気分障害 Mood Disorders
O3-7-5-1 変異Polg1トランスジェニックマウスが示す数週間にわたる行動変化は、大うつ病エピソードの診断基準を満たす Episodic behavioral change in mutant Polg1 transgenic mice meets clinical diagnostic criteria for major depressive episode ○笠原和起1, 亀谷瑞枝1, 石渡みずほ1, 磯野蕗子1, 加藤忠史1 ○Takaoki Kasahara1, Mizue Kametani1, Mizuho Ishiwata1, Fukiko Ishono1, Tadafumi Kato1 理研・脳センター1 RIKEN Brain Science Institute, Wako-shi1 Mood disorders are mental illnesses characterized by episodic mood changes. In clinical settings, mood episodes, major depressive and manic episodes, are diagnosed primarily based on operationally-defined criteria according to Diagnostic and Statistical Manual of Mental Disorder (DSM)-IV-TR. The DSM criteria, however, have not been used to assess mood disorder model animals. Indeed, some of the criteria cannot be applied to non-human animals (e.g. depressed mood), and in addition, episodic behavioral change has been unwatched in models. We generated mutant Polg1 transgenic (Tg) mice modeling a Mendelian inheritance mitochondrial disease, which was frequently associated with mood disorders, and reported that the mutant mice showed mood disorder-like phenotype (Kasahara et al., Mol. Psychiatry 2006). However, the DSM criteria were not used, nor were the phenotypes episodic ones. Now we think that the phenotypes were observed just in a euthymic state (a normal, non-depressed, non-manic mood condition) in comparing the mutant mice with controls. In this study, we discovered episodic behavioral change in mutant Polg1 Tg mice and assessed the episode using the DSM criteria. We measured wheel-running activity for over half a year and found that about two thirds of female Tg mice had episodes of prolonged hypoactivity approximately once per half year, which lasted 2-3 weeks and recovered spontaneously. Next, we recorded wheel-running activity and simultaneously measured body weight and EEG for long periods or performed behavioral tests when the mutant mice lapsed into the episode. As a result, Tg mice during the hypoactivity episode met at least five of the nine DSM criteria for major depressive episode; the mutant mice were to be diagnosed with "Major depressive disorder, recurrent". Mutant Polg1 Tg mice are, as far as we know, the first model experiencing DSM depressive episodes.	O3-7-5-2 前頭前野への反復性経頭蓋磁気刺激法による脳の構造および機能的変化ー抗うつ効果との関連性 Structural and functional brain alterations induced by prefrontal repetitive transcranial magnetic stimulation possibly associated with its antidepressant effect ○中村元昭1,2,3, 野田賀大1, 佐伯隆史1,2, 早坂俊亮1,2, 伊津野拓司1,3, 岩成秀夫1, 平安良雄2 ○Motoaki Nakamura1,2,3, Yoshihiro Noda1, Takashi Saeki1,2, Shunsuke Hayasaka1,2, Takuji Izuno1,3, Hideo Iwanari1, Yoshio Hirayasu2 神奈川県立精神医療センター芹香病院1, 横浜市立大学大学院医学研究科　精神医学部門2, 昭和大学医学部　精神医学教室3 Kinkou Hospital, Kanagawa Psychiatric Center, Yokohama1, Department of Psychiatry, Yokohama City University School of Medicine, Yokohama2, Department of Psychiatry, Showa University School of Medicine, Tokyo3 Structural and electrophysiological brain alterations induced by repetitive transcranial magnetic stimulation (rTMS) on dorsolateral prefrontal cortex (DLPFC) were longitudinally investigated in major depression, using MRI, diffusion tensor imaging (DTI), and quantitative EEG (qEEG) at wake and sleep states.Patients with medication-resistant major depression underwent 10 daily rTMS sessions over two weeks. Stimulation frequency was 20Hz and intensity was 90-110% resting motor threshold. Efficacy was evaluated with the Hamilton Depression Rating Scale 17-item (Ham-D17).Voxel-based morphometry (VBM) (n=38) revealed that rTMS on left DLPFC could increase gray matter volume in left DLPFC (t=5.53, PFWE=0.034). Responders (n=27) showed gray matter volume increase in left DLPFC (t=6.73, PFWE=0.002) compared to non-responders (n=11). Voxel-based analyses of DTI (n=21) revealed that rTMS could decrease gray matter mean diffusivity in bilateral DLPFC (left: t=8.21, PFWE=0.002, right: t=7.37, PFWE=0.009) and increase fractional anisotropy (FA) in left DLPFC subcortical white matter region (t=4.68, uncorrected P<0.0001). qEEG (n=25) showed longitudinal enhancement of spectral power of theta band oscillations at Fz (t=2.20, P=0.038) over 10 rTMS sessions. All night sleep EEG recordings (n=12) showed localized enhancement of slow wave activity (SWA) at F3 (t= 2.76, P=0.018) over initial 5 rTMS sessions.Following 10 rTMS sessions over two weeks, gray matter showed increased volume with decreased mean diffusivity longitudinally, and white matter showed increased FA around the stimulation site. The present findings suggest that rTMS could increase neuropil contents in the stimulation site as well as associated para-limbic region, possibly relating to its antidepressant effect. Prefrontal theta power increase at resting state and localized SWA enhancement could suggest rTMS-induced enhancement of functional neuroplasticity.
