1 Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812.
2 Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA 30310.
3 Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC H4B 1R6, Canada.
4 Department of Mathematics and Statistics, Amherst College, Amherst, MA 01002.
5 Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC H4B 1R6, Canada; shimon.amir@concordia.ca nahum.sonenberg@mcgill.ca rcao@umn.edu.
6 Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; shimon.amir@concordia.ca nahum.sonenberg@mcgill.ca rcao@umn.edu.
7 Goodman Cancer Research Center, McGill University, Montreal, QC H3A 1A3, Canada.
8 Howard Hughes Medical Institute, McGill University, Montreal, QC H3A 1A3, Canada.
9 Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812; shimon.amir@concordia.ca nahum.sonenberg@mcgill.ca rcao@umn.edu.
10 Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455.

Mammalian/mechanistic target of rapamycin (mTOR) signaling controls cell growth, proliferation, and metabolism in dividing cells. Less is known regarding its function in postmitotic neurons in the adult brain. Here we created a conditional mTOR knockout mouse model to address this question. Using the Cre-LoxP system, the mTOR gene was specifically knocked out in cells expressing Vip (vasoactive intestinal peptide), which represent a major population of interneurons widely distributed in the neocortex, suprachiasmatic nucleus (SCN), olfactory bulb (OB), and other brain regions. Using a combination of biochemical, behavioral, and imaging approaches, we found that mice lacking mTOR in VIP neurons displayed erratic circadian behavior and weakened synchronization among cells in the SCN, the master circadian pacemaker in mammals. Furthermore, we have discovered a critical role for mTOR signaling in mediating olfaction. Odor stimulated mTOR activation in the OB, anterior olfactory nucleus, as well as piriform cortex. Odor-evoked c-Fos responses along the olfactory pathway were abolished in mice lacking mTOR in VIP neurons, which is consistent with reduced olfactory sensitivity in these animals. Together, these results demonstrate that mTOR is a key regulator of SCN circadian clock synchrony and olfaction.