pubmed.ncbi.nlm.nih.gov

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

  • ️Sun Jan 01 2012

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

J Halloran et al. Neuroscience. 2012.

Erratum in

  • Neuroscience. 2015 Oct 15;306():151

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.

Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Rapamycin enhances cognitive function in C57BL/6J mice. a-h. mTORC1 but not mTORC2 activity are decreased in rapamycin-treated brains

a, c, e, g. Representative immunoblots of whole brain (a and e) or hippocampal lysates (c and g) from control- and rapamycin-treated mice; b, d, f, h. Quantitative densitometric analyses. Phosphorylated (activated) p70 and phosphorylated 4EBP (b and d), but not S473 phosphorylated PKB/Akt nor phosphorylated PKCalpha (f and h) were decreased in brains of rapamycin-fed mice (P as indicated, unpaired Student’s t test, n=6-10 for each group). Mice were fed with rapamycin-supplemented chow for 16 weeks. i-j. Rapamycin-fed mice C57BL/6J show improved spatial learning and memory. i. Spatial training. Mean latencies to reach a hidden platform were significantly reduced for rapamycin-fed male mice compared to control-fed animals (Significant effect of treatment on performance, F(3,54)=6.40, P as indicated, two-way ANOVA). j. Probe trial. Retention of the former platform site was enhanced in rapamycin-fed male mice with respect to the control-fed group (P as indicated, one-way ANOVA). n=10 for each group. Mice were fed with rapamycin-supplemented chow for 16 weeks. k. Old rapamycin-fed mice show improved memory of an aversive stimulus. Latencies to enter a dark compartment were increased as a result of enhanced memory of an aversive event (2-second foot shock) in rapamycin-fed mice of mixed gender at 25 months of age (P as indicated, upaired Student’s t test). n=9-14 for each group. Data are means ± SEM.

Figure 2
Figure 2. Non-cognitive components of behavior in control- and rapamycin-treated C57Bl/6J mice. a-d. Decreased anxiety in rapamycin-fed mice

a. Percent time spent engaged in thigmotactic swimming was significantly reduced in male rapamycin-fed mice. b. Percent time spent in thigmotactic swimming on the first day of training was indistinguishable between the two experimental groups; percent time of thigmotaxis decreased significantly as training progressed for both groups [significant effect of day number on thigmotaxis, F(3,54)=14.12; P<0.0001, two-way ANOVA]. Rapamycin-fed mice spent less times swimming close to the tank wall at all times during training (P as indicated, Tukey’s post-hoc test applied to a significant effect of day number on thigmotaxis as above, n=10 for each group). c. Swim traces for day 4 trials (3 representative swim traces are shown for each experimental group; Top panel, control-fed; Lower panel, rapamycin-fed mice). Mice were fed with rapamycin-supplemented chow for 16 weeks. d. Elevated plus maze. Fourteen month-old mice fed with rapamycin for 40 weeks spent less time in the closed arms of the elevated plus maze, indicating decreased anxiety (F(1,45)=7.06; P as indicated, two-way ANOVA). n=11-14 for each group. e-f. Decreased depressive-like behavior in rapamycin-fed mice. e. Floating. Percent time spent floating was significantly lower [F(2,75)=3.3, P=0.04, two-way ANOVA] for rapamycin-fed 8 month-old male mice as compared to control-fed animals (P as indicated, unpaired Student’s t test, n=10 for each group). Mice were fed with rapamycin-supplemented chow for 16 weeks. f. Tail suspension test. Both young (4 month-old) and adult (12 month-old) mice fed with rapamycin for 16 and 40 weeks respectively spent less time immobile when suspended from their tails, indicating that rapamycin treatment reduces depressive-like behavior [F(1,83)=7.26; P as indicated, two-way ANOVA). n=10-16 for each group. Data are means ± SEM.

Figure 3
Figure 3. Rapamycin treatment increases monoamines levels in midbrain of rapamycin-treated mice

a and c. Monoamine levels in midbrain. a. Monoamine levels were significantly increased in midbrain of mice fed with rapamycin for 16 weeks (F(1,55)=11.57; P=0.0013, two-way ANOVA) and c. for 40 weeks (F(1,56)=65.8; P<0.0001, two-way ANOVA). DA was significantly increased in midbrain at 16 weeks of rapamycin treatment (P=0.04) while DA, DOPAC, HVA, 5-HT AND 5-HIAA were significantly increased in midbrain at 40 weeks (P=0.007, P=0.01, P<0.001, P=0.02 and P=0.01 respectively). NE levels showed a significant increase when analyzed independently (P=0.018, unpaired Student’s t test). n=5 for each group. c and d. Monoamine levels in hippocampus. Monoamine levels were not significantly different between experimental groups at 16 weeks (b) nor at 40 weeks (d) of rapamycin treatment. e and f. No differences in DA metabolism were found among experimental groups at 16 (e) nor at 40 (f) weeks of rapamycin treatment. g-h. Cortical NET levels are not affected by rapamycin treatment. e. Representative immunoblots of cortical lysates from control- and rapamycin-treated mice probed with antibodies specific for the indicated proteins. f. Quantitative densitometric analyses indicate that cortical NET levels are not affected by rapamycin treatment (P>0.05, unpaired Student’s t test). n=5 for each group. Data are means ± SEM.

Similar articles

Cited by

References

    1. Adams MM, Shi L, Linville MC, Forbes ME, Long AB, Bennett C, Newton IG, Carter CS, Sonntag WE, Riddle DR, Brunso-Bechtold JK. (Caloric restriction and age affect synaptic proteins in hippocampal CA3 and spatial learning ability. Exp Neurol. 2008;211:141–149. - PMC - PubMed
    1. Adell A, Celada P, Abellan MT, Artigas F. Origin and functional role of the extracellular serotonin in the midbrain raphe nuclei. Brain Res Brain Res Rev. 2002;39:154–180. - PubMed
    1. Blagosklonny MV. Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-program. Cell Cycle. 2010;9:3151. - PubMed
    1. Burger JM, Buechel SD, Kawecki TJ. Dietary restriction affects lifespan but not cognitive aging in Drosophila melanogaster. Aging Cell. 2010;9:327–335. - PubMed
    1. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem. 2010;285:13107–13120. - PMC - PubMed

Publication types

MeSH terms

Substances