ポスター発表 (Poster Sessions)

気分障害 Mood Disorders
P2-2-218 概日リズムとうつ病の調節機構としてのPERIOD2-glycogen synthase kinase 3β経路 A molecular link between PERIOD2 and glycogen synthase kinase 3β as a possible regulator in circadian rhythm and depression ○山脇洋輔¹, 高野敦子^3,4, 仲西萌絵^2,5, 玉田紘太^2,3,5, 畠中史幸^2,3,5, 内匠透^2,3,5,6 ○Yosuke Yamawaki¹, Atsuko Takano^3,4, Moe Nakanishi^2,5, Kota Tamada^2,3,5, Fumiyuki Hatanaka^2,3,5, Toru Takumi^2,3,5,6 広島国際大学　薬学部　分子細胞薬理学¹, 広島大学大学院　医歯薬保健学研究院　統合バイオ研究室², 大阪バイオサイエンス研究所³, 大阪大学大学院　薬学研究科　神経薬理学分野⁴, 理化学研究所脳科学総合研究センター⁵, 科学技術振興機構,　CREST⁶ Faculty of Pharmateutical Science, Hiroshima International University, Hiroshima¹, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima², Osaka Bioscience Institute, Osaka³, Graduate School of Pharmaceutical Science, Osaka University, Osaka⁴, RIKEN Brain Science Institute, Saitama⁵, JST, CREST⁶ Objective Although abnormal circadian rhythm is one of the symptoms of major depressive disorders, the molecular link remains unclear. Lithium, using for medication of depression in bipolar disorder, improved the depression-like behavior and lengthened the period in a locomotor activity, which implies that a target of lithium is a key molecule between circadian rhythm and depression. Since glycogen-synthase kinase (GSK) 3β is the one of the targets of lithium, we investigated the involvement between GSK3β and clock proteins, such as PER, CRY, in circadian rhythm and depression. Materials and Methods Sprague-Dawley rats and C57BL/6, Cry1-, Cry2-deficient, and Per2^Brdm1 mutant mice were used. We used Learned Helplessness (LH) as a depression model. Locomotor activity was measured using an infrared recorder. The amount of protein was estimated using Western blot. In vitro kinase assay was performed for identifying the phosphorylation site of PER2 by GSK3β. Results and Discussion The LH rats showed the shortened period, and lithium could recover LH. In addition, lithium could lengthen the period of locomotor activity. The rhythm of phosphorylated GSK3β was lost in suprachiasmatic nucleus (SCN) and prefrontal cortex (PFC) in LH. These results suggest that the interaction between SCN and PFC was important in the short period in the LH rats. On the other hand, in mice, lithium could not lengthen the period only Per2^Brdm1 mutant mice. Interestingly, Per2^Brdm1 mutant mice, lacking region bound with GSK3β, is resistant to LH. Taken together, GSK3β-induced phospho-PER2 plays a key role in link between circadian rhythm and depression. Thus, we identified the phosphorylation site of PER2 by GSK3β. In this study, we showed the possibility that GSK3β-PER2 pathway in SCN and PFC regulates circadian rhythm and depression. Further detailed studies are required for elucidation of PER2 as a regulator in these phenomena.	P2-2-219 気分障害前頭極（BA10）における脂肪酸代謝異常 Abnormal fatty acid composition in the frontopolar cortex of patients with mood disorders ○楯林義孝¹, 二本松-菊池尚美¹, 伊東多恵子¹, 篠崎たき子¹, 林義剛², 松田芳樹¹ ○Yoshitaka Tatebayashi¹, Naomi Nihonmatsu-Kikuchi¹, Taeko Itou¹, Takiko Shinozaki¹, Yoshitaka Hayashi², Yoshiki Matsuda¹ 公益財団法人　東京都医学総合研究所　統合失調症・うつ病プロジェクト　うつ病研究室¹, 滋賀医科大学生理学講座　統合臓器生理学部門² Affective Disorders Research Team, Schizophrenia & Affective Disorders Project, Tokyo Met. Inst. Med. Sci, Tokyo, Japan¹, Department of Integrative Physiology, Shiga University of Medical Science, Seta-Tsukinowa, Ohtsu, Shiga, Japan² Bipolar and major depressive disorders are essentially relapsing and remitting disorders of affect with nearly full recovery between episodes. Although the underlying molecular mechanisms remain unclear, myelin-related abnormalities have long been suspected. Using a well-characterized set of autopsied brains provided by the Stanley Foundation Neuropathological Consortium, we determined the total FA composition of both the frontopolar (FPC, Brodmann Area (BA)10) and inferior temporal cortices (ITC, BA20). We also studied, using rats, the effects of confounding factors and the medication. We found that gamma linoleic (18:3n-6) and docosapentaenoic acids (22:5n-3) abnormally accumulate in the FPC of patients suffering mood disorders but not schizophrenia. In the mood disorder FPC, the levels of oleic acid (18:1n-9) and the ratios of oleic to stearic acids (18:1n-9/18:0), which presumably represent stearoyl-coenzyme A desaturase activities, were significantly downregulated. These abnormalities were all aggravated in a myelin level-dependent manner, suggesting their close relationship with myelination. Animal studies have further revealed that chronic antidepressant treatment induces robust changes in brain FA metabolism, but contributes only part of the abnormalities found in the affective disorder brains. These findings identify a novel neuropathological hallmark of mood disorders that not only supports, biologically, Kreapelin's nosological dichotomy, but which also suggests that the pathogenesis of mood disorders involves a certain type of perturbation in cortical myelination in the adult FPC that may serve as a novel diagnostic and therapeutic target.
