kinase and G-protein-coupled receptor kinase 2. We previously reported that the over-expression of HCNP-pp in the hippocampus may display the depressive-like behavior. In this study, we generated HCNP-pp floxed mice. To further examine whether HCNP-pp may be involved in neuropsychiatric behavior, we investigated behavioral test in HCNP-pp conditional knockout (KO) mice by using Cre reconbinase transgenic mice driven by Calmodulin kinase II (CaMKII) promoter. Further insight of the period influence of HCNP-pp reduction, we also examined behavioral test in mice with HCNP-pp knockdown in the hippocampus at 12-14 week-old by adeno-associated virus. Here, we demonstrated that HCNP-pp reduction at 12-14 week-old may be involved in the disease development of mania-like behavior. We confirmed the decrease of gamma-aminobutyric acid (GABA) A receptor α2/3 subunit in this model mice. These suggested that HCNP-pp in the hippocampus may be involved in bipolar disorder, depressive-like and/or mania-like behavior, through GABAergic neurons.	P3-2-207 慢性的なコルチコステロン投与は扁桃体外側基底核においてオリゴデンドロサイト前駆細胞の増殖を抑制する Chronic corticosterone treatment suppresses proliferation of oligodendrocyte progenitor cells in the basolateral amygdala ○石塚恭理1, 松木則夫1, 野村洋1 ○Masataka Ishizuka1, Norio Matsuki1, Hiroshi Nomura1 東京大学大学院　薬学系研究科　薬品作用学教室1 Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo1 Oligodendrocytes insulate the axon and regulate the conduction in the central nerve system of vertebrates. Recent histological studies reported that the number of oligodendrocytes in the amygdala in patients with major depressive disorder (MDD) was smaller than that of healthy people. However, it remains unclear whether stress reduces the number of oligodendrocytes along with the induction of depressive behaviors. Glucocorticoid is released from the adrenal cortex in response to stress, and its serum concentration is high in the patients with MDD. Therefore, the level of glucocorticoid can be a key factor for the pathology of MDD. In the present study, we investigated the effects of corticosterone on oligodendrocytes. Mice were treated with corticosterone dissolved in water for 20 days. Serum concentration of corticosterone increased during the treatment. Depressive behavior was observed after the treatment. Mice also received BrdU injection in the last 2 days of the treatment to label the newborn cells. The number of NG2 cells, which are progenitor cells of oligodendrocytes, was counted following the visualization with immunohistochemistry. The most of the BrdU+ cells were NG2 cells in the basolateral amygdala (BLA). Chronic corticosterone treatment decreased the density of BrdU+ NG2 cells without affecting the density of the total NG2 cells in the BLA. These results indicate that corticosterone suppresses the proliferation of oligodendrocyte progenitor cells, but not the survival of oligodendrocyte progenitor cells in the BLA. This inhibitory effect on proliferation may contribute to subsequent decrease of oligodendrocytes in the BLA.
P3-2-208 変異Polg1マウスとミトコンドリア病患者における脳内ミトコンドリア障害細胞の組織化学的検討 Histochemical analysis of brains in mutant Polg1 transgenic mice and patients with mitochondrial disease ○窪田-坂下美恵1, 笠原和起1, 福家聡1, 高田篤1, 磯野蕗子1, 柿田明美2, 高橋均3, 加藤忠史1 ○Mie Kubota-Sakashita1, Takaoki Kasahara1, Satoshi Fuke1, Atsushi Takata1, Fukiko Isono1, Akiyoshi Kakita2, Hitoshi Takahashi3, Tadafumi Kato1 理研・脳センター・精神疾患動態1, 新潟大・脳研・生命科学リソース研究センター・脳疾患標本資源解析2, 新潟大・脳研・病態神経科学・病理3 Lab for MDMD, RIKEN BSI, Saitama, Japan1, Dept of Pathological Neuroscience, BRI, Univ of Niigata, Niigata, Japan2, Dept of Pathology, BRI, Univ of Niigata, Niigata, Japan3 [Introduction] Bipolar disorder (BD) is a mood disorder characterized by manic and depressive episodes. Based on several evidences by neuroimaging and genetic studies in patients with BD, we hypothesized that dysfunction of mitochondria in the brain is relevant to the pathophysiology of BD. Because patients with chronic progressive opthalmoplegia (CPEO), a hereditary mitochondrial disease, often have a symptom of BD or depression, we