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.

11β‐Hydroxysteroid dehydrogenase and the brain: Not (yet) lost in translation

“…These extensive preclinical data are consistent with the idea that 11β-HSD1 inhibition effectively lowers intrahippocampal glucocorticoid levels, thus facilitating episodic learning and memory. Intriguingly, acute fear conditioning is attenuated by UE2316 in mouse [114,118] and rat models [119] in keeping with the pleiotropic effects of glucocorticoids on learning and memory and indicating a distinct possible use in attenuating anxiety and post-traumatic stress disorder (PTSD). This remains to be explored in humans.…”

“…Intriguingly, acute fear conditioning is attenuated by UE2316 in mouse [114, 118] and rat models [119] in keeping with the pleiotropic effects of glucocorticoids on learning and memory and indicating a distinct possible use in attenuating anxiety and post‐traumatic stress disorder (PTSD). This remains to be explored in humans.…”