PMID- 21382453 OWN - NLM STAT- MEDLINE DCOM- 20120316 LR - 20211203 IS - 1873-7544 (Electronic) IS - 0306-4522 (Print) IS - 0306-4522 (Linking) VI - 181 DP - 2011 May 5 TI - Circadian regulation of mammalian target of rapamycin signaling in the mouse suprachiasmatic nucleus. PG - 79-88 LID - 10.1016/j.neuroscience.2011.03.005 [doi] AB - Circadian (24-h) rhythms influence virtually every aspect of mammalian physiology. The main rhythm generation center is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and work over the past several years has revealed that rhythmic gene transcription and post-translational processes are central to clock timing. In addition, rhythmic translation control has also been implicated in clock timing; however the precise cell signaling pathways that drive this process are not well known. Here we report that a key translation activation cascade, the mammalian target of rapamycin (mTOR) pathway, is under control of the circadian clock in the SCN. Using phosphorylated S6 ribosomal protein (pS6) as a marker of mTOR activity, we show that the mTOR cascade exhibits maximal activity during the subjective day, and minimal activity during the late subjective night. Importantly, expression of S6 was not altered as a function of circadian time. Rhythmic S6 phosphorylation was detected throughout the dorsoventral axis of the SCN, thus suggesting that rhythmic mTOR activity was not restricted to a subset of SCN neurons. Rather, rhythmic pS6 expression appeared to parallel the expression pattern of the clock gene period1 (per1). Using a transgenic per1 reporter gene mouse strain, we found a statistically significant cellular level correlation between pS6 and per1 gene expression over the circadian cycle. Further, photic stimulation triggered a coordinate upregulation of per1 and mTOR activation in a subset of SCN cells. Interestingly, this cellular level correlation between mTOR activity and per1 expression appears to be specific, since a similar expression profile for pS6 and per2 or c-FOS was not detected. Finally, we show that mTOR activity is downstream of the ERK/MAPK signal transduction pathway. Together these data reveal that mTOR pathway activity is under the control of the SCN clock, and suggests that mTOR signaling may contribute to distinct aspects of the molecular clock timing process. CI - Copyright (c) 2011 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Cao, R AU - Cao R AD - Department of Neuroscience, Ohio State University, Columbus, OH 43210, USA. FAU - Anderson, F E AU - Anderson FE FAU - Jung, Y-J AU - Jung YJ FAU - Dziema, H AU - Dziema H FAU - Obrietan, K AU - Obrietan K LA - eng GR - R01 MH062335-05/MH/NIMH NIH HHS/United States GR - 5P30NS045758/NS/NINDS NIH HHS/United States GR - MH62335/MH/NIMH NIH HHS/United States GR - R01 NS066345/NS/NINDS NIH HHS/United States GR - R01 NS066345-02/NS/NINDS NIH HHS/United States GR - R01 MH062335/MH/NIMH NIH HHS/United States GR - R01 NS067409/NS/NINDS NIH HHS/United States GR - NS067409/NS/NINDS NIH HHS/United States GR - NS066345/NS/NINDS NIH HHS/United States GR - P30 NS045758/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20110305 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Biological Clocks/*physiology MH - Circadian Rhythm/*physiology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Signal Transduction/*physiology MH - Suprachiasmatic Nucleus/cytology/*metabolism MH - TOR Serine-Threonine Kinases/*physiology PMC - PMC3102430 MID - NIHMS284727 EDAT- 2011/03/09 06:00 MHDA- 2012/03/17 06:00 PMCR- 2012/05/05 CRDT- 2011/03/09 06:00 PHST- 2010/10/20 00:00 [received] PHST- 2011/02/27 00:00 [revised] PHST- 2011/03/01 00:00 [accepted] PHST- 2011/03/09 06:00 [entrez] PHST- 2011/03/09 06:00 [pubmed] PHST- 2012/03/17 06:00 [medline] PHST- 2012/05/05 00:00 [pmc-release] AID - S0306-4522(11)00236-3 [pii] AID - 10.1016/j.neuroscience.2011.03.005 [doi] PST - ppublish SO - Neuroscience. 2011 May 5;181:79-88. doi: 10.1016/j.neuroscience.2011.03.005. Epub 2011 Mar 5.