focus on CPEO which accompanies mitochondrial DNA (mtDNA) deletions. The accumulated mtDNA deletions cause a loss of mitochondrial proteins such as cytochrome c oxidase (COX). Previously, we reported that transgenic (Tg) mice expressing neuron-specific mutant Polymerase γ (Polg1), one of causative genes of CPEO, showed BD-like phenotypes. MtDNA deletions analyzed by using qPCR accumulated in several nuclei associated with emotion in the Tg mice. If it is possible to detect mitochondrial deficiency caused by mtDNA deletions at a single-neuron level, that will be helpful to identify the specific neuronal circuits related to pathogenesis of BD. This study aims to reveal the distribution of neurons with loss of mtDNA-encoded COX both in the brains of the Tg mice and human patients with mitochondrial encephalomyopathy. [Method] Double labeling with antibodies against the COX and succinate dehydrogenase (SDH), a nuclear-encoded mitochondrial protein, was performed on paraffin-embedded sections of the Tg mice and postmortem samples of the patients with mitochondrial disease. [Results] COX-negative cells were localized in some nuclei in the brain of Tg mice. In the brain of patients, the COX-negative cells were frequently found in non-pyramidal cells in gray and white matter of cortex and thalamus.v[Conclusion] The procedure of COX/SDH staining will be applied to postmortem samples of patients with BD. It would be a useful approach for detecting the cells with mitochondrial dysfunction.	P3-2-209 フローサイトメーターを用いた新規脳細胞定量法によるヒトおよびカニクイザル脳の解析 A novel method to quantify brain cells using flow cytometer and its application to the histological study of cynomolgus monkey brain ○林義剛1,2, 菊池尚美2, 福家聡1, 伊東多恵子2, 篠崎たき子2, 小山なつ1, 楯林義孝2, 等誠司1 ○Yoshitaka Hayashi1,2, Naomi Kikuchi2, Satoshi Fuke1, Taeko Itou2, Takiko Shinozaki2, Natsu Koyama1, Yositaka Tatebayashi2, Seiji Hitoshi1 滋賀医科大学　生理学講座　統合臓器生理学1, 東京都医学総合研究所　うつ病研究室2 Department of Integrative Physiology, Shiga University of Medical Science, Shiga1, Affective Disorders Research Team, Tokyo Metropolitan Institute of Medical Science, Tokyo2 Stereological methods were usually used to estimate the number of cells in discrete brain regions. However, stereological methods are laborious and intrinsically low throughput, taking typically long periods to complete a large study. We therefore developed a novel quantitative cell-counting method for unfixed, frozen postmortem brains using a flow cytometer. Anisotropic brain tissue was transformed into an isotropic suspention of nuclei and immunostained with nuclear (7-AAD), neuronal (NeuN), and oligodendroglial (olig2) markers. This method was able to count stained nuclei and measure quantitatively their sizes and fluorescence intensities. We applied this method to frozen unfixed postmortem human brains. The entire gray matter of the frontopolar and inferior temporal cortex from patients with major depressive disorder, bipolar disorder and normal controls were analyzed. Most of the available confounding factors were matched between the groups. We found significant reductions of the number of oligodendrocyte lineage cells in the frontopolar cortex of major depressive disorders and bipolar disorders, but no significant differences were found in the inferior temporal cortex. Furthermore, we try to establish a nonhuman primate model of cytokine-induced depression by using interferon-alpha. In preliminary study, we estimated the number and proportion of neuronal, oligodendroglial, and other neural nuclei of gray matter from frontopolar and inferior temporal cortex of normal cynomolgus monkeys (macaca fascicularis). The reduction of oligodendrocyte lineage cell in frontopolar cortex from patients with mood disorders suggests that the pathogenesis of mood disorders may involve some abnormalities in cortical myelination in the frontopolar cortex. To explore further the effects of oligodendrocyte lineage cells, we endeavor to develop an animal model of the interferon-alpha induced behevioral and neuropathological changes using cynomolgus monkeys.
