Dissecting sex hormone effects on genes, neurons, and behavior using cichlid fish

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Juntti | Project Summary The overarching goal of my research program is to understand how hormones shape the neural pathways that control social behavior. Gonadal hormones are key regulators of development and adult neural function, and their signaling leads to profound differences in vertebrate animal reproductive and aggressive behaviors across sexes. Differences in hormone signaling across men and women could contribute to discrepancies in incidence of neuropsychiatric conditions, but the neuronal and transcriptional basis for their actions are not clear. These hormones may determine the connectivity of cells, their activity patterns, or both. Reproductive behaviors in cichlid fish are an ideal model system to understand how hormones impact gene transcription and neural circuit function. Cichlid social behaviors have been studied for nearly a century, and are complex yet stereotyped and quantifiable. Dozens of cichlid species have sequenced genomes, and we have pioneered CRISPR gene editing and transgenesis in these species. We have identified a population of neurons sensitive to the hormones progestin and prostaglandin F2α (PGF) that is essential for spawning behavior. Progestin receptor (PR) signaling regulates gene expression in these cells, while PGF and its receptor, Ptgfr, are sufficient and necessary to initiate spawning. We seek to determine the contribution of Ptgfr+ cells to a variety of social behaviors through genetically directed manipulation of these cells. The implementation of the QF-QUAS system for the first time in cichlids will permit studies of these and other cells. Like other steroid hormone receptors, PR acts as a ligand-activated transcription factor. However, its genomic targets are not known in brain, and so it is not clear how it regulates behavior. We will identify how PR regulates cichlid behavior routines and determine the genomic targets of PR that underlie its actions. The production of progestin (and other steroids) is regulated by the hypothalamic-pituitary-gonadal axis. Sensory inputs regulate the production of progestin in cichlids: male odorants promote its synthesis. We will identify cell groups that mediate this signaling from olfaction to the endocrine system. These approaches will build upon our previous findings and leverage technologies that we have developed, together yielding insights into how the vertebrate brain regulates and responds to sex hormones. These experiments will lay a foundation for understanding the gene networks coordinated by hormones and delineating the neurons that regulate social behaviors.