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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Available from: Michelle M Adams, Jul 24, 2015
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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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    ABSTRACT: Maintaining cholesterol homeostasis in the brain is vital for its proper functioning. While it is well documented that dietary restriction modulates the metabolism of cholesterol peripherally, little is known as to how it can affect cholesterol metabolism in the brain. The present study was designed to elucidate the impact of long-term dietary restriction on brain cholesterol metabolism. Three-month-old male Wistar rats were exposed to long-term dietary restriction until 12 and 24 months of age. The concentrations of cholesterol, its precursors and metabolites, and food-derived phytosterols were measured in the serum, cortex, and hippocampus by gas chromatography/mass spectrometry. Relative changes in the levels of proteins involved in cholesterol synthesis, transport, and degradation were determined by Western blot analysis. Reduced food intake influenced the expression patterns of proteins implicated in cholesterol metabolism in the brain in a region-specific manner. Dietary restriction decreased the concentrations of cholesterol precursors, lanosterol in the cortex, and lanosterol and lathosterol in the hippocampus at 12 months, while the level of desmosterol was elevated in the hippocampus at 24 months. The concentrations of cholesterol and 24(S)-hydroxycholesterol remained unaffected. Food-derived phytosterols were significantly lower after dietary restriction in both the cortex and hippocampus at 12 and 24 months. These findings provide new insight into the effects of dietary restriction on cholesterol metabolism in the brain, lending further support to its neuroprotective effect.
    Age 04/2014; 36(3). DOI:10.1007/s11357-014-9654-z · 3.45 Impact Factor
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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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    ABSTRACT: It has been reported that Growth hormone (GH) has an immediate effect enhancing excitatory postsynaptic potentials mediated by AMPA and NMDA receptors in hippocampal area CA1. As GH plays a role in adult memory processing, this work aims to study the acute effects of GH on working memory tasks in rodents and the possible involvement of NMDA and AMPA receptors and also the MEK/ERK signalling pathway. To evaluate memory processes, two different tests were used, the spatial working memory 8-arm radial maze, and the novel object recognition as a form of non-spatial working memory test. Acute GH treatment (1 mg/kg i.p., 1h) improved spatial learning in the radial maze respect to the control group either in young rats (reduction of 46% in the performance trial time and 61% in the number of errors), old rats (reduction of 38% in trial time and 48% in the number of errors), and adult mice (reduction of 32% in the performance time and 34% in the number of errors). GH treatment also increased the time spent exploring the novel object respect to the familiar object compared to the control group in young rats (from 63% to 79%), old rats (from 53% to 70%), and adult mice (from 61 to 68%). The improving effects of GH on working memory tests were blocked by the NMDA antagonist MK801 dizocilpine (0.025 mg/kg i.p.) injected 10 min before the administration of GH, in both young and old rats. In addition, the AMPA antagonist DNQX (1 mg/kg i.p.) injected 10 min before the administration of GH to young rats, blocked the positive effect of GH. Moreover, in mice, the MEK inhibitor SL 327 (20 mg/kg i.p.) injected 30 min before the administration of GH, blocked the positive effect of GH on radial maze and the novel object recognition. In conclusion, GH improved working memory processes through both glutamatergic receptors NMDA and AMPA and it required the activation of extracellular MEK/ERK signalling pathway. These effects could be related to the enhancement of excitatory synaptic transmission in the hippocampus reported by GH.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2013; 45. DOI:10.1016/j.pnpbp.2013.04.005 · 4.03 Impact Factor
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