A brain-wide form of presynaptic active zone plasticity orchestrates resilience to brain aging in Drosophila

Abstract

The brain as a central regulator of stress integration determines what is threatening, stores memories and regulates physiological adaptations across the aging trajectory. While sleep homeostasis is linked to brain resilience, how age-associated changes intersect to adapt brain resilience remains enigmatic. We here provide evidence that a brain-wide form of presynaptic active zone plasticity (“PreScale”) promotes resilience by coupling sleep, longevity and memory during aging. PreScale increased until mid-age and contributed to the age-adaption of sleep patterns, in effect promoting longevity but not memory of aging flies. Mechanistically, imaging and electrophysiology suggest that genetically-encoded PreScale reprograms neuronal activity, membrane firing patterns and excitability of the sleep-promoting dorsal fan-shaped body neurons, qualitatively similar to aging. Flies metabolically reprogrammed by spermidine towards extended longevity and preserved memory skipped PreScale and subsequently age-associated sleep pattern changes. Acute deep sleep induction in mid-age flies reset PreScale back to juvenile levels and restored memory. Taken together, early along aging trajectory, PreScale seems to steer trade-offs between longevity and memory, illustrating how life strategy manifests on circuit and synaptic plasticity levels.