P2-2-220 Glucagon-like peptide-2 の抗うつ作用における免疫組織化学的な検討 Immunohistochemical determination of the site of antidepressant-like effects of glucagon-like peptide-2 ○濱田幸恵¹, 由利洋一¹, 岡淳一郎¹ ○Sachie Hamada¹, Yoichi Yuri¹, Jun-Ichiro Oka¹ 東京理科大学　薬学部　薬理学¹ Lab Pharmacol, Fac Pharm Sci, Tokyo Univ. Sci, Chiba¹ Proglucagon-derived glucagon-like peptide-2 (GLP-2) is released in enteroendocrine cells and neurons. GLP-2 regulates energy absorption and epithelial integrity in the gastrointestinal tract, and food intake and blood-pressure in the central nervous system (CNS). Previously, we showed that GLP-2 exerted antidepressant-like effects in the forced-swim test in mice. More detailed analysis is required to understand the antidepressant-like effects of GLP-2. Here we investigated the relationship between the antidepressant-like effects of GLP-2 and the distribution of activated neuron in the CNS using normal or model mice of tricyclic antidepressant-resistant depression. Chronic treatment with adrenocorticotropic hormone (ACTH) has proved to be a model of tricyclic antidepressant-resistant depression. The reduction of immobility time in the forced-swim test was induced by central administrated GLP-2 (3 μg/day) for 6 days in normal or model mice of tricyclic antidepressant-resistant depression. Immunohistochemical detection of the c-fos protein (Fos) revealed that central administrated GLP-2 (3 μg/day) for 6 days induced Fos-immunoreactivity (Fos-IR) in the dorsomedial hypothalamic nucleus (DMH). These results suggest that GLP-2 acts on specific brain nuclei to regulate the hypothalamic-pituitary-adrenal (HPA) axis.	P2-2-221 うつ病発症に至るメカニズムの解析：水浸ストレスがラットに及ぼす影響 Studies the onset depression: Effect of water immersion stress on the rat ○鈴木圭祐¹, 柴藤淳子³増尾好則¹ ○Keisuke Suzuki¹, Junko Shibato³, Randeep Rakwal², Yoshinori Masuo¹ 東邦大学大学院　理学研究科　生物学専攻　神経科学研究室¹, 筑波大学　大学院　生命環境科学研究科　生物科学専攻², 昭和大学医学部第一解剖学教室³ Neurosci Lab Graduate Sch Sci Toho Univ, Chiba, Japan¹, Graduate Sch Life & Environ Sci, Tsukuba Univ, Ibaraki, Japan², Dept Anat, Showa Univ Sch Med, Tokyo, Japan³ A chronic stress may cause psychiatric disorders, such as depression. The diagnosis of depression has been based on interviews, and there is little information about biomarkers. A number of previous studies focused on treatment for the patients, and demonstrated curative effects by improving change in the biological materials in the patients. However, it is still difficult to detect pre-symptomatic stage to prevent development of symptoms. Therefore, we are studying the mechanism of the etiology of depression caused by stress, which may contribute to establishment of early diagnosis and/or prevention of depression. In the present study, the effects of stress were analyzed on the rat hippocampus which may play important roles for the onset of depression. The rats received water immersion stress for 12, 24 or 48 h, and showed depressive-behavioral changes. The stress-responsive biomarker candidates were measured by reverse-transcription (RT)-PCR and Western blot. Significant alterations were observed in the expression mRNA and protein levels of matrix metalloproteinases-8 (MMP-8) and fast nerve growth factor receptor (NGFR) in the hippocampus after stress. Moreover, the protein levels of brain derived neurotrophic factor (BDNF) were decreased in the brain of these animals. Since MMP-8 has been reported to have a function of decomposing extra-cellular matrix, the present results suggest that MMP-8 may be involved in the process from the stress to neuro-degeneration in the hippocampus. The change of NGFR, which contributes to modulate behaviors related to stress and anxiety, may induce depression-like behavior.
