Date of Award

Spring 2023

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Ana Pocivavsek

Abstract

Sleep is vital for healthy cognition and mood. Sleep dysregulation is implicated in psychiatric disorders such as schizophrenia and bipolar disorder. Sex differences in sleep and arousal dysregulation are prominent in patients with psychotic disorders. Elevated levels of the neuroactive tryptophan metabolite, kynurenic acid (KYNA), have been found in cerebrospinal fluid and postmortem brain tissue samples from patients with psychotic disorders. KYNA is an astrocyte derived antagonist at N-methyl-D-aspartate (NMDA) glutamate receptors and α7 nicotinic acetylcholine (α7nACh) receptors. KYNA is synthesized in the brain from its biological precursor, kynurenine, via the enzyme kynurenine aminotransferase II (KAT II), a potential therapeutic target for treating psychotic disorders.

To evaluate sleep in rodents, electroencephalogram (EEG) and electromyogram (EMG) telemetry is used, to record rapid-eye movement (REM) and non-REM (NREM) sleep in freely moving rodents. Previously, acute kynurenine administration was sufficient to reduce REM and NREM sleep and elicit hippocampal-dependent contextual memory deficits. To expand upon the premise that brain KYNA elevation contributes to sleep disturbances, sleep and hippocampal neuromodulation were studied in a neurodevelopmental model of KYNA elevation. Further, the investigation of systemic kynurenine administration, while using KYNA synthesis inhibition to reduce brain KYNA levels and evaluate transient impacts on sleep. This research is the first of its kind to investigate sex differences in brain KYNA elevation and sleep disturbances.

The embryonic kynurenine (EKyn) model of prenatal kynurenine elevation elicited sex differences in sleep disturbances, with male subjects having reduced REM sleep, decreased NREM spindle density, altered NREM architecture, and elevated brain KYNA. Female EKyn offspring exhibited a hyperarousal phenotype, lower activity levels, and lower KAT activity levels. Changes in hippocampal neuromodulation of extracellular KYNA, glutamate, and GABA corresponded to sex differences in sleep disturbances in EKyn offspring. Minimal sex differences in sleep were observed with transient increases in brain KYNA, which disrupted REM and NREM sleep, as well as activity levels. KYNA synthesis inhibition successfully prevented acute kynurenine-induced sleep disturbances. Further, a surgical and experimental protocol has been developed to simultaneously record sleep and perform intracerebroventricular infusions, to further explore the direct impact of brain KYNA elevation and KAT II inhibition on sleep.

Available for download on Thursday, May 15, 2025

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