Matthew Kayser, MD/PhD
Assistant Professor, Physician-of-Record
Department of Psychiatry
Perelman School of Medicine
University of Pennsylvania
(April 24, 2022)
Using Fruit Flies to Study Sleep Regulation and Function During Development
A lack of sleep is a universal experience for any new parent when faced with an infant who has no concept of circadian rhythms! Sleeping through the night is a celebrated milestone for the sleep-deprived parent who still needs to wake up in the morning for work. But why are these sleep rhythms so important and how do they develop? Dr. Kayser discussed the work his lab has done to shed light on how and why sleep develops circadian patterns. Using a fruit fly model, they have identified a protein required for normal development of sleep, as well as a potential correlation between the beginnings of circadian sleep and the emergence of long-term memory formation.
Sleep abnormalities are pervasive across nearly all psychiatric disorders, and disrupted sleep early in life has been linked to mental illness in adulthood. Work in the Kayser Lab stands to connect this fundamental behavior — sleep — to both pathogenesis and novel treatment of neuropsychiatric disease. Our particular focus is in understanding how sleep contributes to sculpting brain circuits during development and in other times of life. To answer these questions, we primarily utilize the powerful genetic system Drosophila melanogaster (the fruit fly). The fly provides unparalleled neurogenetic approaches towards unraveling the neural logic of complex behaviors.
All animals exhibit changes to sleep during development (sleep ontogeny), suggesting a crucial role for sleep in early life. Indeed, disrupted sleep specifically within sensitive development periods can have severe neurobehavioral sequelae. Sleep disturbances are also a common co-morbidity in many neurodevelopmental disorders, including autism. However, knowledge of the genetic and molecular factors that drive sleep maturation is lacking. We have identified signals that regulate sleep ontogeny and the development of sleep circuits. For example, a reverse genetic screen targeting Drosophila homologs of human neurodevelopmental-disorder risk genes demonstrated that the chromatin remodeler ISWI is required during development for normal adult fly sleep. Loss of ISWI also leads to disturbances in memory and social behaviors, but critically, ISWI acts in specific neural circuits and developmental periods to coordinate each adult behavior. Ongoing work aims to map the cells, circuits and downstream molecular cues coordinating sleep in early life.
In addition to increased sleep amount/depth, another prominent feature of early life sleep is that it lacks a clear circadian pattern. Little is known regarding mechanisms that control emergence of circadian sleep, or how circadian sleep benefits a juvenile animal. In young fly larvae (2nd instar), sleep is not under circadian control in contrast to adult flies.
Using novel approaches to monitor sleep at multiple developmental stages, we pinpointed exactly when sleep rhythms first begin (early 3rd instar stage). With this platform, we have uncovered the cellular and molecular mechanisms coordinating circadian sleep emergence: in early 3rd instar, a new circuit motif connects central clocks to key outputs, bringing arousal under clock control to generate circadian sleep. We then turned to understand what advantage is conferred to the animal with emergence of circadian sleep, and our findings suggest sleep rhythms facilitate long-term memories. These findings raise the possibility that in human infancy, onset of circadian sleep could be a trigger initiating enduring memory formation.