P2-2-222 リチウム投与による末梢白血球遺伝子発現の変化－マイクロアレイを用いた解析 Microarray analysis of the leukocyte global gene expression profile following lithium treatment ○伊賀淳一¹, 渡部真也¹, 西晃¹, 沼田周助¹, 木下誠¹, 菊地久美子¹, 中瀧理仁¹, 大森哲郎¹ ○Junichi Iga¹, Shinya Watanabe¹, Akira Nishi¹, Shusuke Numata¹, Makoto Kinoshita¹, Kumiko Kikuchi¹, Masahito Nakataki¹, Tetsuro Ohmori¹ 徳島大学大学院ヘルスバイオサイエンス研究部精神医学分野¹ Dept of Psychiatry, Univ of Tokushima, Tokushima¹ Objectives: Lithium is typically prescribed as a mood stabilizer for bipolar disorder and as an augmentation agent for refractory depression despite that the exact molecular mechanism of their clinical actions are still unknown. To elucidate molecular effects of lithium, we studied the global gene expression changes induced by lithium in leukocytes of healthy subjects using microarrays and real-time PCR.Methods: 8 healthy male subjects participated in this study. Lithium was prescribed for 2 weeks enough to reach therapeutic serum concentration (0.6-1.0mM). Leukocyte counts and serum lithium concentrations were determined at baseline (before medication), 1-week, 2-week medication and post-2-week (2-week after stopping medication). Gene expression profiling was performed at each time point using Agilent G4112F Whole Human Genome arrays containing approximately 44,000 probe sets. Some of the candidate gene expressions were also determined by real-time PCR. Results: Leukocyte counts were significantly increased at 1-week and 2-week compared with baseline and normalized at post-2-week. Pathway analysis based on the genes which were changed more than 1.5 folds revealed that Interleukin 6 (IL6) pathway and Inhibitor of differentiation (ID) pathway and methane metabolism pathway were regulated by lithium. We also confirmed that 5 candidate genes such as SOCS3 and MPO in these pathways were significantly changed using real-time PCR.Conclusions: Our investigation suggests that molecular action of lithium may be mediated in part by their effects on IL6, ID and methane metabolism pathways. Gene expressions in these pathways may be useful as a peripheral marker of lithium action.	P2-2-223 セルトラリン慢性投与後の海馬歯状回腹側部及び背側部の遺伝子発現の変化 Induction of galanin after chronic sertraline treatment in mouse ventral dentate gyrus ○山田光彦¹, 山田美佐¹, 牧野祐哉^1,2, 橋本富男¹, 杉山梓^1,2, 稲垣正俊¹, 岡淳一郎², 斎藤顕宜¹ ○Mitsuhiko Yamada¹, Misa Yamada¹, Yuya Makino^1,2, Tomio Hashimoto¹, Azusa Sugiyama^1,2, Masatoshi Inagaki¹, Jun-Ichiro Oka², Akiyhoshi Saitoh¹ 国立精神セ・精神薬理¹, 東京理科大・薬・薬理² Dept Neuropsychopharmacol, NCNP, Tokyo¹, Lab Pharmacol, Fac Pharmaceut Sci, Tokyo Univ Sci² A number of studies implicate neuroplasticity in therapeutic mechanisms of antidepressants, specifically neuroplasticity in the dentate gyrus of the hippocampal formation. The dorsal hippocampal region in rodents is preferentially involved in spatial learning and memory, while the ventral hippocampal region plays a more important role in stress, emotion, and affect behaviors. These findings led us to investigate behavioral changes and gene expression changes in the ventral dentate gyrus after chronic treatment in mice with the antidepressant sertraline. Four-week treatment with sertraline significantly decreased immobility in the modified forced swim test, a behavioral test for assessing antidepressant-like effects in rodents. In the novelty suppressed feeding test, performance of which is affected by functional changes in the dentate gyrus, sertraline treatment significantly decreased latency to feed. Next, we examined by real-time RT-PCR the expression of several neuroplasticity-related genes in mice (those for Notch receptors, basic helix-loop-helix transcription factors and related factors, SoxC transcription factors, and glial-related genes) in ventral and dorsal dentate gyrus after sertraline treatment. The gene encoding the neuropeptide galanin was significantly induced in only ventral dentate gyrus, not in dorsal dentate gyrus. The expression of GalR2 mRNA remained unchanged after sertraline treatment, suggesting that GalR2 was not downregulated. These results suggest that sertraline-related galanin induction in ventral dentate gyrus may play a role in therapeutic mechanisms of antidepressant. This work was supported by MEXT KAKENHI Grant Number 22500346.
