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.

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.