P3-2-210 変異型ミトコンドリアDNA合成酵素を前脳で発現する気分障害モデルマウスの遺伝子発現解析 Gene expression analysis of mood disorder model mice expressing mutant form of mitochondrial DNA polymerase in the forebrain ○加藤智朗1, 小森敦子1, 窪田-坂下美恵1, 笠原和起1, 加藤忠史1 ○Tomoaki M Kato1, Atsuko Komori1, Mie Kubota-Sakashita1, Takaoki Kasahara1, Tadafumi Kato1 理研・脳センター・精神疾患動態1 RIKEN BSI, Saitama, Japan1 Although mood disorders, including bipolar disorder and major depressive disorder, are very common, the pathogenetic processes of these diseases remain poorly understood. Several epidemiological studies have shown that mitochondrial diseases are highly associated with mood disorders. We previously generated transgenic mice expressing mutant form of mitochondrial DNA polymerase (Polg1) driven by CamKII alpha promoter (mutPolg1 Tg, T. Kasahara et al. 2006). In the brains of these mice, prominent increase in the amount of partially deleted mitochondrial DNA during aging was observed. Further, we found that female mutPolg1 Tg mice often showed repetitive episodes of reduced wheel-running activity. These episodes lasting about two weeks may be similar to the pathology of mood disorders. In this study, to clarify the mechanism underlying these episodes, we used microarrays to examine gene expression differences between the brains of mutPolg1 Tg mice and those of wild-type mice. We found that corticotropin-releasing hormone (Crh) was up-regulated in mutPolg1 Tg mice, while glucocorticoid-attenuated response gene-16 (GARG-16), alternatively Ifit1, was down-regulated. These results suggest hyperactivation of the hypothalamus-pituitary-adrenal (HPA) axis occurs in mutPolg1 Tg mice, which is known to play a role in the pathophysiology of mood disorders. Thus, HPA axis dysregulation may be involved in mood instability caused by mitochondrial dysfunction.	P3-2-211 児童期・青年期のトラウマ体験は抑うつ気分誘導時のBOLD反応に影響を与える The traumatic events in childhood and adolescence modulate the BOLD response underlying the induced depressive mood ○山本哲也1,2, 土岐茂1, 高村真広1, 高石佳幸1, 吉村晋平1, 中尾敬1, 岡本泰昌1, 山脇成人1 ○Tetsuya Yamamoto1,2, Shigeru Toki1, Masahiro Takamura1, Yoshiyuki Takaishi1, Shinpei Yoshimura1, Takashi Nakao1, Yasumasa Okamoto1, Shigeto Yamawaki1 広大院・医歯薬保健・精神神経医科学1, 日本学術振興会2 Dept Psychiatry and Neurosciences, Hiroshima Univ, Hiroshima, Japan1, JSPS, Tokyo, Japan2 Introduction: There is extensive evidence that cognitive vulnerability to depression develops from personal experiences of traumatic events in childhood and adolescence. However, despite intensive investigation of this vulnerability, little is known about the effect of stressful or traumatic events on neural basis of the vulnerability in mood regulation. To clarify this clinically important issue, we investigated the relationship between the neural circuitry underlying the induced depressed mood and the experiences of traumatic events in childhood and adolescence. Methods: Twenty-two participants were scanned using functional magnetic resonance imaging (fMRI) while performing sad mood induction (a combination of re-experiencing an autobiographical sad personal event and listening to somber music). Before the mood induction, we measured (a) the early experiences of traumatic events (CATS), (b) depressive symptoms (BDI-II), and (c) the negative life stress during the recent past (LES). Results: The experiences of traumatic events were positively correlated with bilateral amygdala and VMPFC (BA25,32) response, and negatively correlated with left DLPFC (BA9) response. Furthermore, individual mean contrast estimates for significant clusters of DLPFC response predicted decreased depressive symptoms. In contrast, there were no association between the experiences of traumatic events and amount of sad mood change. Conclusions: Considering that the experiences of traumatic events were not associated with subjective sad mood, but with neural responses during mood induction, the traumatic events affect the cognitive vulnerability below the level of consciousness. Thus, we suggest that brain reactivity to sad mood provocation may serve as a marker of vulnerability to depression, particularly for people who experienced stressful or traumatic life events in childhood and adolescence.
