We all have memories and we all know that we forget some of the crucial ones - especially as we grow older. Our long-term objective is to understand how a brain encodes memory at the molecular and cellular level. We use the fruit fly Drosophila as our model system because it can learn, it has a relatively simple brain and it is amenable to a genetic approach. This application focuses on the Drosophila amnesiac (amn) mutant. Mutant amn flies have poor memory. The amn gene encodes a putative preproneuropeptide with homology to the mammalian neuromodulator pituitary adenylyl cyclase activating peptide (PACAP). We will take molecular genetic and behavioral approaches to understand the role of amn in memory. Our specific aims are: 1. Identify the AMN neuropeptide fragment(s) that are required for memory. Are all the putative fragments of the precursor required for memory and if not, which ones are? Is the PACAP homology important? 2, Identify the memory-relevant AMN receptor(s). Are the predicted fly PACAP-type receptors involved in memory? Are they the AMN receptor(s)? 3. Delineate the intracellular signaling cascade affected by AMN. We have a mutant in a new potential component of PACAP signaling - a receptor tyrosine kinase, off-track. We will analyze the involvement of off-track in learning and more specifically, in AMN signaling. The genes involved in Drosophila learning have related mammalian genes that function similarly. Furthermore, it is becoming increasingly clear that learning-like synaptic plasticity is engaged- in the relevant neural circuits - by drugs of human abuse. Therefore molecules we identify in Drosophila learning may ultimately be useful in human mnemonic and drug rehabilitation therapy.