Electrophysiological Signatures of Stress Adaptability in the BNST-VTA Pathway

Chronic stress has detrimental effects on psychological and physiological health. Incapability to adapt to chronic stress can lead to depression, anxiety disorders, and addiction. The brain regions critical for reward processing share diverse physiological and molecular changes linked to depressive-like behaviors as a result of chronic stress. Cumulative evidence shows that counteraction or prevention of these alterations in neurons, occasionally in a projection-specific manner, can enhance stress adaptation or resilience. Chronic stress induces various changes in the brain, including in the bed nucleus of the stria terminalis (BNST) and the ventral tegmental area (VTA). The neural projections from the BNST to the VTA have been shown to be vital for regulating behaviors linked to stress-reward interactions. Specifically, the intrinsic membrane properties of these neurons are important as they set the threshold for action potentials. Based on electrophysiological features, the BNST has diverse neuronal types: Type I, Type II, and Type III, each potentially possessing distinct sensitivity and responses to chronic stress. These properties shape the neurons\u27 firing patterns, which govern signal transduction and ultimately affect behavioral outcomes, including stress susceptibility or stress resilience. The diversity and plasticity within this pathway offer an intriguing opportunity for exploring the mechanisms that underpin resilience. In this dissertation, I offer evidence that chronic stress differently affects the electrophysiological properties of the VTA-projecting BNST neurons, and the changes are related to stress susceptibility and resilience. First, I establish a comprehensive characterization of electrophysiologically diverse VTA-projecting BNST neurons in mice by utilizing retrograde viral-mediated neuronal labeling combined with whole-cell patch-clamp recording. This set of experiments discovered previously unseen Type III neurons in mice. Further, I show that quantified electrophysiological parameters can be used to classify BNST neurons in an unsupervised way. Next, I demonstrate the unique sensitivity of Type III neurons to chronic stress. The excitability of Type III neurons is altered as a result of chronic stress, and this physiological change is correlated with stress-related behaviors. Given dense GABAergic projections from the BNST to VTA, the higher excitability of Type III neurons may contribute to the hyperactivity of VTA dopaminergic neurons, a signature of susceptibility, through disinhibition

超音波検査の結果に基づいた摂食嚥下ケアの推奨による誤嚥性肺炎予防のための介入研究

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 高戸 毅, 東京大学教授 秋下 雅弘, 東京大学准教授 春名 めぐみ, 東京大学准教授 深柄 和彦, 東京大学講師 高井 ゆかりUniversity of Tokyo(東京大学

Differential responses of normal human coronary artery endothelial cells against multiple cytokines comparatively assessed by gene expression profiles

AbstractEndothelial cells play an important role in terms of biological functions by responding to a variety of stimuli in the blood. However, little is known about the molecular mechanism involved in rendering the variety in the cellular response. To investigate the variety of the cellular responses against exogenous stimuli at the gene expression level, we attempted to describe the cellular responses with comprehensive gene expression profiles, dissect them into multiple response patterns, and characterize the response patterns according to the information accumulated so far on the genes included in the patterns. We comparatively analyzed in parallel the gene expression profiles obtained with DNA microarrays from normal human coronary artery endothelial cells (HCAECs) stimulated with multiple cytokines, interleukin-1β, tumor necrosis factor-α, interferon-β, interferon-γ, and oncostatin M, which are profoundly involved in various functional responses of endothelial cells. These analyses revealed that the cellular responses of HCAECs against these cytokines included at least 15 response patterns specific to a single cytokine or common to multiple cytokines. Moreover, we statistically extracted genes contained within the individual response patterns and characterized the response patterns with the genes referring to the previously accumulated findings including the biological process defined by the Gene Ontology Consortium (GO). Out of the 15 response patterns in which at least one gene was successfully extracted through the statistical approach, 11 response patterns were differentially characterized by representing the number of genes contained in individual criteria of the biological process in the GO only. The approach to dissect cellular responses into response patterns and to characterize the pattern at the gene expression level may contribute to the gaining of insight for untangling the diversity of cellular functions

足底への荷重と頸部への振動刺激が立位時の重心動揺に及ぼす影響―busy-line effectの影響―

　The purpose of this study was to investigate the effects of changes in forefoot pressure on postural responses to vibrations of the neck muscles in healthy humans. Previous studies showed that balance instability in upright posture alters the role of proprioceptive information and the state of system balance. For example, it was reported that proprioceptive information resulting from vibrational stimulation is blocked during dynamic motor tasks. In this study, we hypothesized that proprioceptive information would be blocked during static movement tasks on receiving multiple sensory inputs, affecting postural responses. Subjects consisted of 15 healthy individuals, standing upright on a force platform for 30 seconds with their eyes closed. To change the pressure of the forefoot as cutaneous sensor information, the posture response without heel lift, with 7 cm heel lift, and with 14 cm heel lift to one side vibration stimulation or bilateral stimulation of the neck muscles given as proprioceptive information was compared with muscle stimulation. In this study, a root mean square value was calculated from the center of pressure as a measure of body sway, and a two-way repeated-measures ANOVA was performed. There was a significant interaction between the heel height and vibration stimulation, indicating that increasing the forefoot pressure on both sides of the muscle resulted in a decrease in the root mean square value. The results of this study suggest that increasing the forefoot pressure and location of vibration stimuli causes vibration-induced suppression of sensory information input and reduces body sway

