| Budget Amount *help |
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2004: ¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 2003: ¥7,300,000 (Direct Cost: ¥7,300,000)
|
|---|
| Research Abstract |
Vitamin A has been implicated in a wide range of biological functions, such as reproduction, growth, differentiation, and vision. The all-trans- and 9-cis-isomers of retinoic acid(RA), the biologically active forms of vitamin A, are metabolized from retinol through dehydrogenization. These two RAs bind to specific nuclear receptors, RAR and RXR respectively. These complexes function as ligand-dependent transcription factors and regulate the transcription of target genes through binding to the retinoic acid responsive element(RARE). Although all members of retinoic acid receptors widely express in brain, roles of retinoids in brain function remains unknown.
To understand roles of retinoids in brain function, we examined effects of systemic injections of agonists for RAR on emottional behavior in mice. The administration of agonists for retinoic acid receptors (all-trans retinoic acid,9-cis retinoic acid, Am80 ; synthetic ligands) into mice leads to increase in anxiety in open field test
… More
and elevated zero maze test, and abnormal social behavior in social interaction and social dominance tube test. These pharmacological studies suggested that RARs regulate emotional behavior such as anxiety and social behaviors.
To further clarify the roles of RARs in emotional behaviors, we have generated transgenic mice expressing RAR-alpha or dominant negative RAR in forebrain using tetracycline(tTA) systems. We observed up-regulation of target gene expression of RARs in forebrain of transgenic mice showing tTA-induced overexpression of RAR-alpha, indicating that RAR signaling cascade is activated in forebrain of these transgenic mice. These mice showed an increase in anxiety behavior in open field, elevated zero maze and light-dark transition tests. Interestingly, these mice also showed decrease in serotonin transporter(SERT) mRNA level. To understand mechanisms of regulation of SERT expression by retinoic acid, we investigated roles of retinoic acid in promoter activity of SERT gene using Hela cells, which express RARs and RXRs. We found RA-responsive negative elements in SERT promoter region. These results strongly suggest that activation of RAR signaling leads to an increase in anxiety through down-regulation of SERT expression. Less
|
