Neurotransmitter Plasticity and Regulation of Behavior

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Project Summary Neurons have classically been defined by the neurotransmitter they release. This “identity” has been considered to be both singular (i.e. one transmitter) and immutable (i.e. genetically hardwired). While the astonishing prevalence of cotransmission has changed thinking about the singularity of neurotransmitter identity there has been considerably less appreciation of the ability of neurons to exhibit plasticity in their expression. Recently, we discovered that the microRNA miR-190 is a potent regulator of adult sleep. Spatial and temporal mapping of its site of action demonstrates that it is required during pupation in a population of cells that transcribes both cholinergic and glutamatergic genes but differentiates to become a small subset of the adult glutamatergic neurons. This subset includes components of the core sleep homeostasis circuit. We will test the hypothesis that a neurotransmitter plasticity event is critical to function of the mature circuit and that it provides a novel mechanism for establishing, and potentially modifying, the sleep set-point of the homeostatic machinery. Aim 1 will determine the role of neurotransmitter plasticity in the control of adult sleep, with a focus on understanding the circuit-level changes. Aim 2 will investigate the role of neuronal activity in transmitter switching and homeostat plasticity, with a focus on understanding the molecular events. In this proposal, we bring the power of Drosophila genetics to bear on this novel and important type of plasticity. We demonstrate that programmed transmitter plasticity during pupal life is crucial to adult function of the sleep circuitry. The genetic reagents we have developed will allow us to address basic mechanisms underlying transmitter plasticity in the context of both the developing and mature nervous systems and, for the first time, link this type of plasticity to sleep.