Monday, April 29, 2024
4/29/2024
Mechanistic properties of circadian rhythms and sleep are conserved between insects and mammals. In both taxonomic groups, brain astrocytes cooperate with neurons to modulate sleep and circadian behavior 1-7. However, neither the astrocyte subtypes regulating rhythmicity nor mechanisms for reciprocal communication with neurons are well understood. In this application, we propose to address these important gaps in our understanding of reciprocal astrocyte-neuron communication and how it influences sleep and activity rhythms. To begin to define relevant mechanisms, we have employed Drosophila enhancer-Gal4 transgenic strains with expression in specific astrocyte subpopulations to conditionally manipulate adult fly astrocytes to identify subpopulations that modulate sleep or circadian behavior. Preliminary results for this application demonstrate that activation or inhibition of different astrocyte subpopulations can alter circadian activity cycles and sleep, with selective effects on nighttime sleep. The observation that fly astrocytes exert modulatory effects primarily in the night is similar to the nighttime role of mammalian astrocytes in regulating circadian behavior 3. It also highlights the importance of this cell class in regulating deep and homeostatically-controlled sleep, which occurs predominantly in the night 8. Our proposal will test specific hypotheses concerning communication between astrocytes and neurons with an emphasis on understanding how such communication modulates sleep and activity cycles. Aim 1 of this application will employ methods to activate or inhibit astrocytes to test the hypothesis that distinct astrocyte subpopulations and particular signaling molecules modulate specific properties of sleep and circadian behavior. This aim will also utilize genetic methods to visualize connections between astrocyte and neuronal processes to identify potentially communicating cell types. Aim 2 will employ genetic cell activation techniques in live brains together with genetic reporters of neural excitation and second messenger signaling to define mechanisms of reciprocal communication between specific astrocyte subpopulations and neurons regulating sleep or circadian rhythms. This aim will test hypotheses about roles for specific astrocyte signaling molecules in regulating the physiology of the relevant neuron classes. Aim 3 will utilize genome-wide transcriptome profiling methods and behavioral protocols to identify intracellular pathways and signaling molecules required for normal sleep or circadian behavior. Given the conservation of molecular and neuronal mechanisms controlling sleep and circadian behavior in flies and humans, our proposed studies have relevance for understanding roles of neuron-glia communication in neural development, normal brain function, and the behavioral/neurological diseases that are known to result from abnormal neuron-glia communication 9,10.
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