Scott Waddell - US grants

DESCRIPTION (provided by applicant): 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.

DESCRIPTION (provided by applicant): 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.

DESCRIPTION (provided by applicant): We use our memories to guide our life. For the most part, we are able to effectively use memory to direct behavior as, and when, we want to. For example, although you know where your fridge is, you do not go there unless you are hungry. However, in certain disease-states, such as affective disorders and addiction, motivational control goes awry and behavior becomes compulsive. The long-term goal of this proposal is to understand how the brain systems encoding memory integrate with the neural networks that determine motivation. We will specifically investigate how the `motivation to feed' network interacts with appetitive memory (formation and retrieval) to guide food-seeking behavior at the appropriate time. 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 sophisticated genetic approach. We will use the most up to date technology available in Drosophila to manipulate and elucidate the role of monoaminergic and Neuropeptide Y signaling systems in the fly brain that have conserved counterparts in the mammalian brain. We therefore expect that these studies will have a major impact on strategies for human mnemonic therapy, addiction and a wide variety of mental disorders. PUBLIC HEALTH RELEVANCE The ability to appropriately direct behavior using our memories is something we take for granted. However, in certain disease-states, such as affective disorders and addiction, our motivational control goes awry and behavior runs amok. This proposal will explore how the brain systems encoding memory integrate with the neural networks that determine motivation. Our work will provide fundamental knowledge of how conserved cell signaling systems motivate behavioral memory performance and we expect these studies will provide relevant therapeutic avenues against a wide variety of mental disorders.

DESCRIPTION (provided by applicant): Memory is a fundamental element of human life yet it remains one of the greatest mysteries of modern biological research. Memory loss through neurological disease, such as Alzheimer's, or head trauma, has a devastating impact on the quality of life. Understanding the molecular process of memory would therefore provide potential avenues for mnemonic therapy. The long- term goal of this proposal is to understand how memories are formed, consolidated and retrieved at the molecular, cellular and neural network 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 sophisticated genetic approach. We will use the most up-to-date technology available with a new appetitive long-term memory assay to investigate how conserved signaling molecules function within the context of defined neural circuits to encode memory. We expect that these studies will have a major impact on strategies for human mnemonic therapy. PUBLIC HEALTH RELEVANCE: Memory is a critical element of human existence. Consequently, memory loss through neurological disease, such as Alzheimer's, or head trauma, severely impacts quality of life. Our work will provide a fundamental understanding of the cellular, molecular and neural circuit processes of memory providing potential avenues for mnemonic therapy in humans.