Brain Specific Elevations of Kynurenic Acid

Individuals who suffer from neurocognitive disorders often suffer from sleep disturbances. Kynurenic acid (KYNA) is a tryptophan metabolite implicated in the pathophysiology of these disorders. Modest increases in KYNA, which acts as an antagonist at N-methyl-D-aspartate (NMDA) and α7 nicotinic acetylcholine (α7nACh) receptors, result in cognitive impairments and alterations in sleep-wake behavior. Specifically, KYNA negatively impacts rapid eye-movement (REM) sleep and increases wakefulness. The goals of the present project were to determine the impact of a dose response (0 µM, 1 µM, 3 µM, 10 µM; dissolved in PBS) elevation of KYNA locally in the brain. Wistar rats (N=10 female, 7 male) were cannulated with a guide targeting the lateral ventricle and simultaneously implanted with telemetry devices to record electroencephalogram (EEG) and electromyogram (EMG) polysomnography. Upon a week of recovery from surgical procedures, a within animal design employed intracerebroventricular (ICV) infusion to deliver each dose of KYNA (1 µl/min for 10 min) at Zeitgeber time (ZT) 0, the start of the light phase, to rats across different 24-hour recording days. Vigilance states were classified into wake, REM sleep and non-REM (NREM) sleep by an artificial intelligence neural network in 10 sec epochs and reviewed by an expert. We presently evaluated vigilance state durations from ZT 0-4 and found a dose-dependent impact of KYNA on sleep duration. Notably, 3 µM KYNA increased wake duration by 35.01% (P