P2-2-224 希望は期待による知覚変化を推進する Hope boosts perceptual alteration induced by expectation ○横川啓太¹, 山田真希子^1,2, 高野晴成¹, 須原哲也¹ ○Keita Yokokawa¹, Makiko Yamada^1,2, Harumasa Takano¹, Tetsuya Suhara¹ 独立行政法人放射線医学総合研究所・分子イメージング・分子神経¹, 科学技術振興機構（JST）戦略的創造研究推進事業　さきがけ（脳情報の解読と制御）² Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan¹, Decoding and controlling brain information, PRESTO, Japan Sience and Technology Agency (JST), Saitama, Japan² Although antidepressant is believed to improve mood, its efficacy of real chemical acts is often intertwined with psychological expectations, known as the placebo effect. In the currently, we investigated how expectations alter visual perception with pharmacological interventions.Ten healthy subjects were tested with the binocular rivalry task under two medication conditions, with orwithout antidepressant (Duloxetine). The task contained three blocks: 1) baseline block, 2) learning block, 3) test block. In each block, subjects were asked to report perceptual reversals. In the baseline block, subjects were presented with Gabor stimuli with two different directions (leftward and rightward tilts) whose contrasts are the same. In the learning block, stimuli with two directions were changed in their contrasts (high and low) to bias subjects' perception toward high contrast. In the test block, the same contrast stimuli with the baseline block were again presented. After completing the task, subjects filled out the Beck Hopelessness Scale. Under medication, biased perception towards the expected direction in the test block was negatively correlated with the level of hopelessness. While perception of subjects with lower hopelessness was biased towards the expected direction, perception of those with higher hopelessness was unbiased. Thus, the results indicated that expectations altered perceptual experience only when antidepressant effectively worked on mood. The finding implicates that expectation modulates perceptual experience which might be related to the placebo effect of antidepressant.	P2-2-225 双極性障害における前注意機能障害の検討 Preattentive dysfunction in patients with bipolar disorder: relation to clinical status ○勝木聡美¹, 鬼塚俊明¹, 織部直弥², 前川敏彦¹, 土本利架子¹, 平野昭吾¹, 上野雄文¹, 平野羊嗣², 三浦智史¹, 神庭重信¹ ○Satomi Katsuki¹, Toshiaki Onitsuka¹, Naoya Oribe², Toshihiko Maekawa¹, Rikako Tsuchimoto¹, Shogo Hirano¹, Takefumi Ueno¹, Yoji Hirano², Tomofumi Miura¹, Shigenobu Kanba¹ 九州大学大学院医学系学府精神病態医学¹, ハーバード大学² Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka¹, Clinical Neuroscience Division, Laboratory of Neuroscience, Department of Psychiatry, Boston VA Healthcare System, Brockton Division and Harvard Medical School, Brockton, MA, USA² Objectives: The mismatch negativity (MMN) and its magnetic counterpart (MMNm) are thought to reflect an automatic process that detects a difference between an incoming stimulus and the sensory memory trace of preceding stimuli. In schizophrenics, an attenuation of the MMN/MMNm amplitude has been repeatedly reported. However, in bipolar disorder patients, the MMN/MMNm has received less attention. The present study investigated the pitch-MMNm in bipolar patients using whole-head 306-ch magnetoencephalography (MEG). Methods: Twenty-two bipolar patients and 22 healthy controls participated in this study. In one session, subjects were presented with approximately 2600 binaural tone pips with 400-msec interstimulus intervals. Standard tones were 1000 Hz or 1200 Hz, 80 dB SPL, 100 msec (2340 stimuli). Deviant tones were 1200 Hz or 1000 Hz, 80 dB SPL, 100 msec (260 stimuli). Two sessions were performed (standard/deviant: 1000 Hz/1200 Hz or 1200 Hz/1000 Hz). Event-related brain responses to standard tones were subtracted from responses to deviant tones. Results: Bipolar patients showed a significant bilateral reduction in magnetic global field power (mGFP) amplitudes (p=0.02) and dipole moments of the MMNm (p=0.04) compared with healthy controls. No significant differences in mGFP latencies and dipole locations of MMNm were observed between patients and controls. Patients with admission experience showed significantly reduced mGFP amplitudes of MMNm compared to patients without admission experience (p=0.004). Additionally, patients with more severe manic symptoms had smaller mGFP amplitudes of MMNm (rho=-0.504, p=0.02). Conclusions: The results of this study suggest that bipolar patients may exhibit preattentive auditory dysfunction indexed by reduced pitch-MMNm responses.
