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

Abstract

SUMMARYThe 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.GRAPHIC ABSTRACT Presynaptic plasticity at the active zone (AZ) during early aging triggers sleep pattern changes, and subsequently steers trade-offs between memory formation and longevity. Interventions like spermidine (Spd) and Gaboxadol (THIP) supplementation suppress PreScale and allow for new memory formation and lifespan extension.