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Caloric restriction and age affect synaptic proteins in hippocampal CA3 and spatial learning ability

Department of Neurobiology and Anatomy, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
Experimental Neurology (Impact Factor: 4.62). 06/2008; 211(1):141-9. DOI: 10.1016/j.expneurol.2008.01.016
Source: PubMed

ABSTRACT Caloric restriction (CR) is a daily reduction of total caloric intake without a decrease in micronutrients or disproportionate reduction of any one dietary component. CR can increase lifespan reliably in a wide range of species and appears to counteract some aspects of the aging process throughout the body. The effects on the brain are less clear, but moderate CR seems to attenuate age-related cognitive decline. Thus, we determined the effects of age and CR on key synaptic proteins in the CA3 region of the hippocampus and whether these changes were correlated with differences in behavior on a hippocampal-dependent learning and memory task. We observed an overall, age-related decline in the NR1, N2A and N2B subunits of the N-methyl-d-aspartate (NMDA)-type and the GluR1 and GluR2 subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-type ionotropic glutamate receptors. Interestingly, we found that CR initially lowers the glutamate receptor subunit levels as compared to young AL animals, and then stabilizes the levels across lifespan. Synaptophysin, a presynaptic vesicle protein, showed a similar pattern. We also found that both CR and ad libitum (AL) fed animals exhibited age-related cognitive decline on the Morris water maze task. However, AL animals declined between young and middle age, and between middle age and old, whereas CR rats only declined between young and middle age. Thus, the decrease in key synaptic proteins in CA3 and cognitive decline occurring across lifespan are stabilized by CR. This age-related decrease and CR-induced stabilization are likely to affect CA3 synaptic plasticity and, as a result, hippocampal function.

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    • "Interestingly, CR is associated with greater electrical and synaptic activity throughout neuronal circuits when compared to satiated and resting states [43]. In addition, CR stabilizes the levels of glutamate receptors and synaptic proteins required for excitatory transmission and thought to underlie hippocampal-dependent learning and memory [43] [44]. The generation of neurotrophic factors is another important adaptive and neuroprotective response to CR [45]. "
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    ABSTRACT: Dietary interventions have emerged as effective environmental inducers of brain plasticity. Among these dietary interventions, we here highlight the impact of caloric restriction (CR: a consistent reduction of total daily food intake), intermittent fasting (IF, every-other-day feeding), and diet supplementation with polyphenols and polyunsaturated fatty acids (PUFAs) on markers of brain plasticity in animal studies. Moreover, we also discuss epidemiological and intervention studies reporting the effects of CR, IF and dietary polyphenols and PUFAs on learning, memory, and mood. In particular, we evaluate the gap in mechanistic understanding between recent findings from animal studies and those human studies reporting that these dietary factors can benefit cognition, mood, and anxiety, aging, and Alzheimer's disease-with focus on the enhancement of structural and functional plasticity markers in the hippocampus, such as increased expression of neurotrophic factors, synaptic function and adult neurogenesis. Lastly, we discuss some of the obstacles to harnessing the promising effects of diet on brain plasticity in animal studies into effective recommendations and interventions to promote healthy brain function in humans. Together, these data reinforce the important translational concept that diet, a modifiable lifestyle factor, holds the ability to modulate brain health and function.
    Neural Plasticity 05/2014; 2014:563160. DOI:10.1155/2014/563160 · 3.60 Impact Factor
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    • "Both of these brain regions exhibit high responsiveness to the beneficial effects of DR. Studies on the rodent central nervous system (CNS) have revealed that long-term DR can improve learning and memory, and diminish age-related behavioral impairments and cognitive decline (Means et al. 1993; Halagappa et al. 2007; Adams et al. 2008) caused by disruptions of the pivotal brain functions associated with the cortex and hippocampus. Furthermore, DR alleviates t he decline in hippocampal neurogenesis (Park et al. 2013) and counteracts the age-related decrease of synaptic plasticity (Fontán- Lozano et al. 2008; Mladenovic Djordjevic et al. 2010). "
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    • "In good agreement, the enhancement induced by GH on hippocampal excitatory synaptic transmission mediated by AMPA and NMDA receptors required MEK pathway activation (Mahmoud and Grover, 2006). Moreover, ageing is associated with a decline of subunits that comprise the NMDA receptors in the hippocampus (Adams et al., 2008; Foster, 2002; Newton et al., 2008; Shi et al., 2007), and NMDA receptor-mediated synaptic transmission is reduced as well (Barnes, 1990; Barnes et al., 1997). Chronic systemic treatment with GH alters the pattern of expression of NMDA receptor subunits in the hippocampus (Le Greves et al., 2002) and this could at least partially explain the effects of GH on memory function. "
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