P2-2-226 道具的行動の遂行パターンにおける個体差は慢性ストレスに対する反応の違いを予測する Individual differences in instrumental performance in naive rats predict distinctive responses to chronic unpredictable stress ○井口善生¹, 小杉桜子¹, 三邉義雄¹, 戸田重誠¹ ○Yoshio Iguchi¹, Sakurako Kosugi¹, Yoshio Minabe¹, Shigenobu Toda¹ 金沢大学医薬保健研究域　医学系　脳情報病態学¹ Dept Psychiatry & Neurobiol, Kanazawa Univ, Kanazawa, Japan¹ The representative symptoms in major depressive disorder (MDD), such as loss of motivation or inflexible decision-making, imply the involvement of several brain regions, such as prefrontal cortex and the nucleus accumbens. In animal model studies of MDD, chronic unpredictable stress (CUS) is widely used to induce MDD-like phenotypes. However, as in the case of human MDD, the existence of individual differences makes the prediction of vulnerability or resilience to CUS very difficult. We hypothesized that individual differences in motivation or flexible behaviors in naive rats would result in different pathophysiological outcomes after the exposure to CUS. To verify this model, we first tried to classify some distinctive subgroups from naive Sprague-Dawley rats (n = 48) by monitoring the individual performance of motivation-dependent behavior and goal-directed or flexible behavioral switching in a saccharin-rewarded instrumental training. As a result, the original group was divided into three subgroups as follows; Low Motivation (LM: characterized by consistent low completed ratio, population = 25%), Switching (SW: high completed ratio in the first session followed by drastic reduction, 48%), and Hyper Motivation (HM: consistent high completed ratio, 27%). Of note, the basal level of serum corticosterone was markedly higher in LM than in HM, and the response to footstock stress of serum corticosterone in LM was significantly higher than in other subgroups. We next examined if these subgroups would perform differently in the progressive ratio instrumental performance after CUS. We found that HM showed a significant reduction in completed ratio immediately after CUS whereas LM showed a significant increase in completed ratio 4 weeks after CUS. The completed ratio was not affected in SW. Thus, these results suggested the predictability of the MDD-like pathophysiological consequence based on the cognitive or motivational differences in naive condition.	P2-2-227 神経可塑性とうつ様行動におけるヒストン脱アセチル化酵素Sirtuinsの役割の検討 Sirtuins might play a role in neural plasticity and depression-like behavior ○阿部尚子¹, 内田周作¹, 山形弘隆¹, 大朏孝治¹, 芳原輝之¹, 柴田朋彦¹, 樋口文宏¹, 渡邉義文¹ ○Naoko Abe¹, Shusaku Uchida¹, Hirotaka Yamagata¹, Koji Otsuki¹, Teruyuki Hobara¹, Tomohiko Shibata¹, Fumihiro Higuchi¹, Yoshifumi Watanabe¹ 山口大学大学院　医学系研究科高次脳機能病態学分野¹ Dept Neurosci, Yamaguchi Univ ,Yamaguchi¹ Recent reports have suggested that epigenetic gene regulations via the class I and II histone deacetylases (HDACs) can contribute to behavioral responses to chronic stress and antidepressants in rodents. Sirtuins(SIRTs), Class III HDACs, are the NAD+- dependent protein deacetylase family, and are critical regulators of cellular functions. We previously reported that the SIRT1, 2 and 6 mRNA levels in peripheral white blood cells of major depressive disorder and bipolar disorder patients were decreased during depressive states. However, the involvement of SIRTs in the pathophysiology of mood disorders is largely unknown. The purpose of this study is to clarify the role of sirtuin on depression-like behavior. First, we used quantitative real-time PCR to measure the mRNA levels of SIRTs in the hippocampus of the stressed