The long-term goal of this project is to understand the role that Notch mediated intercellular interactions play in adult brain function. While the role of Notch in animal development has been extensively studied, its role in the maintenance and function of adult nervous systems is less well understood. Recent findings are consistent with the possibility that Notch activity in neurons may influence synaptic structure and memory. However, none of these studies have allowed direct visualization of the effects of neural activity on Notch signaling in the brain, nor have they indicated how such signaling might alter brain function. The proposed research builds upon a direct visualization of Notch activation in Drosophila melanogaster at the single neuron level in response to environmental input. Specifically, Notch is activated in olfactory receptor neurons (ORNs) in an odorant specific fashion. This response requires the Notch ligand Delta and depends on functional olfactory receptors and synaptic transmission by the ORN. Notch activity in ORNs is necessary but not sufficient for long-term behavioral adaptation to odors. This proposal will explore the hypothesis that in response to chronic odor exposure, Notch regulated gene expression in ORNs alters the state of the neuron, leading to a change in the behavior of the fly. This hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism by which synaptic transmission by ORNs activates the Notch pathway. 2) Characterize the role Notch plays in behavioral long-term adaptation. 3) Identify the cellular and molecular changes induced in the ORN by Notch activation.
These aims will be addressed by a combination of genetic, behavioral, and microarray experiments. The pro- posed research is expected to provide a detailed understanding of how an environmental stimulus activates the Notch pathway in ORNs, leading to a change in the physiology of the sensory neuron, which ultimately leads to a change in behavior. This contribution is significant because it will be a first step in defining at a molecular level both the role Notch plays in behavioral plasticity and the changes in sensory neurons that mediate long-term behavioral adaptation. The proposed research is innovative because it presents new approaches to identifying and manipulating the requirement for Notch in the adult brain. Because the Notch pathway is evolutionarily conserved, understanding the role of Notch in long-term behavioral adaptation in flies is likely to be highly relevant to an understanding of both adaptation and memory in humans. Neuronal adaptation plays a role in addiction to drugs of abuse. Insight into the mechanism of adaptation may lead to novel treatments for addiction. Furthermore, as the average age of human populations increase, problems with memory become more common, and understanding the molecular basis of memory will become crucial for therapeutic intervention.
The proposed research is relevant to public health, because understanding evolutionary conserved signaling pathways in the brain that are involved in memory and adaptation is expected to provide insight into the pathologies of both the aging brain and drug addiction. This research is relevant to the part of NIH's mission that fosters fundamental creative discoveries to improve human health.
|Kidd, Simon; Lieber, Toby (2016) Mechanism of Notch Pathway Activation and Its Role in the Regulation of Olfactory Plasticity in Drosophila melanogaster. PLoS One 11:e0151279|
|Kidd, Simon; Struhl, Gary; Lieber, Toby (2015) Notch is required in adult Drosophila sensory neurons for morphological and functional plasticity of the olfactory circuit. PLoS Genet 11:e1005244|
|Lieber, Toby; Kidd, Simon; Struhl, Gary (2011) DSL-Notch signaling in the Drosophila brain in response to olfactory stimulation. Neuron 69:468-81|