Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice
Highlights
► Chronic rapamycin decreased mTORC1 but not mTORC2 activity in mouse brains. ► Chronic rapamycin enhanced learning and memory in young adult C57BL/6J mice. ► Chronic rapamycin improved memory in aged mice. ► Chronic rapamycin decreased anxiety and depressive-like behavior at all ages. ► Monoamines were increased by rapamycin in midbrain but not in hippocampus.
Introduction
The target of rapamycin (TOR) is a major cellular signaling node that controls cellular metabolism and organismal lifespan in invertebrates and mammals (Kapahi and Zid, 2004). Mammalian TOR (mTOR) controls cell growth, proliferation, and survival through two distinct multiprotein complexes, mTORC1 and mTORC2. mTORC1 functions as a nutrient/energy/redox sensor and controls protein homeostasis. mTORC2 activates Akt/protein kinase B (PKB) by phosphorylation of Ser473 (Martin and Hall, 2005). This event inhibits the activity of FoxO transcription factors, which have a central role in the control of metabolism, cell stress resistance and autophagy (Michalek and Rathmell, 2008, Salih and Brunet, 2008). In addition, mTOR is involved in the modulation of long-lasting synaptic plasticity (Hoeffer and Klann, 2009). Although acute inhibition of mTOR has generally been associated with defects in long-term plasticity required for memory (Tang et al., 2002), inhibition of mTOR can also block the opposite process, the long-term reduction in synaptic responsiveness or long-term depression (LTD) (Huber et al., 2001). Moreover, disruption of signaling mechanisms that inhibit mTOR results in high mTOR activity and significant plasticity and memory deficits (Hoeffer and Klann, 2009). These observations suggest that mTOR does not act as a synaptic ‘on-off’ switch but may serve as a rheostat that modulates long-lasting synaptic change. The mechanisms by which mTOR inhibits memory have not been explored. Partial inhibition of mTOR function in vivo in rodent experimental models became possible only recently, when a method for effective chronic oral delivery of this drug was developed and used to establish that chronic systemic inhibition of mTOR in mice extends lifespan (Harrison et al., 2009). In agreement with these studies, we previously showed that treatment of mice modeling Alzheimer’s disease (AD) fed with the same rapamycin-supplemented diet that extends lifespan blocked AD-like impairments in spatial learning and memory (Spilman et al., 2010). To explore the effect of chronic rapamycin treatment on normal brain aging we determined cognitive and non-cognitive components of behavior in C57BL/6J animals that were fed control- or rapamycin-supplemented chow at different ages throughout their lifespan, and for periods ranging from 8 to 40 weeks. Our results demonstrate that rapamycin treatment enhances cognitive function in young C57BL/6J mice and blocks age-associated cognitive decline in older animals. In addition, our data suggest that rapamycin has anxiolytic and antidepressant-like effects at all ages tested. Levels of three major monoamines (norepinephrine, dopamine and 5-hydroxytryptamine) were significantly augmented in midbrain of rapamycin-treated mice, suggesting that the effects of rapamycin on cognitive and non-cognitive components of behavior may be explained by the stimulation of major monoamine pathways in brain.
Section snippets
Mice
Mice used in these studies were C57BL/6J obtained from the Jackson Laboratories (JAX, Bar Harbor, ME, USA) or were non-transgenic mice arising from crosses of C57BL/6J breeders from JAX and heterozygous transgenic hAPP(J20) mice fully congenic in the C57BL/6J background as indicated in the figure legends and in the Results section. The twenty-five month-old C57BL/6 mouse group was purchased from Charles River. Numbers of animals per experimental group are indicated in the legends to the figures.
Chronic rapamycin treatment inhibits mTORC1 but not mTORC2 in brains of C57BL/6J mice
It had been previously shown (Cloughesy et al., 2008) that rapamycin crosses the blood–brain barrier. Similarly, C57BL/6J mice fed a diet containing 14 ppm encapsulated rapamycin had rapamycin brain concentrations of 8.65 ± 0.66 ng/mg wet weight, similar to the rapamycin levels found in plasma in the same animals (Randy Strong, personal communication). Food consumption was higher for rapamycin-fed females, but not for males, during the first 8 weeks of treatment (by an average of 1.25 ± 0.12
Discussion and conclusions
Normal aging is associated with specific changes in brain structure and connectivity, and frequently with declines in cognitive function that significantly affect quality of life. Signaling pathways that regulate the aging process have in common a role in the control of cellular metabolism in response to availability of nutrients or growth factors (Kapahi et al., 2010). mTOR controls cellular metabolism and organismal lifespan in invertebrates and mammals (Kapahi and Zid, 2004). It was recently
Role of the funding source
This work was supported by NIRG 04-1054 from the Alzheimer’s Association, AG-NS-0726-10 New Scholar Award in Aging from the Ellison Medical Foundation, and a University Research Council Award from UTHSCSA to VG, the San Antonio Nathan Shock Center of Excellence in the Basic Biology of Aging to AR and RS, the RC2AG036613 NIH Recovery Act Grand Opportunities “GO” Grant to AR, and T32AG21890 to SAH.
Disclosure statement
The authors have no conflicts of interest to disclose.
Acknowledgements
The authors thank Ms. Katrine Krueger for excellent administrative assistance. We are also grateful to Dr. Elisabeth Fernandez and to Ms. Xiang Bai for their help with monoamine measurements, and to Ms. Vanessa Soto and Mr. John Ramos and to the South Texas Center for Biology in Medicine Animal Facility staff for excellent animal care. This work was supported in part by the San Antonio Nathan Shock Center of Excellence in the Basic Biology of Aging (AR and RS), RC2AG036613 NIH Recovery Act
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These authors contributed equally to the present study.