BALB/c mice, as an animal model of depression (Uchida et al., Neuron 2011), and non-stressed BALB/c mice. We found that the mRNA level of SIRT1 was significantly decreased in the hippocampus of stressed BALB/c mice. With Golgi method, we found that sirtinol, an inhibitor of SIRT1, and resveratrol, an activator of SIRT1 have effects on dendritic morphology of granule neurons in the dentate gyrus and of CA3 pyramidal neurons. So, the role of SIRT1 in dendritic development was evaluated in cultured hippocampal neurons which were treated SRT1720, an activator of SIRT1. We found that SRT1720 significantly increased neurite outgrowth and branching in primary neurons. Thus, these finding together with our previous data in Neuro2a cells, that revealed differentiative effect of SIRT1, suggest that the SIRT1 plays a role in structural plasticity and subsequent behavioral responses to chronic stress. We postulate that dysfunction of hippocampal SIRT1 might be involved in depression-like behavior in mice.
P2-2-228 うつ様行動と神経可塑性におけるmicroRNA-124とHDAC7の役割の解析 Possible involvement of microRNA-124 and HDAC7 in depression-like behavior and neuronal plasticity ○樋口文宏¹, 内田周作¹, 山形弘隆¹, 大朏孝治¹, 芳原輝之¹, 阿部尚子¹, 柴田朋彦¹, 渡邉義文¹ ○Fumihiro Higuchi¹, Syusaku Uchida¹, Hirotaka Yamagata¹, Koji Otsuki¹, Teruyuki Hobara¹, Naoko Abe¹, Tomohiko Shibata¹, Yoshifumi Watanabe¹ 山口大学大学院医学系研究科高次脳機能病態学分野¹ Dept Neurosci, Yamaguchi Univ Sch of Med¹ MicroRNAs (miRNAs) are hairpin-derived RNAs 20-24 nucleotides (nt) long, which posttranscriptionally repress the expression of target genes usually by binding to the 3'-UTR of messenger RNA (mRNA). In the CNS, miRNAs have been shown to regulate neuronal development, survival, function and plasticity. Several lines of evidence have suggested that dysfunction of miRNAs pathway is involved in the pathophysiology of psychiatric disorders such as schizophrenia, bipolar disorder, and autism. miR-124 was first identified as one of the mouse brain-specific miRNAs, and its nucleotide sequence is conserved with mammals. miR-124 is the most abundant miRNA in the brain and a role of miR-124 in promoting adult neurogenesis in vivo has been reported in the last few years. However, the involvement of miR-124 in the depression and antidepressant action remains to be elucidated. In this study, we examined an alteration of miR-124 expression in the brain of a mouse model for depression, and a function of miR-124 in neuronal plasticity in vitro. We found that the expression of miR-124 was significantly reduced in the hippocampus of the mouse model for depression, that revealed depression-like behaviors after 6 weeks ultra mild stress paradigm (Uchida et al., Neuron 2011). Both these stress-induced behaviors and the reduction of miR-124 expression were rescued by chronic administration of imipramine and by subchronic administration of histone deacetylase (HDAC) inhibitor (SAHA). In cultured mouse neuroblastoma cells (Neuro2a cells), we found that the overexpression of miR-124 promoted neurite outgrowth and SAHA-mediated neurite outgrowth was inhibited by miR-124 inhibitor. In addition, HDAC7 promoted neurite outgrowth and the outgrowth was inhibited by miR-124 inhibitor. These results suggest that miR-124 and HDAC7 might be involved in the mechanism of depression-like behavior and play the role on structural plasticity.	P2-2-229 急性及び慢性ストレス下における外側手綱核の活性化 Activation of the lateral habenula under the acute and chronic stress ○崔万鵬¹, 田中光一¹, 相澤秀紀¹ ○Wanpeng Cui¹, Kohichi Tanaka¹, Hidenori Aizawa¹ 東京医歯大・難治研・分子神経科学分野¹ Dept. of Mol. Neurosci., Med Res Inst, Tokyo Med. & Dent. Univ., Tokyo¹ Lateral habenula (LHb) attracts a surge of interests as a source of negative reward signal and regulatory center for monoaminergic system. It remains, however, unclear how LHb acts in the brain under acute and chronic stress. To address this, we examined the neuronal activity in LHb in response to acute stress such as tail suspension test (TST) by expression of immediate early gene