Crustal structure and growth of the Forearc region of Izu-Ogasawara arc

（独）海洋研究開発機構(JAMSTEC)では、2002年から伊豆・小笠原・マリアナ島弧において、大陸地殻の生成過程を明らかにすることを目的に構造調査を進め、現在の島弧地殻のボリュームより多くの玄武岩マグマが必要で島弧地殻を生成する過程でマフィックな島弧地殻の一部をマントル内に戻していること（Takahashi et al., 2007, 2008; Tatsumi et al., 2008）、火山フロントと背弧側の地殻の厚さ分布には相関があり過去のリフティングが検出されたこと（Kodaira et al., 2009）などがわかってきた。前弧域の地殻に関しては、厚い地殻と薄い地殻が存在すること（Takahashi et al., 2011）、地磁気異常から島弧的な構造があること（Yamazaki and Yuasa, 1998）がわかっているが、地殻構造から実証されていなかった。前弧域の地殻構造を求め、地殻進化の影響をどの程度受けているのか、前弧域の島弧成長を明らかにするために、（独）海洋研究開発機構の深海調査船「かいれい」を用いて人工地震探査を行った。 地震探査の測線は、新黒瀬からスミス海脚、第二東鳥島海丘、大町海山を通って、小笠原トラフに至る。得られた速度構造から前弧域は25km程度の地殻の厚い部分と10～15km程度の薄い部分があることが明らかになった。厚い地殻は、北緯32.5度付近、スミス海脚、第二東鳥島海丘、大町海山の下に分布する。新黒瀬側は厚い地殻を持たない。大町海山の内部には異常に厚い下部地殻が分布する。薄い地殻が分布するところでは、堆積層が厚く地殻の厚さの半分近くを占める。大町海山以外の地殻が厚く分布するところでは、P波速度6km/sの速度コンターが上に凸、7km/sの速度コンターが下に凸の形状を示す。火山フロントに沿った地殻構造では、むしろ6km/s以下の速度を持つ層が厚いことが示されている（Kodaira et al., 2007）。これは、前弧域下の島弧地殻は、火山フロント下と比較して未分化な物質を多く含むことを示唆おり、過去の掘削結果とも整合する（e.g., Taylor, 1992）。前弧海盆下の島弧地殻の分布は、地磁気異常の空間分布（Yamazaki and Yuasa, 1998）とよく合致する。新黒瀬周辺で見られる地磁気異常は、本研究から明らかになった地殻が薄く地殻全体が盛り上がっている形状と合致する。伊豆小笠原島弧の本州弧への衝突が新黒瀬の浅海部を作っているものと示唆される。SCG66-03発表要旨 / 日本地球惑星科学連合2012年大会（2012年5月20日～5月25日, 幕張メッセ国際会議場） / 日本惑星科学連合の許諾に基づき本文ファイルを掲

Mitochondrial intermediate peptidase is a novel regulator of sirtuin-3 activation by caloric restriction

Sirtuin-3 (SIRT3) regulates mitochondrial quality and is involved in the anti-ageing and pro-longevity actions of caloric restriction (CR). Here, we show that CR upregulates the mature form of SIRT3 and mitochondrial intermediate peptidase (MIPEP), a mitochondrial signal peptidase (MtSPase), in white adipose tissue. We also demonstrate that upregulation of mature SIRT3 is dependent on MIPEP in 3T3-L1 cells, suggesting that MIPEP may contribute to the maintenance of mitochondrial quality during CRvia activation of SIRT3. This novel mechanism of SIRT3 activation through MIPEP facilitates the elucidation of additional molecular pathways of CR

A series of ENU-induced single-base substitutions in a long-range cis-element altering Sonic hedgehog expression in the developing mouse limb bud

AbstractMammal–fish-conserved-sequence 1 (MFCS1) is a highly conserved sequence that acts as a limb-specific cis-acting regulator of Sonic hedgehog (Shh) expression, residing 1 Mb away from the Shh coding sequence in mouse. Using gene-driven screening of an ENU-mutagenized mouse archive, we obtained mice with three new point mutations in MFCS1: M101116, M101117, and M101192. Phenotype analysis revealed that M101116 mice exhibit preaxial polydactyly and ectopic Shh expression at the anterior margin of the limb buds like a previously identified mutant, M100081. In contrast, M101117 and M101192 show no marked abnormalities in limb morphology. Furthermore, transgenic analysis revealed that the M101116 and M100081 sequences drive ectopic reporter gene expression at the anterior margin of the limb bud, in addition to the normal posterior expression. Such ectopic expression was not observed in the embryos carrying a reporter transgene driven by M101117. These results suggest that M101116 and M100081 affect the negative regulatory activity of MFCS1, which suppresses anterior Shh expression in developing limb buds. Thus, this study shows that gene-driven screening for ENU-induced mutations is an effective approach for exploring the function of conserved, noncoding sequences and potential cis-regulatory elements