Understanding Foxp2-Mediated Molecular Signaling in Fear Learning

Project Summary/Abstract Post-Traumatic Stress Disorder (PTSD) is a common and debilitating mental illness with limited available personalized treatments. Recent Genome-Wide Association Studies (GWAS) have begun to elucidate significant target genes implicated in this disease. One of these recently identified targets is the transcription factor Foxp2. Foxp2 has been previously implicated in language learning disorders, however, its role in adult fear learning is unknown. In adult mice, Foxp2 mRNA is expressed in clusters of Intercalated Cells surrounding the basolateral amygdala. Intercalated Cells are functionally important for conditioned fear response and fear extinction; however, the role of the Foxp2 transcription factor, its upstream mediators and downstream targets, in modulating fear-related behaviors in the amygdala remains unknown. Recent evidence suggests that Foxp2 is regulated by multiple components of the Wnt signaling pathway and, in turn, acts in a feedback loop to modulate regulation of Wnt pathway members. In this proposal, I will test the hypothesis that Foxp2 regulates specific components of fear learning through its interaction with the Wnt signaling pathway in the Intercalated Cells of the amygdala. In Aim 1, I will test transcriptional regulation of Foxp2 in the amygdala during fear learning. I will perform a time-course analysis of Foxp2 transcription after fear learning using RT-PCR and RNAscope. I will also use single nuclei sequencing following Foxp2 knockout to characterize Foxp2 targets in specific cell types within amygdala after fear learning. Finally, I will perform fear-related behavioral characterization with amygdala-specific Foxp2 knockout using male and female adult mice. In Aim2, I will mechanistically test the hypothesis that Foxp2 is regulated by Wnt signaling pathway during fear learning, building on prior work from the Ressler Lab that showed the role of Wnt signaling pathway components in adult learning and memory. The outlined K08 proposal will build on my prior experience in developmental pathways, molecular biology and genetics, while continuing training in a mammalian model of disease-relevant neural circuitry. The ultimate goal of this proposal is to further my technical and professional skills while collecting data that will form the basis for obtaining independent funding on a path to becoming an independent Physician-Scientist.