Login | Register

mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction


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 ORCID: https://orcid.org/0000-0003-1919-5023, Sonenberg, Nahum and Cao, Ruifeng (2018) mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction. Proceedings of the National Academy of Sciences . pp. 1-9. ISSN 0027-8424

Text (published ahead of print) (application/pdf)
mTOR signaling in VIP neurons.pdf - Published Version
Available under License Spectrum Terms of Access.

Official URL: http://dx.doi.org/10.1073/pnas.1721578115


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.

Divisions:Concordia University > Research Units > Centre for Studies in Behavioural Neurobiology
Item Type:Article
Authors:Liu, Dong and Stowie, Adam and de Zavalia, Nuria and Leise, Tanya and Pathak, Salil Saurav and Drewes, Lester R. and Davidson, Alec J. and Amir, Shimon and Sonenberg, Nahum and Cao, Ruifeng
Journal or Publication:Proceedings of the National Academy of Sciences
Date:19 March 2018
  • Faculty Start-Up Grant from the University of Minnesota Medical School
  • Canadian Institutes of Health Research Grants MOP7214
  • MOP142458
  • NIH Grant SC1 GM112567
Digital Object Identifier (DOI):10.1073/pnas.1721578115
Keywords:mTOR VIP SCN circadian clock olfaction
ID Code:983594
Deposited By: MONIQUE LANE
Deposited On:21 Mar 2018 20:16
Last Modified:21 Mar 2018 22:48


1. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484.
2. Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168:960–976.
3. Ferrari S, Bandi HR, Hofsteenge J, Bussian BM, Thomas G (1991) Mitogen-activated 70K S6 kinase. Identification of in vitro 40 S ribosomal S6 phosphorylation sites. J Biol Chem 266:22770–22775.
4. Pende M, et al.(2004) S6K1(−/−)/S6K2(−/−) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 24:3112–3124.
5. Weng QP, et al.(1998) Regulation of the p70 S6 kinase by phosphorylation in vivo. Analysis using site-specific anti-phosphopeptide antibodies. J Biol Chem 273:16621–16629.
6. Lipton JO, Sahin M(2014) The neurology of mTOR. Neuron 84:275–291.
7. Murakami M, et al. (2004) mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 24:6710–6718.
8. Gangloff YG, et al. (2004) Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol 24:9508–9516.
9. Banko JL, Hou L, Poulin F, Sonenberg N, Klann E (2006) Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor-dependent long-term depression. J Neurosci 26:2167–2173.
10. Hoeffer CA, et al. (2008) Removal of FKBP12 enhances mTOR-Raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron 60:832–845.
11. Antion MD, Hou L, Wong H, Hoeffer CA, Klann E (2008) mGluR-dependent long-term depression is associated with increased phosphorylation of S6 and synthesis of elongation factor 1A but remains expressed in S6K-deficient mice. Mol Cell Biol 28:2996–3007.
12. Huang W, et al. (2013) mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat Neurosci 16:441–448.
13. Cota D, et al. (2006) Hypothalamic mTOR signaling regulates food intake. Science 312:927–930.
14. Seibt J, et al. (2012) Protein synthesis during sleep consolidates cortical plasticity in vivo. Curr Biol 22:676–682.
15. Tudor JC, et al. (2016) Sleep deprivation impairs memory by attenuating mTORC1-dependent protein synthesis. Sci Signal 9:ra41.
16. Santini E, Klann E (2014) Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders. Sci Signal 7:re10.
17. Cao R, Lee B, Cho HY, Saklayen S, Obrietan K (2008) Photic regulation of the mTOR signaling pathway in the suprachiasmatic circadian clock. Mol Cell Neurosci 38:312–324.
18. Cao R, Anderson FE, Jung YJ, Dziema H, Obrietan K (2011) Circadian regulation of mammalian target of rapamycin signaling in the mouse suprachiasmatic nucleus. Neuroscience 181:79–88.
19. Cao R, Li A, Cho HY, Lee B, Obrietan K (2010) Mammalian target of rapamycin signaling modulates photic entrainment of the suprachiasmatic circadian clock. J Neurosci 30:6302–6314.
20. Cao R, et al. (2013) Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling. Neuron 79:712–724.
21. Aton SJ, Herzog ED (2005) Come together, right...now: Synchronization of rhythms in a mammalian circadian clock. Neuron 48:531–534.
22. Tsien JZ, et al. (1996) Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87:1317–1326.
23. Taniguchi H, et al. (2011) A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71:995–1013, and erratum (2011) 72:1091.
24. Larsson O, et al. (2012) Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc Natl Acad Sci USA 109:8977–8982.
25. Daan S, Pittendrigh CS (1976) A functional analysis of circadian pacemakers in nocturnal rodents. J Comp Physiol 106:253–266.
26. Evans JA, Leise TL, Castanon-Cervantes O, Davidson AJ (2011) Intrinsic regulation of spatiotemporal organization within the suprachiasmatic nucleus. PLoS One 6:e15869.
27. Colwell CS, et al. (2003) Disrupted circadian rhythms in VIP- and PHI-deficient mice. Am J Physiol Regul Integr Comp Physiol 285:R939–R949.
28. Aton SJ, Colwell CS, Harmar AJ, Waschek J, Herzog ED (2005) Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci 8:476–483.
29. Yoo SH, et al. (2004) PERIOD2:LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci USA 101:5339–5346.
30. Gonze D, Bernard S, Waltermann C, Kramer A, Herzel H (2005) Spontaneous synchronization of coupled circadian oscillators. Biophys J 89:120–129.
31. Gall C, Seroogy KB, Brecha N (1986) Distribution of VIP- and NPY-like immunoreactivities in rat main olfactory bulb. Brain Res 374:389–394.
32. Gracia-Llanes FJ, Crespo C, Blasco-Ibáñez JM, Marqués-Marí AI, Martínez-Guijarro FJ (2003) VIP-containing deep short-axon cells of the olfactory bulb innervate interneurons different from granule cells. Eur J Neurosci 18:1751–1763.
33. Miller JE, et al. (2014) Vasoactive intestinal polypeptide mediates circadian rhythms in mammalian olfactory bulb and olfaction. J Neurosci 34:6040–6046.
34. Onoda N (1992) Odor-induced fos-like immunoreactivity in the rat olfactory bulb. Neurosci Lett 137:157–160.
35. Guthrie KM, Anderson AJ, Leon M, Gall C (1993) Odor-induced increases in c-fos mRNA expression reveal an anatomical “unit” for odor processing in olfactory bulb. Proc Natl Acad Sci USA 90:3329–3333.
36. Amir S, Cain S, Sullivan J, Robinson B, Stewart J (1999) In rats, odor-induced Fos in the olfactory pathways depends on the phase of the circadian clock. Neurosci Lett 272:175–178.
37. Funk D, Amir S (2000) Circadian modulation of fos responses to odor of the red fox, a rodent predator, in the rat olfactory system. Brain Res 866:262–267.
38. Witt RM, Galligan MM, Despinoy JR, Segal R (2009) Olfactory behavioral testing in the adult mouse. J Vis Exp (23):949.
39. Gozes I (2008) VIP, from gene to behavior and back: Summarizing my 25 years of research. J Mol Neurosci 36:115–124.
40. Fahrenkrug J (2010) VIP and PACAP. Results Probl Cell Differ 50:221–234.
41. Waschek JA (2013) VIP and PACAP: Neuropeptide modulators of CNS inflammation, injury, and repair. Br J Pharmacol 169:512–523.
42. Harmar AJ, et al. (2002) The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109:497–508.
43. Maywood ES, et al. (2006) Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr Biol 16:599–605.
44. Gozes I, et al. (1995) Superactive lipophilic peptides discriminate multiple vasoactive intestinal peptide receptors. J Pharmacol Exp Ther 273:161–167.
45. Weston MC, Chen H, Swann JW (2012) Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission. J Neurosci 32:11441–11452.
46. Evans JA, Leise TL, Castanon-Cervantes O, Davidson AJ (2013) Dynamic interactions mediated by nonredundant signaling mechanisms couple circadian clock neurons. Neuron 80:973–983.
47. Lipton JO, et al. (2017) Aberrant proteostasis of BMAL1 underlies circadian abnormalities in a paradigmatic mTOR-opathy. Cell Rep 20:868–880.
48. Dávid C, Schleicher A, Zuschratter W, Staiger JF (2007) The innervation of parvalbumin-containing interneurons by VIP-immunopositive interneurons in the primary somatosensory cortex of the adult rat. Eur J Neurosci 25:2329–2340.
49. Somogyi P, et al.(2003) High level of mGluR7 in the presynaptic active zones of select populations of GABAergic terminals innervating interneurons in the rat hippocampus. Eur J Neurosci 17:2503–2520.
50. Schneider SP, Macrides F (1978) Laminar distributions of internuerons in the main olfactory bulb of the adult hamster. Brain Res Bull 3:73–82.
51. Lee S, Kruglikov I, Huang ZJ, Fishell G, Rudy B (2013) A disinhibitory circuit mediates motor integration in the somatosensory cortex. Nat Neurosci 16:1662–1670.
52. Jackson J, Ayzenshtat I, Karnani MM, Yuste R (2016) VIP+ interneurons control neocortical activity across brain states. J Neurophysiol 115:3008–3017.
All items in Spectrum are protected by copyright, with all rights reserved. The use of items is governed by Spectrum's terms of access.

Repository Staff Only: item control page

Downloads per month over past year

Back to top Back to top