P3-2-212 社会報酬による条件づけ場所嗜好と不安・うつ様行動の関連ー近交系マウスを用いた遺伝的背景の影響の評価 Association between social-reward conditioned place preference and anxiodepressive-like behavior in three inbred strains of mice ○千葉秀一1, 平田奈緒1, 古澤孝太1, 氷見敏行1 ○Shuichi Chiba1, Nao Hirata1, Kota Furusawa1, Toshiyuki Himi1 武蔵野大・薬・安全性学1 Faculty Pharm and Res Inst Pharmaceutical Science, Musashino Univ1 Social withdrawal is one of the common signs of the depression, although its biological basics are not substantially understood. Recently, we have developed the relatively efficient method for the evaluation of social reward using conditioned place preference (CPP). In this test (SCPP), place preference in cubic chamber is measured as conditioned response after Pavlovian conditioning using social interaction as an unconditioned stimulus. In the present study, we analyzed the associations among consequence of SCPP, anxiety-, depression-like behavior, learning and memory in inbred mice to elucidate the genetic contribution to rewarding propensity of social interaction as well as its possible mechanisms. Three strains (AKR, BALB/C and C57BL/6J) of male mice were subjected to sequential behavioral tests when they were 5-weeks old, which were done in the following order; elevated plus-maze (EPM), open field (OFT), SCPP, saccharin preference (SPT) and passive avoidance tests (PAT). Data acquisition and statistical analysis were done using Any-maze and R-software, respectively. BALB/C displayed more anxiety- and depressive-like phenotype and stronger response to social interaction, while AKR is weakly conditioned by foot-shock stimulus in PAT. Statistical analysis have demonstrated that staying time increase in the conditioned area of SCPP is positively correlated with anxiety-like behavior in EPM (r=0.45), OFT (0.53), and depression-like behavior in SPT (r=0.56). No significant correlation between responses to social interaction in SCPP and to foot-shock stimulus in PAT (r=0.03). These data suggest that conditioning by social reward is affected by genetic background and that anxiety- and depressive-like tendency can predict the response to social reward.	P3-2-213 近赤外線分光法を用いた健常人前頭葉活動の課題依存的変化及び気分との関連 Task related gender difference in prefrontal activity and its correaltion with mood in healthy controls: A NIRS study ○松澤大輔1, 武田湖太郎2, 大塚裕之1, 高杉潤1, 須藤千尋1, 下山一郎3, 中澤健1, 清水栄司1 ○Daisuke Matsuzawa1, Kotaro Takeda2, Hiroyuki Ohtsuka1, Jun Takasugi1, Chihiro Sutoh1, Ichiro Shimoyama3, Ken Nakazawa1, Eiji Schimizu1 千葉大学大学院医学研究院1, 国立病院機構 村山医療センター 臨床研究センター2, 千葉大学フロンティアメディカル工学研究センター3 Department of Cognitive Behavioral Physiology, Chiba University Graduate School of Medicine, Chiba, Japan1, Clinical Research Center, National Hospital Organization Murayama Medical Center, Tokyo, Japan2, Section for Human Neurophysiology, Frontier Medical Engineering, Chiba University, Chiba, Japan3 Near-infrared spectroscopy (NIRS) is a non-invasive method of measuring the relative change in the concentrations of oxygenated and deoxygenated hemoglobin, which are closely correlated to the neural activity of the brain. Although most of previous studies employed a single task such as letter version of verbal fluency test (VFT-l), there has been few NIRS studies with multiple task for a single individual. In addition, although evidence with mental disorders such as major depression, bipolar disorder, and schizophrenia has been accumulating, whether a temporarily depressed or anxious mood in healthy individuals affects the prefrontal blood oxygen level has rarely been considered. In the current NIRS study, three cognitive tasks, VFT-l, stroop test, and emotional stroop test were employed. Prefrontal oxygenated hemoglobin (Oxy-Hb) levels during those cognitive tests were measured, and the correlation between the Oxy-Hb levels and temporal depressed/anxiety mood were investigated in healthy individuals. Depressed/anxious mood was assessed by the Hospital Anxiety and Depression Scale (HADS). Moreover, we examined the possible relationships between prefrontal activation and the functional Val66Met polymorphisms of the brain derived neurotropic factor (BDNF) gene and serum BDNF level. As a result, the course of the prefrontal Oxy-Hb increase was different depending on the cognitive tasks, i.e., the VFT-l or the Stroop test, in both genders. The increased prefrontal Oxy-Hb levels during the cognitive tasks were significantly correlated with the severity of depressed mood only in males. Correlations of BDNF genotype and serum BDNF level with the prefrontal Oxy-Hb levels during those cognitive tasks were negative. Our results suggest that the temporal mood state alter the prefrontal activation only in males dependent on task, which is not correlated with the individual properties of BDNF.
