0257 EFFECTS OF ACUTE SLEEP DEPRIVATION IN RATS: SEXUALLY DIMORPHIC INCREASE IN HIPPOCAMPAL KYNURENIC ACID AND IMPAIRED CONTEXTUAL MEMORY

Abstract

While restful periods at night have been associated with memory consolidation, prolonged periods of poor sleep quality result in neurocognitive dysfunction. Our current experiments were designed to test the hypothesis that kynurenic acid (KYNA), an astrocyte-derived metabolite of the kynurenine pathway (KP) of tryptophan degradation, is elevated in the brain after sleep disturbances. KYNA is an antagonist of α7 nicotinic acetylcholine (α7nACh) and NMDA receptors, and elevations in KYNA negatively impact learning and memory. We investigated the effect of sleep deprivation (SD) on KP metabolism in both male and female adult Wistar rats. Animals were sleep deprived by gentle handling for 6 h from Zeitgeber time (ZT) 0 to ZT6, where ZT 0 is the start of the light-phase. KP metabolites were analyzed in the brain and plasma immediately after SD. In separate adult animals, we tested contextual memory using the passive avoidance paradigm (PAP). Animals were sleep deprived from ZT0 to ZT6 and underwent PAP training at ZT3. Twenty-four hours after training, animals were tested in the retention trial. In the hippocampus, a region that mediates learning and memory, KYNA levels were 1.4-fold elevated in male rats after SD, but not changed after SD in female rats. In the serum, no significant changes in KYNA or its bioprecursor kynurenine were observed in either sex. In male rats, SD induced significant PAP deficits, evidenced as decreased avoidance latency during the retention trial. Conversely, in female animals, the avoidance latency was not significantly reduced after SD. To test our hypothesis that KYNA elevations mediate memory impairments after SD, we have used a KYNA synthesis inhibitor, BFF-816, that targets the enzyme kynurenine aminotransferase (KAT) II and prevents de novo KYNA production. In male rats, BFF-816 treatment (30 mg/kg, p.o. at ZT0 and Z3) attenuated SD-induced contextual memory impairments. Collectively, our results demonstrate a striking sexual dimorphism in the elevation of hippocampal KYNA and contextual memory retention after an acute period of SD. Additionally, we introduce KAT II inhibition as an efficacious strategy to combat cognitive disruption after SD. NIH K12 HD43489.