Dissertations, Theses, and Capstone Projects

Date of Degree

9-2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Biology

Advisor

Orie Shafer

Committee Members

Susana Mingote

Nesha Burghardt

Maria de la Paz Fernandez

Daniel McCloskey

Subject Categories

Behavioral Neurobiology | Behavior and Behavior Mechanisms | Biology | Neuroscience and Neurobiology | Pharmacology

Keywords

Sleep, Circadian rhythm, Serotonin, Neuromodulation, Two-process model, Drosophila

Abstract

Sleep is a fundamental biological need, and sufficient sleep is required for physical and mental well-being. Sleep is regulated by two biological mechanisms: sleep-wake homeostasis and circadian rhythm. Circadian rhythms are near 24-h rhythms in behavior and physiology that are generated by endogenous mechanisms. In mammals, the suprachiasmatic nucleus (SCN) is the central circadian pacemaker, which is known to receive a significant amount of serotonergic input that likely modulates sleep rhythms. In addition to circadian modulation, sleep is subject to homeostatic regulation. Several neuromodulators have been proposed as mediators of sleep homeostasis. Serotonin has been implicated in sleep drive and has been considered as a sleep-promoting neurotransmitter. Both sleep disturbance and the serotonergic system are etiologically linked in psychopathology, and there are clear links between the two. Patients with negative valence psychopathology exhibit circadian disturbances in sleep, hormonal, mood, and temperature rhythms. Furthermore, the first-line pharmacological treatments are serotonin-replenishing agents, such as selective serotonin reuptake inhibitors (SSRIs). Understanding the relationships between serotonergic modulation and sleep is therefore important.

Owing to the remarkable conservation of molecular clocks and serotonergic neurotransmission across taxa, Drosophila serves as a powerful model to study the relationship between serotonin neurotransmission and rhythms in sleep. Previous research has established clear links between serotonin and sleep. This thesis explores the role of serotonergic signaling in modulating sleep. We used pharmacological and thermogenetic approaches to dissect its functional contribution to sleep architecture. Aside from that, my work integrates a novel behavioral framework that categorizes Drosophila sleep into distinct stages based on bout duration, drawing parallels to light and deep sleep observed in mammals. In addition, we evaluated the effects of non-serotonergic agents, including caffeine and Gaboxadol, to examine broader pharmacological influences on sleep regulation. Central to this work is the utilization of the behavioral framework that categorizes Drosophila sleep into discrete stages based on bout duration, allowing us to analyze the effects of these manipulations on “short”, “intermediate” and “long-bout” sleep states.

Our results revealed serotonin as a major modulator of sleep pressure. Overall, this work advances our understanding of sleep as a complex process regulated by a neuromodulator system. Also, it provides a foundation for future therapeutic and clinical improvements.

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