Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice

J. Halloran, S. A. Hussong, R. Burbank, N. Podlutskaya, K. E. Fischer, L. B. Sloane, S. N. Austad, John R Strong, A. Richardson, Matthew J Hart, Veronica Galvan Hart

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

Aging is, by far, the greatest risk factor for most neurodegenerative diseases. In non-diseased conditions, normal aging can also be associated with declines in cognitive function that significantly affect quality of life in the elderly. It was recently shown that inhibition of Mammalian TOR (mTOR) activity in mice by chronic rapamycin treatment extends lifespan, possibly by delaying aging {Harrison, 2009 #4}{Miller, 2011 #168}. To explore the effect of chronic rapamycin treatment on normal brain aging we determined cognitive and non-cognitive components of behavior throughout lifespan in male and female C57BL/6 mice that were fed control- or rapamycin-supplemented chow. Our studies show that rapamycin enhances cognitive function in young adult mice and blocks age-associated cognitive decline in older animals. In addition, mice fed with rapamycin-supplemented chow showed decreased anxiety and depressive-like behavior at all ages tested. Levels of three major monoamines (norepinephrine, dopamine and 5-hydroxytryptamine) and their metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid) were significantly augmented in midbrain of rapamycin-treated mice compared to controls. Our results suggest that chronic, partial inhibition of mTOR by oral rapamycin enhances learning and memory in young adults, maintains memory in old C57BL/6J mice, and has concomitant anxiolytic and antidepressant-like effects, possibly by stimulating major monoamine pathways in brain.

Original languageEnglish (US)
Pages (from-to)102-113
Number of pages12
JournalNeuroscience
Volume223
DOIs
StatePublished - Oct 25 2012

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Sirolimus
Inbred C57BL Mouse
Cognition
Young Adult
3,4-Dihydroxyphenylacetic Acid
Homovanillic Acid
Anti-Anxiety Agents
Brain
Mesencephalon
Inhibition (Psychology)
Neurodegenerative Diseases
Antidepressive Agents
Dopamine
Serotonin
Norepinephrine
Anxiety
Quality of Life
Learning
Acids
Therapeutics

Keywords

  • Anxiety
  • Brain aging
  • Depression
  • Mammalian target of rapamycin
  • Memory
  • Monoamines

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. / Halloran, J.; Hussong, S. A.; Burbank, R.; Podlutskaya, N.; Fischer, K. E.; Sloane, L. B.; Austad, S. N.; Strong, John R; Richardson, A.; Hart, Matthew J; Galvan Hart, Veronica.

In: Neuroscience, Vol. 223, 25.10.2012, p. 102-113.

Research output: Contribution to journalArticle

Halloran, J. ; Hussong, S. A. ; Burbank, R. ; Podlutskaya, N. ; Fischer, K. E. ; Sloane, L. B. ; Austad, S. N. ; Strong, John R ; Richardson, A. ; Hart, Matthew J ; Galvan Hart, Veronica. / Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. In: Neuroscience. 2012 ; Vol. 223. pp. 102-113.
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