Secreted astrocyte proteins regulating rhythmic behavior

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Summary In both mammals and insects, brain astrocytes cooperate with neurons to modulate sleep and circadian behavior (reviewed in [1-3]). To identify Drosophila astrocyte genes that modulate rhythmic behaviors, we conducted an astrocyte-specific transcriptome-wide expression analysis to define mRNAs that are regulated in a circadian manner. We show that >250 astrocyte mRNAs exhibit circadian changes in ribosome association, suggesting rhythmic translation of these transcripts (You et al., submitted). A number of these “cycling” genes encode small secreted astrocyte proteins (cytokine-like or antibacterial) of the Bomanin (Bom), Turandot (Tot) or Growth Blocking Peptide (Gbp) families that are known to be induced by mechanical or immune stress. A number of these genes are regulated by the conserved Toll/Immune Deficiency (IMD) signaling pathways and our studies show that components of these pathways also cycle in abundance in adult astrocytes. Cytokine-like secreted factors modulate sleep during pathological immune responses, but there is also evidence that they normally regulate rhythmic behavior. Given that these cycling cytokine and antibacterial genes are stress- induced, we hypothesize that they function to promote sleep in response to the stress associated with wakefulness. Indeed, our unpublished results show that an astrocyte deficit for BomBc2 – a Toll-regulated, cycling gene that encodes a cytokine-like protein – results in decreased sleep amount and quality. Of related significance, it has been shown that deficits for the mouse Toll-4 or Toll-2 receptors, respectively, alter the response to sleep loss [4] or consolidation of mouse circadian activity [5]. This application proposes 2 related aims to test the hypothesis that rhythmically activated astrocyte signaling pathways and secreted proteins contribute to the regulation of circadian behavior or sleep plasticity. Aim 1 will define the cell types of the adult fly brain that require cycling secreted proteins or Toll/IMD signaling components for normal rhythmic behaviors (circadian and sleep). As these secreted proteins are induced by mechanical or immune stress, this aim will also test the novel hypothesis that they are induced by sleep deprivation, in a Toll/IMD-regulated manner, to function in sleep homeostasis. Aim 2 will determine the in vivo expression patterns for the secreted proteins and Toll/IMD signaling components encoded by cycling mRNAs. It will also ask whether they cycle in abundance in specific cell types of the adult fly brain. This aim will also employ CRISPR methods to determine the contribution(s) of neuronal and glial circadian clocks to the regulation of cycling astrocyte proteins. Altogether, these aims will identify astrocyte factors that are required for circadian behavior or sleep plasticity and define intracellular signaling pathways regulating their cycling expression.