Project Details
Projekt
Non-cell autonomous regulation of synaptic upscaling by neuronal autophagy
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 447288260
Macroautophagy is an evolutionarily conserved cellular maintenance program, capable to protect the brain from premature aging and neurodegeneration. How neuronal autophagy intersects with neuronal processes mediating brain maintenance and ageing remains to be explored. We found that impairing autophagy in the Drosophila learning center (mushroom body, MB) but not in other brain regions triggered changes normally restricted to aged brains: it resulted in impaired associative olfactory memory as well as a brain-wide ultrastructural increase of presynaptic active zones (“upscaling”), a state acutely incompatible with effective memory formation. Mechanistically, decreasing autophagy within the MBs reduced expression of a Neuropeptide Y (NPY)-family neuropeptide, and interfering with autocrine NPY signaling of the MBs provoked similar brain-wide metaplastic changes. Thus, autophagy-regulated neuropeptide signaling emanating from a specific brain integration center executes higher-level non-cell autonomous control over other brain regions to steer life-strategy decisions such as whether or not to form memories. In mice, NPY was found to mediate beneficial effects exerted by caloric restriction and nutrient-sensing pathways via autophagy induction in hypothalamic neurons. We will now study both fly mushroom body and murine hypothalamus in a comparative way to test the hypothesis that a bidirectional interaction of autocrine NPY signaling with macroautophagy exists in NPY secreting neurons. We propose that these neurons send signals such as NPY and potentially others to age-protect aspects of metabolic state and synaptic function for the remaining brain.
DFG Programme
Research Units
