Autophagy-driven Presynaptic Reorganization as a Molecular Signature of Brain Resilience.

Neural circuits must remain functionally stable while responding flexibly to changing demands, stressors, and aging-related decline. While this balance is thought to be maintained through plasticity programs that integrate molecular, metabolic, and activity-dependent signals to reconfigure synapses structurally and functionally, direct mechanistic models of how such adaptations are orchestrated remain scarce. Here, we show that targeted impairment of autophagy in the Drosophila mushroom body (MB), a key sleep-regulatory and integrative center in the fly brain, triggers a brain-wide remodeling at presynaptic active zones (AZ). Quantitative proteomics revealed a specific upregulation of AZ scaffold proteins (including BRP, RIM, and Unc13A), accompanied by reduced levels of calcium channel subunits and increased Shaker-type potassium channels. These changes occurred largely independent of transcription and highlight a coordinated, excitability-tuning response centered on the AZ. Behaviorally, MB-specific autophagy impairment increased sleep and modestly extended lifespan. These adaptations resembled a previously described resilience program termed PreScale, which promotes restorative sleep homeostasis in response to sleep deprivation and early, still reversible brain aging. Conversely, overexpression of Atg5 in the MB delayed the onset of PreScale. Notably, autophagic disruption confined to MB neurons also caused widespread, non-cell autonomous accumulation of Ref(2)P and ATG8a-positive aggregates across the brain, revealing systemic propagation of proteostatic stress. Together, our findings identify MB autophagy as a key regulator of synaptic architecture and sleep-associated resilience. Such early acting programs may actively preserve circuit function and behavioral output by regulating synaptic plasticity, and define a genetically tractable model for how local stress signals can orchestrate brain-wide adaptation via post-transcriptional synaptic reprogramming.