O3-7-5-3 DISC1のTDP43との共凝集による機能低下と精神障害 Loss of function of DISC1, a risk factor for psychiatric diseases, by co-aggregation with TDP43 in frontotemporal lobar degeneration ○遠藤良1, 小見悠介1, 猫沖陽子1, 村山繁雄2, 澤明3, 田中元雅1 ○Ryo Endo1, Yusuke Komi1, Yoko Nekooki1, Shigeo Murayama2, Akira Sawa3, Motomasa Tanaka1 理研BSI1, 東京都老人総合研究所2, ジョンズホプキンス大学3 RIKEN Brain Science Institute, Saitama, Japan1, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan2, Johns Hopkins University, Baltimore, USA3 Frontotemporal lobar degeneration (FTLD) is one of the neurodegenerative disorders associated with atrophy in the frontal lobe and temporal lobe of the brain. TAR DNA-binding protein 43 (TDP43) is a RNA binding protein which is a major constituent of the ubiquitin-positive proteioneous inclusions observed in FTLD patients. In addition to the neuronal degeneration, FTLD patients show some psychiatric symptoms. Indeed, patients with FTLD in early stages are often misdiagnosed as schizophrenia, which is a major mental illness with cortical pathology, especially frontal and temporal cortices. Thus, we hypothesized that these two diseases may share some common pathological mechanisms leading to neuronal dysfunctions and neural circuit deficits. Further, we proposed that co-aggregation (cross-seeding) of TDP43 and risk factors for psychiatric diseases may lead to loss of function of these factors, which may elicit neuronal dysfunctions, leading to mental disorders. Based on these hypotheses, we have studied whether aggregation of TDP43 in FTLD may play pathological roles in mental disorders, including the investigation on protein interactions with risk factors for mental illnesses. Here we demonstrated that Disrupted in schizophrenia 1 (DISC1), which is initially identified as a genetic risk factor for major mental illnesses such as depression, formed co-aggregates with TDP43 in neurons. Moreover, we show that DISC1 is one of the RNA binding proteins and involved in RNA granule stability and mRNA trafficking, and thereby regulates local translation in neurites. The co-aggregation of TDP43 and DISC1 induced the defects of local translation, indicating that this interaction may play critical roles in the mental disorders in FTLD. This study will not only reveal the molecular basis common to mental disorders and neurodegenerative diseases but also shed a new light for a therapeutic strategy for both FTLD and psychiatric diseases.	O3-7-5-4 白質障害に関連するストレス脆弱性について―ラット白質障害モデルにおける検討― Analysis of stress vulnerability related to selective white matter injury using rat model ○小野秀明1, 今井英明1, 宮脇哲1, 宮田茂雄2, 倉知正3, 石崎泰樹3, 中冨浩文1, 三國雅彦2, 斉藤延人1 ○Hideaki Ono1, Hideaki Imai1, Satoru Miyawaki1, Shigeo Miyata2, Tadashi Kurachi3, Yasuki Ishizaki3, Hirofumi Nakatomi1, Masahiko Mikuni2, Nobuhito Saito1 東京大学大学院　医学系研究科　脳神経外科学1, 群馬大学大学院　医学系研究科　神経精神医学2, 群馬大学大学院　医学系研究科　分子細胞生物学3 Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo1, Department of Psychiatry and Neuroscience, Gunma University2, Department of Molecular and Cellular Neurobiology, Gunma University3 [Background]In the 21st century, late onset depression (LOD) gets familiar with growing elderly population. The occurrence of white matter hyperintensities on T2-weighted magnetic resonance images is more frequent in patients with LOD, compared with early-onset depression. This fact indicates that white matter injuries (WMI) may provoke some stress vulnerability leading to depression. In this study, we have developed a selective WMI rat model with restraint stress (RS) to evaluate stress vulnerability related to WMI.[Method]Sprague-Dawley rats (302-380g, n=62) were used. Selective WMI was induced under general anesthesia with bilateral endothelin-1 injection. Animals were randomly assigned to 4 groups: WMI with RS (group 1); sham operation with RS (group2); WMI no RS (group3); sham operation, no RS (group 4). Two weeks after surgery, group 1 and 2 animals received 2 hours of RS a day, for 13 days. Body weight (BW) was recorded daily and animals underwent a forced swimming test (FST) on the day following the 13th RS day. Animals were euthanized after the FST, and brain sections analyzed. [Result]RS significantly suppressed weight gain in groups 1 and 2 compared with non RS groups. Moreover the change in BW over time in group 1 was significantly different from group 2. The immobility time on the FST for group 1 was longer than that of other groups. Conventional histopathology revealed the selective damage of the internal capsule. The study using the retrograde tracer Fluoro-gold suggested the connectivity of WMI with rostral frontal and caudate nucleus.[Discussion]Accompanied with WMI, repeated RS induced a reduction in weight gain and prolongation of immobility time in FST. These results provide preliminary evidence that WMI could influence stress vulnerability. Although further investigation is needed, this study provides the hypothesis that an adverse function of the frontal cortex caused by WMI may have the potential to contribute to the stress vulnerability.

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