Remembering dinner: OEAsy does it

Lipidomics Gateway (27 May 2009) [doi:10.1038/lipidmaps.2009.6]

A lipid mediator released by dietary fat strengthens recent memories.

Rat swimming in a Morris water maze — a behavioral neuroscience experiment.
Jean-Etienne Poirrier

N-oleoyl ethanolamine (OEA, also known as oleoylethanolamide) is related to the cannabinoid anandamide but it does not activate cannabinoid receptors. Produced by enterocytes in response to fat consumption, it is instead a potent peroxisome proliferator-activated receptor-α (PPAR-α) agonist, triggering expression of genes involved in lipid absorption and inducing satiety. Now, as Piomelli and colleagues report in the Proceedings of the National Academy of Sciences, the reach of this lipid mediator and its nuclear receptor has been extended to include the enhancement of memory consolidation.

Significant emotional events are often well remembered: the release of stress hormones influences central noradrenergic mechanisms in the amygdala to promote recent memory enhancement. Wild animals remember where and when to find food safely, suggesting that hormonal and neural responses to feeding might have a similar effect. The authors tested the effect of OEA on the ability of rats to retain contextual and spatial information about two cognitive tasks, inhibitory avoidance training and the Morris water maze. Administered immediately after training, OEA injections caused a marked dose-dependent improvement in the 24 hour retention performance of the inhibitory avoidance task. Pre-training injections caused a more modest increase, and a delay of three hours post-training resulted in no improvement in retention. Two days after training in the Morris water maze, rats given immediate post-training OEA injections were better able to locate a hidden underwater platform.

The effect of OEA on appetite requires the sensory vagus nerve in the nucleus tractus solitarii in the brain. This route to the forebrain was also required for OEA to strengthen memory, as shown by specific local anesthetization. OEA itself did not enter the brain, but caused increased expression of c-fos messenger RNA in the nucleus tractus solitarii. The transformation of emotional experiences into stable memories occurs by activation of noradrenergic projections from the nucleus tractus solitarii to the basolateral complex of the amygdala, which projects to other brain regions. Blocking noradrenergic transmission in the basolateral complex of the amygdala with a β-adrenergic antagonist prevented the memory-enhancing effects of OEA, indicating that nutritional and emotional stimuli activate the same neuromodulatory system. Despite this, OEA and stress hormones such as epinephrine elicit different behavioral responses. Administration of OEA did not provoke anxiety responses; nor did it increase plasma glucose, a typical effect of adrenergic activation. PPAR-α was shown to be necessary for the effect of OEA on memory. In PPAR-α^–/– mice, the OEA response to training was absent, and two PPAR-α agonists administered to rats post-training had similar effects on memory to OEA.

The regulation of memory is a novel role for PPAR-α, and the target genes responsible remain undetermined. Nevertheless, the ability of OEA to improve memory consolidation suggests that strategies to mimic or amplify OEA signaling might lead to new therapies for cognitive disorders.

Emma Leah