Analyses of roles of nutritional factors in brain function using mouse genetics and application for the treatment of brain disease

利用小鼠遗传学分析营养因素对脑功能的作用及其在脑疾病治疗中的应用

• 批准号: 18580129
• 负责人: KIDA Satoshi
• 金额: $ 2.51万
• 依托单位: Tokyo University of Agriculture
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18580129/
• 关键词: Retinoic Acid; Retinoic Acid Receptor; Brain Function; Mouse Genetics; Learning and Memory; Trwtophan; Emotional behavior; Hippocampus; 転写調節

To understand roles of nutritional factors in brain function and develop the treatment for brain diseases, we have investigated roles of Vitamin A (Retinoic Acid) and essential amino acid tryptophan (TRP) in brain function.(1) Generation and Analyses of Transgenic mice that enable to regulate expression of wild type or dominant negative Retinoic Acid Receptor (RAR) in forebrain.Retinoic acid receptors (RARs) ubiquitously and highly express in brain. Previous studies have shown that RA-deficient mice and RARs knock out mice exhibit impairments of both hippocampal LTP and spatial memory, suggesting an essential role of RARs in learning and memory. To further clarify the roles of RARs in learning and memory, we generated conditional mutant mice that enable to regulate forebrain-specific overexpression of RAR-alpha or dominant negative mutant (dn) of RAR-alpha using tetracycline system. Biochemical analyses showed that overexpression of RAR-alpha leads to an increase in expression of RARs- … More target gene in forebrain, suggesting the activation of retinoid signaling pathway in these mutant mice. Importantly, behavioral analyses revealed that RAR-alpha overexpression mice show enhancement of formation of spatial, social recognition and contextual fear memories. Taken together with previous findings, we suggest that RAR-alpha functions as a positive regulator for learning and memory.(2) Roles of TRP in brain function and the application of TRP on the treatment for anxiety-related behavior.The depletion of systemic TRP is an important tool to study the effects of reduced 5-HT on cognition. We first examined the effects of chronic consumption of a low TRP diet on memory formation in mice. TRP-limited mice showed impaired formation of contextual fear memory that is hippocampus-dependent. In contrast, these mice showed normal hippocampus-dependent spatial memory, as well as in cued fear and conditioned taste aversion memories, which are amygdala-dependent memory processes. Thus, dietary TRP restriction appears to result in selective impairments in hippocampus-dependent contextual fear memory formation in mice.We have shown that limitation of TRP-intake also affect emotional behaviors in mice. To develop the treatment of anxiety-related behavior, we next examined effects of TRP-limitation on anxiety related behavior observed in transgenic mice overexpressing alplaCaMKII in forebrain. TRP-limitation leads to the improvement of anxiety-related behavior in CaMKII transgenic mice, raising the possibility that TRP-limitation is applicable for the treatment of anxiety-related disease. Less

为了了解营养因素在脑功能中的作用并开发脑疾病的治疗方法，我们研究了维生素A（视黄酸）和必需氨基酸色氨酸（TRP）在脑功能中的作用。(1)能够调节野生型或显性负性视黄酸受体（RAR）在前脑中表达的转基因小鼠的产生和分析视黄酸受体（RAR）在脑中广泛且高度表达。先前的研究表明，RA缺陷小鼠和RAR基因敲除小鼠表现出海马LTP和空间记忆的损伤，表明RAR在学习和记忆中的重要作用。为了进一步阐明RAR在学习和记忆中的作用，我们使用四环素系统产生了能够调节前脑特异性RAR-α过表达的条件突变小鼠或RAR-α的显性负突变体（dn）。生化分析表明，RAR-α的过度表达导致RAR-α表达的增加。 ...更多信息 在前脑中的靶基因，表明在这些突变小鼠中类维生素A信号通路的激活。重要的是，行为分析显示，RAR-α过表达小鼠显示出空间，社会识别和背景恐惧记忆的形成增强。结合以前的研究结果，我们认为RAR-α是学习和记忆的正调节因子。(2)TRP在脑功能中的作用及其在焦虑相关行为治疗中的应用全身TRP耗竭是研究5-HT减少对认知功能影响的重要工具。我们首先研究了长期食用低TRP饮食对小鼠记忆形成的影响。TRP限制的小鼠表现出海马依赖性背景恐惧记忆的形成受损。相反，这些小鼠表现出正常的视丘依赖性空间记忆，以及暗示恐惧和条件性味觉厌恶记忆，这是杏仁核依赖性记忆过程。因此，饮食TRP限制似乎会导致小鼠大脑皮层依赖的背景恐惧记忆形成的选择性障碍。我们已经证明，限制TRP摄入量也会影响小鼠的情绪行为。为了开发焦虑相关行为的治疗，我们接下来检查了TRP限制对在前脑中过表达alplaCaMKII的转基因小鼠中观察到的焦虑相关行为的影响。TRP限制导致CaMKII转基因小鼠中焦虑相关行为的改善，提高了TRP限制适用于治疗焦虑相关疾病的可能性。少

项目成果

Chronic reduction in dietary tryptophan leads to a selective impairment of contextual fear memory in mice

• DOI: 10.1016/j.brainres.2007.02.049
• 发表时间: 2007-05
• 期刊: Brain Research
• 影响因子: 2.9
• 作者: S. Uchida;Hisahiro Umeeda;A. Kitamoto;S. Masushige;S. Kida

Characterization of the Promoter of the Mouse Preproorexin Gene

小鼠前食欲蛋白原基因启动子的表征

• 发表时间: 2007
• 期刊: Biosci.Biotechnol.Biochem 71
• 作者: Kato;H;Hosoda;H.;Fukuda;T;Masushige;S;Kida;S.
• 通讯作者: S.

Tight regulation of transgene expression by tetracycline-dependent activatol and repressor in brain

大脑中四环素依赖性激活剂和阻遏物对转基因表达的严格调节

• 发表时间: 2006
• 期刊: Genes Brain Behay 5
• 作者: Uchida;S.;Sakai;S.;Furuichi;T.;Hosoda;H.;Toyota;K.;Ishii;T.;Kitamoto;A.;Sekine;M.;Koike;K.;Masushige;S.;Murphy;G.;Silva;A.J.;Kida;S
• 通讯作者: S

Mechanisms of Memory Formation by Transcription Factors

转录因子形成记忆的机制

• 发表时间: 2007
• 作者: 長谷川俊介;細田浩司;本間清一;喜田聡;喜田 聡
• 通讯作者: 喜田 聡

CaMKIV過剰発現による加齢に伴う記憶能力減衰の抑制

CaMKIV 过表达抑制与年龄相关的记忆能力下降

• 发表时间: 2007
• 作者: 坂東 真一;福島 穂高;鈴木 章円;前田 良太;鈴木 良祐;遠藤 健吾;喜田 聡
• 通讯作者: 喜田 聡