Molecular and cellular mechanisms of circuit evolution

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Project Summary Regenerative therapies offer the potential to reverse deficits arising from neurodegenerative disease, stroke, and traumatic brain injury. But the development of such treatments requires a comprehensive understanding of how to direct neurons to adopt appropriate functional properties and circuit identities. This proposal seeks to reveal fundamental principles of circuit design by identifying the permissible and predisposed molecular mechanisms evolution uses to drive changes in the courtship behaviors of drosophilids. Using a new model for comparative neurobiology that I have developed with my collaborators, I will compare homologous neurons in the pheromone processing pathways of four closely related Drosophila species. First, I will take advantage of highly stereotyped, species-specific pheromone preferences and in vivo neuroimaging to identify the sites of adaptation in pheromone processing circuits. By quantifying the courtship of each species in high resolution, I will be able to correlate differences in the pheromone preference behaviors observed between species to the changes observed in how pheromone cues are processed (Aim 1). This will elucidate the circuit motifs and dynamics that control the differential activation of an essential population of P1 interneurons that gate male entry into courtship across species. Next, to reveal the molecular underpinnings of adaptations in P1 connectivity and excitability, I will perform RNA sequencing on the P1 neurons of each species. This analysis will identify differentially expressed genes which I will test to determine how they regulate the functional properties of P1 and mate preference behaviors (Aim 2). Finally, I will assess when and how the transcription factor Fruitless–which specifies the male courtship circuitry–acts to organize the sexually dimorphic anatomy and function of P1 neurons in melanogaster males. Further, taking advantage of genetic pipelines I have built, I will use Targeted DamID to determine how changes in Fruitless target genes specify novel courtship behaviors across species (Aim 3). Under the continued mentorship of Dr. Vanessa Ruta, and supported by the substantial resources of Rockefeller University, I am well poised to complete the proposed research and shed new light on the molecular and cellular mechanisms that evolution uses to encode novel behaviors. In addition, a comprehensive career development plan, supported by my advisory committee, will ensure that I receive the conceptual, technical, and career training I require to successfully transition to independence at a top research institution.