演題番号 : P1-m15
長谷川 俊介 / Shunsuke Hasegawa:1,2 太田 美穂 / Miho Ohta:1 細田 浩司 / Hiroshi Hosoda:1 喜田 聡 / Satoshi Kida:1,2
1:東京農業大学 応用生物科学部 バイオサイエンス学科 / Dept. of Bioscience, Tokyo Univ. of Agriculture 2:CREST・科学技術振興機構 / CREST, JST
Basic-Helix-Loop-Helix-Per-Arnt-Sim (bHLH-PAS) transcription factor, Brain-Muscle-Arnt-Like-protein 1 (BMAL1) has been shown to play essential roles in circadian rhythm. BMAL1 functions by forming a heterodimer with either CLOCK or NPAS2 and regulates circadian transcriptional rhythm. Importantly, previous studies have shown that BMAL1 ubiquitously expresses in the brain and other peripheral tissues, thereby regulating circadian transcription cycles in not only SCN but also other cells including neurons in the forebrain. In this study, we have tried to understand roles of BMAL1 in the forebrain in learning and memory. To do this, we have derived conditional mutant mice that enable to induce the inhibition of BMAL1 function in the forebrain by regulating expression of a dominant negative mutant of BMAL1 (BMAL1 R91A) that forms a heterodimer with CLOCK but loses the binding activity with E-box (Hosoda et al, 2004). Biochemical analyses showed that these mutant mice exhibit decreased expression level of BMAL1 target genes including Cry1, Dbp, and Rora and disruptions of circadian expression cycle of these mRNAs in the forebrain, but exhibit normal expression level and circadian expression cycle of these mRNAs in the hypothalamus. These results indicated that inhibition of BMAL1 activity forebrain-specifically impaired circadian rhythm including positive and negative feedback loops at the molecular level. Interestingly, behavioral analyses using social recognition and contextual fear conditioning tasks showed that these mutant mice displayed normal memory retrieval at ZT4 when mice were trained at ZT4 or 10. In contrast, these mutant mice exhibited impairments of memory retrieval tested at ZT10 in a dnBMAL1 expression-dependent manner. These findings indicate that CLOCK/BMAL1 signaling pathway in the forebrain contributes to circadian regulation of memory retrieval.