Caspase Inhibition in Select Olfactory Neurons Restores Innate Attraction Behavior in Aged Drosophila

摘要

Sensory and cognitive performance decline with age. Neural dysfunction caused by nerve death in senile dementia and neurodegenerative disease has been intensively studied; however, functional changes in neural circuits during the normal aging process are not well understood. Caspases are key regulators of cell death, a hallmark of age-related neurodegeneration. Using a genetic probe for caspase-3-like activity (DEVDase activity), we have mapped age-dependent neuronal changes in the adult brain throughout the lifespan of Drosophila . Spatio-temporally restricted caspase activation was observed in the antennal lobe and ellipsoid body, brain structures required for olfaction and visual place memory, respectively. We also found that caspase was activated in an age-dependent manner in specific subsets of Drosophila olfactory receptor neurons (ORNs), Or42b and Or92a neurons. These neurons are essential for mediating innate attraction to food-related odors. Furthermore, age-induced impairments of neural transmission and attraction behavior could be reversed by specific inhibition of caspase in these ORNs, indicating that caspase activation in Or42b and Or92a neurons is responsible for altering animal behavior during normal aging. Author Summary The approaching era of an “aging society” is receiving considerable attention amongst biomedical researchers in advanced nations. In order to understand the molecular mechanisms underlying age-related alterations of neural circuitry, we focused on caspase-3, a cysteine protease that induces apoptotic cell death, using the fruit fly Drosophila melanogaster , a model often used to study aging due to a short lifespan of approximately 30–60 days. Here, we describe the spatiotemporal activation of caspase-3 in aged fly brains and show that caspase-3 is specifically activated in select olfactory neurons essential for innate odor attraction behavior. Furthermore, we discuss how inhibition of caspase-3 activation in those select olfactory neurons can rejuvenate the sensitivity of innate attraction behavior in aged flies. These findings suggest that caspase-3 plays an active role in producing age-related alterations to neuronal physiology and circuit function associated with animal behavior.