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

点击翻译按钮获取中文摘要

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