Date of Award

Spring 2025

Degree Type

Thesis

Department

Pharmacology, Physiology and Neuroscience

Director of Thesis

Ana Pocivavsek

Second Reader

Maria Piroli

Abstract

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

First Page

1

Last Page

22

Rights

© 2025, Charles A. Grant

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