Candidate for PhD in Molecular, Cellular, and Developmental Biology

Abstract:
I aim to understand the interaction between the environment and the developing brain through investigating how sensory experience shapes behavior. Sensory experience modifies neural connections through activity-dependent plasticity, enabling animals to cope with environmental variability. Classic work, particularly those in vertebrate visual systems, has provided important insights into the mechanisms that underlie experience-dependent plasticity of the developing circuit. However, there are significant gaps explaining the mechanism by which sensory experience shapes circuit function during development. Particularly, how experience-dependent changes in synaptic transmission during development affect behavior in the mature animal are poorly understood. This dissertation examines how noxious sensory experience during development changes synaptic transmission in the nociceptive circuit to shape behavior in Drosophila melanogaster. Drosophila provides a relatively simple and genetically amenable model for analyzing both neural development and mechanisms underlying behaviors, and is thus a powerful model for discovering basic principles underlying experience-dependent plasticity during development. One well-characterized set of Drosophila sensory neurons is the nociceptors. The nociceptors respond to noxious environmental cues such as intense radiation, chemical or mechanical stimuli. The cell bodies and dendrites of these neurons lie just underneath the larval cuticle, and their dendrites receive sensory inputs from the environment. Their axons, in turn, project to the central nervous system to provide inputs to the nociceptive circuits, which eventually leads to appropriate motor responses. In larvae, activation of the nociceptors elicits a robust behavioral response. To address how noxious stimuli alters the nociceptive circuit, I have established a calcium live-imaging technique to physiologically measure neural dynamics within larval brains and have developed a behavioral assay to probe motor output. Through the use of these experimental techniques, I have determined that excessive noxious experience during a sensitive period in development modifies nociceptive behavior through an intrinsic program of circuit development. These findings suggest that the development of the larval nociceptive circuit is shaped by sensory inputs and neural activity. Moreover, my collaborative work demonstrates that the developmental plasticity is es¬tablished through serotonergic inhibition which specifically modifies synapses in the nociceptive, but not mechanosensory, pathway. We further show that excessive stimulation of nociceptors activates serotonergic neurons to sensitize the presynaptic terminals of nociceptors to serotoninergic inhibition after development is completed, leading to abated nociceptive behavior. This is the first demonstration, to our knowledge, that noxious sensory experience shapes the development of Drosophila, and reveals a neural mechanism involved in offsetting harmful environmental stimuli.