Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

Abstract

Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues, including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate agerelated cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging. For 5-6 mo, middle-aged F344 rats were fed diets containing low, medium (typical amount), or high (100, 1,000, or 10,000 international units/kg diet, respectively) vitamin D3, and hippocampal-dependent learning and memory were then tested in the Morris water maze. Rats on high vitamin D achieved the highest blood levels (in the sufficient range) and significantly outperformed low and medium groups on maze reversal, a particularly challenging task that detects more subtle changes in memory. In addition to calcium-related processes, hippocampal gene expression microarrays identified pathways pertaining to synaptic transmission, cell communication, and G protein function as being up-regulated with high vitamin D. Basal synaptic transmission also was enhanced, corroborating observed effects on gene expression and learning and memory. Our studies demonstrate a causal relationship between vitamin D status and cognitive function, and they suggest that vitamin D-mediated changes in hippocampal gene expression may improve the likelihood of successful brain aging.V itamin D, a secosteroid hormone known for its role in bone and calcium homeostasis, is now well recognized for its many diverse functions and actions on a variety of tissues and cell types (1, 2). Vitamin D typically refers to the precursor forms of the hormone obtained through the skin's exposure to sunlight [vitamin D3 (VitD3)] or from dietary sources (VitD3 or VitD2). A metabolite of vitamin D, 25-hydroxyvitamin D (25OHD), is a serum biomarker of vitamin D status or repletion. In recent years, there is particular concern that large segments of the population may have low levels of 25OHD, and therefore are vitamin D-deficient (3). Due to factors such as reduced intake, absorption, and decreased exposure to sunlight, aging adults (≥50 y of age) are especially susceptible (3-6). Notably, this predisposition for lower 25OHD levels in the elderly has been linked to higher risk for numerous age-related disorders, including cancer and metabolic and vascular diseases (7-10).Inadequate vitamin D status also correlates with a greater risk for cognitive decline in the elderly (4,(11)(12)(13)(14)(15), suggesting that optimal levels may promote healthy brain aging (16,17). Because the brain expresses vitamin D receptors (VDRs) and can synthesize the active form of the hormone, the possible cognitive enhancing effects of vitamin D may reflect a primary action in the brain rather than a result of secondary systemic effects (18)(19)(20)(21)(22). Indeed, we and others have shown that vitamin D, as ...

Medium-Chain Triglycerides in Combination with Leucine and Vitamin D Benefit Cognition in Frail Elderly Adults: A Randomized Controlled Trial

“…Recent meta-analyses showed that lower concentrations of vitamin D were associated with poor cognitive function and a higher risk of AD (14,15). Vitamin D supplementation may prevent cognitive decline as observed in aged rats (16). It is therefore possible that the combination of cholecalciferol and MCTs could have led to the more favorable effects rather than by MCTs alone.…”

The impact of vitamin D deficiency on behaviour and brain function in rodents

“…Those fed a diet high in vitamin D showed superior spatial reversal memory relative to both a control and AVD deficient group, revealing that an increase in dietary vitamin D can ameliorate cognitive decline in aging animals [41]. Overall, aberrant behaviour that follows vitamin D deficiency appears to fall within similar domains, however the resulting phenotypes of AVD deficiency appear to be more subtle than seen with DVD deficiency.…”

The role of adult vitamin D deficiency in cognition and brain function in mice

“…A recent study performed in rats showed no effect of vitamin D supplementation in young (6 month old) rats, however in older rats (20 month old), vitamin D supplementation significantly improved learning and memory (Briones & Darwish, 2012). Another study showed that long-term vitamin D dietary manipulation in aging rats (11-13 months old at the start of the study and on diet for 5-6 months), had a significant impact on learning with only the rats on a high vitamin D diet able to perform a complex memory task, compared to those on low or mid levels (Latimer et al, 2014). Therefore, perhaps combining vitamin D deficiency with ageing or another secondary insult such as social stress, could lead to a depressivelike phenotype in BALB/c mice.…”

“…The effect of longer-term exposure (6 months) to diets containing varying amounts of vitamin D on cognitive performance was recently tested in middle-aged (5-6 month old) F344 rats (Latimer et al, 2014). Rats on high vitamin D (10,000 IU/kg food) significantly outperformed low (100 IU/kg food) and medium vitamin D (1,000 IU/kg food) groups in a challenging memory task, demonstrating a causal link between vitamin D status and cognitive function in aging animals.…”

“…However, another study in ageing C57BL/6J mice, showed no effect on cognitive performance of a long-term vitamin D deficient diet (on diet at 10 months and tested at 22-23 months) (Brouwer-Brolsma et al, 2014), although the task design varied between studies (Latimer et al, 2014) (Brouwer-Brolsma et al, 2014.…”