mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction

Dong Liu, Adam Stowie, Nuria de Zavalia, Tanya Leise, Salil Saurav Pathak, Lester R Drewes, Alec J. Davidson, Shimon Amir, Nahum Sonenberg, Ruifeng Cao

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E3296-E3304
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number14
DOIs
StatePublished - Apr 3 2018

Fingerprint

Circadian Clocks
Smell
Sirolimus
Neurons
Suprachiasmatic Nucleus
Olfactory Bulb
Olfactory Pathways
Vasoactive Intestinal Peptide
Neocortex
Brain
Interneurons
Knockout Mice
Mammals
Cell Proliferation
Growth

Keywords

  • Circadian clock
  • MTOR
  • Olfaction
  • SCN
  • VIP

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction. / Liu, Dong; Stowie, Adam; de Zavalia, Nuria; Leise, Tanya; Pathak, Salil Saurav; Drewes, Lester R; Davidson, Alec J.; Amir, Shimon; Sonenberg, Nahum; Cao, Ruifeng.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 14, 03.04.2018, p. E3296-E3304.

Research output: Contribution to journalArticle

Liu, Dong ; Stowie, Adam ; de Zavalia, Nuria ; Leise, Tanya ; Pathak, Salil Saurav ; Drewes, Lester R ; Davidson, Alec J. ; Amir, Shimon ; Sonenberg, Nahum ; Cao, Ruifeng. / mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 14. pp. E3296-E3304.
@article{25f33738c4904fbca2faf4ef42e0f9cc,
title = "mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction",
abstract = "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.",
keywords = "Circadian clock, MTOR, Olfaction, SCN, VIP",
author = "Dong Liu and Adam Stowie and {de Zavalia}, Nuria and Tanya Leise and Pathak, {Salil Saurav} and Drewes, {Lester R} and Davidson, {Alec J.} and Shimon Amir and Nahum Sonenberg and Ruifeng Cao",
year = "2018",
month = "4",
day = "3",
doi = "10.1073/pnas.1721578115",
language = "English (US)",
volume = "115",
pages = "E3296--E3304",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "14",

}

TY - JOUR

T1 - mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction

AU - Liu, Dong

AU - Stowie, Adam

AU - de Zavalia, Nuria

AU - Leise, Tanya

AU - Pathak, Salil Saurav

AU - Drewes, Lester R

AU - Davidson, Alec J.

AU - Amir, Shimon

AU - Sonenberg, Nahum

AU - Cao, Ruifeng

PY - 2018/4/3

Y1 - 2018/4/3

N2 - 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.

AB - 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.

KW - Circadian clock

KW - MTOR

KW - Olfaction

KW - SCN

KW - VIP

UR - http://www.scopus.com/inward/record.url?scp=85044855428&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044855428&partnerID=8YFLogxK

U2 - 10.1073/pnas.1721578115

DO - 10.1073/pnas.1721578115

M3 - Article

VL - 115

SP - E3296-E3304

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 14

ER -