Understanding the mechanisms of regulation of brain function by fat-soluble nutrient factors and application of these mechanisms for the improvement of brain function and treatment for brain diseases

了解脂溶性营养因子调节脑功能的机制，并应用这些机制改善脑功能和治疗脑疾病

• 批准号: 20380078
• 负责人: KIDA Satoshi
• 金额: $ 5.24万
• 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 (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20380078/
• 关键词: 学習・記憶; ビタミンA; 不飽和脂肪酸; トランスジェニックマウス; 脳機能障害; レチノイン酸; 情動行動; 長期増強(LTP); カナビノイド; 恐怖記憶; 記憶不安定化; トランスジュニックマウス; 認知症; トレーニング

Understanding roles of nutrient factors in brain function and mechanisms of the regulation of brain function by nutrient factors is important to develop the treatment for brain diseases. To do this, we have investigated roles of fat soluble-nutrient factors (Vitamin A (Retinoic Acid) and cannabinoids) in brain function.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 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. We showed that dnRAR mice display impairments of AMPA receptor-mediated excitatory postsynaptic potentials and LTP in the hippocampus and hippocampus-dependent memory forma … More tion in a dnRAR expression-dependent manner. These observations suggest that RARs play important roles in hippocampus-dependent learning/memory and hippocampal LTP. Interestingly, we also found that dnRAR mice display down-regulation of PSD-95 and AMPA receptor subunit GluR1, but not NMDA receptor subunit NR1, in the hippocampus in a dnRAR expression-dependent manner. Therefore, we suggest that down-regulations of PSD-95 and GluR1 lead to impairments of hippocampus-dependent learning/memory and hippocampal LTP in dnRAR mice.There is growing evidence that the reactivated long-term memory is de-stabilized and then re-stabilized through a gene expression dependent reconsolidation process. However, little is known about molecular mechanisms underlying destabilization of retrieved memory. Therefore, we examined roles of cannabinoid receptor CB1 in the destabilization of reactivated spatial and fear memory using Morris water maze and contextual fear conditioning tests. Infusion of an antagonist of CB1 receptor (SR141716A) together with anisomycin into hippocampus immediately after memory retrieval prevented the disruption of reactivated memory by protein synthesis inhibition. These results suggest that reactivated memory is destabilized through activation of hippocampal CB1 receptor.From these studies, we suggest that vitamin A and endogenous cannabinoid are important to maintain and improve brain functions such as learning and memory. We are now examining effects of these fat-soluble factors on brain diseases using mouse model of brain diseases such as PTSD, memory deficits and anxiety. Less

了解营养因子在脑功能中的作用以及营养因子对脑功能的调节机制，对开发脑疾病的治疗方法具有重要意义。为此，我们研究了脂溶性营养因子（维生素A（视黄酸）和大麻素）在脑功能中的作用。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）。我们发现，dnRAR小鼠表现出海马AMPA受体介导的兴奋性突触后电位和LTP的损伤，以及海马依赖性记忆形式。 ...更多信息 以dnRAR表达依赖的方式表达。这些观察结果表明，RAR在海马依赖性学习/记忆和海马LTP中发挥重要作用。有趣的是，我们还发现，dnRAR小鼠显示下调PSD-95和AMPA受体亚基GluR 1，但不是NMDA受体亚基NR 1，在海马中的dnRAR表达依赖的方式。因此，我们认为PSD-95和GluR 1的下调导致了dnRAR小鼠海马依赖性学习记忆和海马LTP的损伤，越来越多的证据表明，重新激活的长时记忆通过基因表达依赖性的再巩固过程去稳定，然后再稳定。然而，很少有人知道的分子机制不稳定的检索记忆。因此，我们研究大麻素受体CB 1的作用，在重新激活的空间和恐惧记忆的不稳定，使用Morris水迷宫和上下文恐惧条件反射测试。CB 1受体拮抗剂（SR 141716 A）与茴香霉素一起注入海马后立即记忆检索防止破坏蛋白质合成抑制再激活的记忆。这些结果表明，再激活的记忆是通过激活海马CB 1受体不稳定的。从这些研究中，我们认为，维生素A和内源性大麻素是重要的，以维持和改善大脑功能，如学习和记忆。我们现在正在研究这些脂溶性因子对大脑疾病的影响，使用大脑疾病的小鼠模型，如创伤后应激障碍，记忆缺陷和焦虑。少

项目成果

受動回避記憶再固定化・強化及び不安定化機構に対する前脳領域の役割の解析

前脑区域在被动回避记忆再巩固/强化和不稳定机制中的作用分析

• 发表时间: 2010
• 作者: 福島穂高;喜田聡
• 通讯作者: 喜田聡

転写因子CREBと神経栄養因子BDNFによる協調作用による記憶能力の向上

通过转录因子CREB和神经营养因子BDNF的协同作用提高记忆能力

• 发表时间: 2010
• 作者: 福島穂高;夢川琢也;鈴木章円;遠藤健吾;喜田聡
• 通讯作者: 喜田聡

Calcium/calmodulin-dependent kinase IV contributes to translation-dependent early synaptic potentiation in the anterior cingulate cortex of adult mice.

• DOI: 10.1186/1756-6606-3-27
• 发表时间: 2010-09-16
• 期刊: Molecular brain
• 影响因子: 3.6
• 作者: Toyoda H;Zhao MG;Mercaldo V;Chen T;Descalzi G;Kida S;Zhuo M
• 通讯作者: Zhuo M

レチノイン酸受容体情報伝達経路による海馬神経可塑性の制御

视黄酸受体信号通路调控海马神经可塑性

• 发表时间: 2010
• 作者: 野本真順;武田陽平;榎本初音;崔泰樹;内田周作;喜田聡
• 通讯作者: 喜田聡

Mechanisms for enhancement and reconsolidation of reactivated fear memory in passive avoidance task

被动回避任务中重新激活的恐惧记忆的增强和重新巩固机制

• 发表时间: 2009
• 作者: Fukushima H;Kida S
• 通讯作者: Kida S