Vitamin A deficiency impairs contextual fear memory in rats: Abnormalities in the glucocorticoid pathway

Abstract

Vitamin A and its active metabolite, retinoic acid (RA), play a key role in the maintenance of cognitive functions in the adult brain. Depletion of RA using the vitamin A deficiency (VAD) model in Wistar rats leads to spatial memory deficits in relation to elevated intrahippocampal basal corticosterone (CORT) levels and increased hippocampal 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. All of these effects are normalised by vitamin A supplementation. However, it is unknown whether vitamin A status also modulates contextual fear conditioning (CFC) in a glucocorticoid-associated fear memory task dependent on the functional integrity of the hippocampus. In the present study, we investigated the impact of VAD and vitamin A supplementation in adult male rats on fear memory processing, plasma CORT levels, hippocampal retinoid receptors and 11β-HSD1 expression following a novelty-induced stress. We also examined whether vitamin A supplementation or a single injection of UE2316, a selective 11β-HSD1 inhibitor, known to modulate local glucocorticoid levels, had any beneficial effects on contextual fear memory and biochemical parameters in VAD rats. We provide evidence that VAD rats exhibit a decreased fear conditioning response during training with a poor contextual fear memory 24 hours later. These VAD-induced cognitive impairments are associated with elevated plasma CORT levels under basal conditions, as well as following a stressful event, with saturated CORT release, altered hippocampal retinoid receptors and 11β-HSD1 expression. Vitamin A supplementation normalises VAD-induced fear conditioning training deficits and all biochemical effects, although it cannot prevent fear memory deficits. Moreover, a single injection of UE2316 not only impairs contextual fear memory, but also reduces plasma CORT levels, regardless of the vitamin A status and decreases slightly hippocampal 11β-HSD1 activity in VAD rats following stress. The present study highlights the importance of vitamin A status with respect to modulating fear memory conditioning in relation to plasma CORT levels and hippocampal 11β-HSD1.

Keywords: 11β-hydroxysteroid dehydrogenase type 1; contextual fear memory; glucocorticoid; hippocampus; retinoic acid receptor; vitamin A.