Biology subjects

Killiany, S.

Publications and source records attributed to Killiany, S..

3 recordsLinked to original sources

bioRxiv2025

Sleep controls peroxisomal abundance to reduce wake-induced brain oxidation

Sleep is increasingly linked to the regulation of Reactive Oxygen Species (ROS) and lipid metabolism. However, the mechanisms underlying this interaction are underexplored. Here, we use Drosophila melanogaster to report a bidirectional relationship between sleep and peroxisomes, cellular organelles that process lipids and alleviate ROS. Of the genes that change expression after sleep deprivation in the dorsal fan-shaped body, knockdown of the peroxisomal biogenesis factor Pex16 results in decreased sleep. Pex16 acts in several brain regions to modulate sleep amount, with ellipsoid body neurons (EB) producing the highest sleep reduction of the sleep-promoting regions. Consistent with a general role for peroxisomes, knockdown of other peroxisomal enzymes relevant for lipid import and synthesis also decreases sleep. Whole-brain peroxisomal numbers increase with wake, which is supported by lipidomic analysis indicating that peroxisomal-derived phospholipids are the major contributors to phospholipid changes after wake or sleep deprivation. Peroxisomal proliferation in the EB is driven by neuronal activity and increased oxidation, suggesting that these mediate the effect of wake/sleep loss. In turn, peroxisomes alleviate the oxidation accumulated during wake, such that loss of Pex16 in the EB works non-cell autonomously to increase lipid peroxidation brain-wide. This likely contributes to sleep loss, as sleep is rescued with an antioxidant. Together, these results position peroxisomes as key players in sleep, regulating ROS and thereby maintaining normal cycles.

neuroscience↗

bioRxiv2025

Sleep-dependent clearance of brain lipids by peripheral blood cells

Sleep is typically viewed through a brain-centric lens, with little known about the role of the periphery. Here, we identify a sleep function for peripheral macrophage-like cells (hemocytes) in the Drosophila circulation, showing that hemocytes track to the brain during sleep and take up lipids accumulated in cortex glia due to wake-associated oxidative damage. Through a screen of phagocytic receptors expressed in hemocytes, we discovered that knockdown of eater, a member of the Nimrod receptor family, reduces sleep. Loss of eater also disrupts hemocyte adhesion to the brain and lipid uptake, which results in increased brain levels of Acetyl CoA and acetylated proteins, including mitochondrial proteins PGC1 and DRP1. Dysregulation of mitochondria, reflected in high oxidation and reduced NAD+, is accompanied by impaired memory and lifespan. Thus, peripheral blood cells, which we suggest are precursors of mammalian microglia, perform a daily function of sleep to maintain brain function and fitness.

molecular biology↗

bioRxiv2023

Sleepiness, not total sleep amount, increases seizure risk

Sleep loss has been associated with increased seizure risk since antiquity. Despite this observation standing the test of time, how poor sleep drives susceptibility to seizures remains unclear. To identify underlying mechanisms, we restricted sleep in Drosophila epilepsy models and developed a method to identify spontaneous seizures using quantitative video tracking. Here we find that sleep loss exacerbates seizures but only when flies experience increased sleep need, or sleepiness, and not necessarily with reduced sleep quantity. This is supported by the paradoxical finding that acute activation of sleep-promoting circuits worsens seizures, because it increases sleep need without changing sleep amount. Sleep-promoting circuits become hyperactive after sleep loss and are associated with increased whole-brain activity. During sleep restriction, optogenetic inhibition of sleep-promoting circuits to reduce sleepiness protects against seizures. Downregulation of the 5HT1A serotonin receptor in sleep-promoting cells mediates the effect of sleep need on seizures, and we identify an FDA-approved 5HT1A agonist to mitigate seizures. Our findings demonstrate that while homeostatic sleep is needed to recoup lost sleep, it comes at the cost of increasing seizure susceptibility. We provide an unexpected perspective on interactions between sleep and seizures, and surprisingly implicate sleep- promoting circuits as a therapeutic target for seizure control.

neuroscience↗