P3-2-214 Investigating the role of p70 S6 kinase signaling in mediating neuronal and behavioral resilience to stress and antidepressant effects ○Jason M. Dwyer1, Jaime Maldonado-Aviles1, Ashley E. Lepack1, Ralph J. DiLeone1, Ronald S. Duman1 Laboratory of Molecular Psychiatry, Yale University School of Medicine1 Major depressive disorder is a neuropsychiatric disorder that affects nearly 20% of the population and exacts devastating personal and societal costs (Kessler et al., 2007). Currently available antidepressant treatments can take several weeks to produce remission of depressive symptoms. Recent studies in our lab have identified that the rapid-acting antidepressant effects of ketamine, which is effective in humans within hours, are mediated by a unique mechanism through mTOR-dependent synaptogenesis in the medial prefrontal cortex (mPFC) (Li et al., 2010; 2011). The present studies focus on p70 S6 kinase (S6K), a critical downstream substrate of mTOR that mediates induction of protein translation and cytoskeletal rearrangement. Ketamine rapidly activates S6K signaling (30 min-1 hr) in the mPFC. On the other hand, chronic stress suppresses S6K signaling and produces neuronal atrophy and loss of dendritic spines in the mPFC. Indeed, recent studies have demonstrated decreases in S6K in human post-mortem mPFC tissue taken from patients with MDD (Jernigan et al., 2011). In the present experiments, we use a constitutively active mutant of S6K (Dr. John Blenis; Addgene Plasmid 8993) delivered to the rodent mPFC using an AAV2 viral-mediated approach to demonstrate that activation of S6K signaling in the mPFC is sufficient to produce antidepressant-like effects in rats. Rats receiving bilateral infusion of the constitutively active S6K mutant in the mPFC had reduced immobility times in the forced swim test (40% reduction compared to control; P < 0.002) suggesting an antidepressant-like response. These effects are not due to differences in locomotor activity. Studies are currently underway to characterize the role of S6K signaling in mediating behavioral and neuronal resilience to chronic unpredictable stress using sucrose preference, novelty-suppressed feeding and elevated plus maze tests, as well as spine density and sholl analyses to assess neuronal morphology.	P3-2-215 Diagnosis of Depression by means of Group L1 regularized logistic regression of fMRI Data ○Yu Shimizu1, Jun Yoshimoto1, Shigeru Toki2, Masahiro Takamura2, Shinpei Yoshimura2, Yasumasa Okamoto2, Shigeto Yamawaki2, Kenji Doya1 Okinawa Institute of Science and Technology Graduate School, Neural Computation Unit1, Hiroshima University, Department of Psychiatry and Neurosciences2 ObjectiveDiagnosis of depression is currently based on clinical interviews. In the search for biological markers and a more objective method to diagnose this complex disease, we explore the use of machine learning methods to classify depression patients and healthy controls based on their functional magnetic resonance imaging (fMRI) data. To cope with a large data dimension as opposed to a limited number of samples, we test L1 regularized logistic regression, known as LASSO, and compare the performance of the standard LASSO, which selects a sparse subset of input dimensions to that of the group LASSO, which selects sparse subgroups of the input dimensions.Material and MethodsfMRI data of a semantic verbal fluency task of 21 severely depressed patients and 39 healthy controls was pre-processed using SPM8 (UCL, UK) In the standard LASSO, the Z-scores for all voxels were used as the input. In the group LASSO, we took the 116 anatomical regions of the MNI atlas as the input groups. We evaluated the performance and stability of the algorithm while optimizing the sparseness parameter lambda by cross validation.ResultsThe standard LASSO achieved a classification accuracy of 85.71% (specificity 95.24%, sensitivity 76.19%), where voxels from 43 brain areas were selected. The group LASSO achieved an accuracy of 92.86% (specificity 90.48%, sensitivity 95.24%), where the main contributing brain areas were left Precuneus, superior and mid temporal lobe, left Thalamus and left superior parietal area. Discussion The group LASSO outperforms the standard LASSO and provides a reliable and easily interpretable way to classify depression patients and controls by means of their fMRI data.

上部に戻る

前に戻る