c-Fos. Results showed that increased c-Fos expression was observed in LHb as well as regions sending the axons to LHb such as the entopeduncular nucleus and prefrontal cortexand the regions receiving the inputs from LHb such as rostromedial tegmental nucleus (RMTg).This suggests that multiple brain regions along the LHb pathway are activated in the animals with behavioral despair. Glutamate mediates the excitatory synaptic transmission in LHb, and glutamate transported play a major role in regulation of glutamate concentration at the synapse. To examine the effects of hyperactivation in LHb on the animal behaviors, we developed a head-restrained system which allowed us to administerthe inhibitor for glutamate transporter GLT-1 specifically to LHb. Upon application to the bilateral LHb, GLT-1 inhibitor induced a large number of cells expressing c-Fos specifically in LHb as well as in RMTg without tissue damage or gliosis. With activated LHb, immobility time during TST was significantly longer than control, suggesting that increased glutamatergic transmission in LHb exacerbated the behavioral despair under acute stress. Furthermore, we examined the neuronal activity in LHb in social avoidance test under the chronic social defeat stress. Results showed that chronically-defeated mice showed a larger number of c-Fos-positive cells in LHb than control. Intriguingly, the number of c-Fos-positive cells in LHb were positively correlated with the interaction with aversive aggressors suggesting that LHb neurons are also activated in response to the aversive stimuli under the chronic stress.
P2-2-230 うつ病患者における血清DHEAとDHEA-sの健常者との比較 Serum dehydroepiandrosterone (DHEA) and DHEA-sulfate (S) levels inmedicated patients with major depressive disorder compared with controls ○島野嵩久¹, 前嶋仁¹, 手塚直人¹, 馬場元¹, 鈴木利人¹, 新井平伊¹ ○Takahisa Shimano¹, Hitoshi Maeshima¹, Naoto Tezuka¹, Hajime Baba¹, Toshihito Suzuki¹, Heii Arai¹ 順天堂大学　精神医学教室¹ Dept Psychiatry,Univ of Juntendo, Tokyo¹ Background:Dehydroe-piandrosterone (DHEA) and its sulfate derivative (DHEA-S), play a critical role in controlling affect,mood, and anxiety. Changes in serum adrenal androgen levels have been reported in conditionspertaining to stress as well as in psychiatric disorders. The objective of the present study was to investigate differences in serum levels of adrenal androgens in male and female patients with major depressive disorder (MDD).Methods: Participants included 90 inpatients with MDD at Juntendo Koshigaya Hospital who were receiving antidepressants. Serum levels of DHEA and DHEA-S were assessed at the time of admission. Matched controls included 128 healthy individuals. First, data from male and female MDD patients and controls were compared. Second,correlations between serum hormone levels and scores on the HAM-D of patients with MDD were assessed by gender. In addition, effects of various factors on adrenal androgens were analyzed using multiple regression analysis(MRA).Results: Serum DHEA levels were increased in both male and female MDD patients compared with controls. Serum levels of DHEA-S in male patients were decreased compared with male controls, whereas no significant differences were seen in female patients and controls. No significant correlations among adrenal androgens were observed in male patients with MDD, whereas significant positive correlations were found in both male and female controls. No significant correlations were seen between adrenal androgens and HAM-D scores in male or female patients. MRA showed that both hormones were affected by the age at onset of depression.Conclusions: Elevated levels of serum DHEA may be associated with the biological pathophysiology ofdepression, as DHEA administration has been found to be effective for the treatment.Findings of differential changes in DHEA-S levels in men compared with women may suggest distinct characteristics of these hormones between men and women with depression.

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