Orally Administered Vitamin D Ameliorates Cognitive Decline in Early Stage of Vitamin D Deficiency

Vitamin D (VD) deficiency has been associated with cognitive impairment; however, the mechanisms underlying this relationship remain unclear. In this study, we examined the impact of dietary VD deficiency on cognitive function and explored the potential involvement of gastrointestinal signaling pathways independently of changes in circulating VD levels. Mice fed a VD-deficient (VD-Def) diet exhibited impaired cognitive performance in behavioral tests, including the novel object recognition test and the object location test, despite unchanged circulating 25-hydroxyvitamin D [25(OH)D] levels. Notably, this cognitive impairment was ameliorated by oral, but not intraperitoneal, administration of VD, indicating a route-dependent effect. Furthermore, the cognitive improvement induced by oral VD was abolished by oral administration of methyllycaconitine, an α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, whereas intraperitoneal administration had no effect. These findings suggest that α7nAChRs via the gastrointestinal tract are required for the cognitive benefits of orally administered VD. Collectively, our results demonstrate that VD deficiency can impair cognitive function independently of systemic VD depletion and metabolic changes, and highlight a previously unrecognized role of gastrointestinal cholinergic signaling in mediating the cognitive effects of VD.