BRC-BIO: The role of serotonin signaling in autoregulation of axon morphology, connectivity, and behavior in Drosophila

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The primary role of the nervous system is to perceive conditions in our surroundings and elicit the appropriate behavioral response. This is controlled by complex neural circuits that are interconnected through long cable-like structures called axons. One important group of axons arises from serotonin-producing brain cells, which integrate with circuits throughout the nervous system to modulate behaviors such as mood, sleep, appetite, and cognition. Ultimately, these behavioral outputs are determined by the precise growth and wiring of axons. Recent work by the PI and others in the field has shown that serotonin-producing brain cells use serotonin itself to help shape its axons during early stages of development. This research will utilize cutting-edge genetic tools available in fruit flies, Drosophila melanogaster, to understand how this molecular mechanism works inside the cells, how it shapes circuits in the brain, and how it impacts behavioral output. The fruit fly nervous system is built with the same basic components, which assemble and direct neural activities as they do in the human nervous system. The knowledge gained will therefore provide insight into how abnormal serotonin exposure during development can lead to behavioral disorders in humans. These studies will provide students with multidisciplinary research experiences in genetics, cellular biology, and neuroscience through paid research positions. By reducing financial barriers to undergraduate research at an institute serving large populations of low-income and first-generation college students, this project advances the NSF mission to grow a diverse STEM workforce.Preliminary in vitro experiments indicate the serotonin receptor 5-HT1A initiates signaling events that autoregulate serotonergic axon outgrowth. The first objective of this project is to determine the intracellular mechanisms 5-HT1A engages using genetic and pharmacological manipulation of candidate serotonin signaling pathways in primary Drosophila serotonergic neurons paired with morphometric analysis of axon outgrowth and live cell imaging of actin dynamics. The second objective of this project is to determine how autoregulation shapes anatomical circuits using a single serotonergic neuron (SP2-1) as a model. This neuron innervates the larval visual system and can be labeled selectively using existing genetic tools, allowing 3D reconstructions of the SP2-1 neuron under various experimental conditions. A novel anterograde trans-synaptic Brainbow labeling approach will be used to ask how changes in serotonin signaling alter connectivity of the SP2-1 neuron. The third objective is to understand how defects in serotonin autoregulation can alter behavioral outputs by manipulating serotonin signaling and correlating changes in SP2-1 morphology to changes in vision-based behaviors. These studies will provide the first molecular mechanism of serotonin autoregulation and its impact on the morphological and functional development of the serotonergic system. This research pipeline will also serve as a foundation for future research including analysis of different cell types and/or circuits, behavioral paradigms, other signaling molecules, and developmental stages.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.