title: Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice.
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.
authors: Barshop Institute, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245, United States.
authors: J
authors: J
authors: Halloran
authors: S A
authors: SA
authors: Hussong
authors: R
authors: R
authors: Burbank
authors: N
authors: N
authors: Podlutskaya
authors: K E
authors: KE
authors: Fischer
authors: L B
authors: LB
authors: Sloane
authors: S N
authors: SN
authors: Austad
authors: R
authors: R
authors: Strong
authors: A
authors: A
authors: Richardson
authors: M J
authors: MJ
authors: Hart
authors: V
authors: V
authors: Galvan
mesh_terms: D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D019417:Hindlimb Suspension / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D012737:Sex Factors; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors
chemical_list: D015306:Biogenic Monoamines; D007166:Immunosuppressive Agents; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus