0219 Acute Sleep Deprivation During Late Pregnancy Rapidly Elevates Maternal Corticosterone and Fetal Brain Kynurenic Acid in Rats

Abstract

Introduction: While loss of sleep during pregnancy adversely affects brain development, the mechanisms underlying the lasting physiological and behavioral consequences in the offspring remain unknown. The present study was designed to investigate the hypothesis that sleep deprivation (SD) during pregnancy impacts tryptophan metabolism via the kynurenine pathway in the in utero environment. Elevations in kynurenine pathway metabolism, specifically kynurenic acid (KYNA), an endogenous astrocyte-derived antagonist of α7 nicotinic acetylcholine (α7nACh) and NMDA receptors, in utero have been demonstrated to induce long-lasting negative behavioral consequences relevant to the study of psychiatric disorders including schizophrenia (reviewed in Notarangelo and Pocivavsek, Neuropharm. 2017). Methods: Pregnant Wistar rat dams were sleep deprived by gentle handling for 5 h from zeitgeber time (ZT) 0 to ZT 5. Experimental cohorts included: A) one session of SD on embryonic (ED) 18 or B) three sessions of SD on ED 16 to ED 18. Maternal (plasma, brain) and fetal (placenta, plasma, brain) tissues were collected immediately after the last session of SD or after 24 h of recovery from SD. Respective controls were euthanized at ZT 5 on ED 18 and ED 19. Results: Maternal plasma tryptophan and kynurenine, and fetal brain KYNA, were significantly elevated only after one session of SD on ED 18. Importantly, plasma corticosterone, a measure of the endocrine stress response, was significantly elevated in maternal plasma after one day of SD, and this measure, as well as maternal tryptophan, correlated significantly with fetal brain KYNA. Conclusion: Collectively, our results demonstrate that sleep loss during pregnancy can adversely impact kynurenine pathway metabolism and impact fetal brain KYNA levels. We introduce KYNA as a novel molecular target influenced by sleep loss during pregnancy. Future experiments are designed to unravel the contribution of kynurenine pathway changes during maternal sleep loss on long-lasting biochemical and behavioral outcomes in developing offspring.