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

了解营养因子在脑功能中的作用以及营养因子对脑功能的调控机制，对发展脑疾病的治疗具有重要意义。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。视黄酸受体（Retinoic acid receptor, RARs）在大脑中普遍存在并高度表达。先前的研究表明，ra缺陷小鼠和RARs敲除小鼠均表现出海马LTP和空间记忆的损伤，提示RARs在学习和记忆中发挥重要作用。为了阐明RARs在学习和记忆中的作用，我们利用四环素系统生成了条件突变小鼠，这些小鼠能够调节rar - α的前脑特异性过表达或rar - α的显性负突变（dn）。我们发现，dnRAR小鼠在海马和海马依赖记忆形式中表现出AMPA受体介导的兴奋性突触后电位和LTP的损伤，更多的是dnRAR表达依赖的方式。这些观察结果表明，RARs在海马体依赖性学习/记忆和海马体LTP中起重要作用。有趣的是，我们还发现dnRAR小鼠海马中PSD-95和AMPA受体亚基GluR1下调，而NMDA受体亚基NR1不下调，并以dnRAR表达依赖的方式表达。因此，我们认为PSD-95和GluR1的下调导致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，重新激活的长期记忆是失稳的，然后通过基因表达依赖性的再巩固过程重新稳定。然而，对检索记忆不稳定的分子机制知之甚少。因此，我们使用Morris水迷宫和情境恐惧条件反射测试来研究大麻素受体CB1在重新激活的空间记忆和恐惧记忆的不稳定性中的作用。在记忆检索后立即将CB1受体拮抗剂（SR141716A）与大霉素一起注入海马，可以防止蛋白质合成抑制对重新激活的记忆的破坏。这些结果表明，重新激活的记忆是通过激活海马CB1受体而不稳定的。从这些研究中，我们认为维生素A和内源性大麻素对维持和改善大脑功能（如学习和记忆）很重要。我们现在正在研究这些脂溶性因素对脑部疾病的影响，使用的是创伤后应激障碍、记忆缺陷和焦虑等脑部疾病的小鼠模型。少

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