Project Summary Frontotemporal dementia (FTD) is a leading cause of presenile dementia and is characterized by progressive atrophy of the frontal and/or temporal lobes. There is no cure nor FDA-approved treatment to slow disease progression. The most prevalent cause is a G4C2 repeat expansion located in the non-coding region of C9orf72, leading to several pathologies including the formation of dipeptide repeat proteins. Arginine-containing dipeptide repeat proteins, including poly(GR), are especially toxic. The most common form of FTD is behavioral variant FTD (bvFTD), where marked changes in personality occur, including the loss of empathy, considered one of the most distressing symptoms. Treatments aimed at alleviating the loss of empathy are limited and the neural mechanisms underlying loss of empathy are poorly understood. Therefore, there is a critical need to identify and develop therapeutic treatments to restore loss of empathy in bvFTD. The overall goal is to elucidate the neural mechanisms underlying this loss of empathy and to identify potential therapeutic targets to restore empathy in bvFTD. The dorsomedial prefrontal cortex (dmPFC) is a main site of FTD pathogenesis and regulates empathy-driven consolation. We use a poly(GR) mouse model for bvFTD, where poly(GR) accumulates in an age-dependent manner. Strikingly, mutant mice exhibit a complete loss of consolation starting at 9-months of age, coinciding with middle-age. In mutant mice, we found that dmPFC layer 5 pyramidal neurons become hypoexcitable during a transition into middle-age and that oxytocin can restore empathy. In the F99 phase, I will establish oxytocin as a novel therapeutic strategy for the treatment of lost empathy in bvFTD and delineate the detailed neural mechanisms and circuitry by which oxytocin restores consolation using behavior, slice electrophysiology, and opto- and chemogenetic circuit manipulations to establish that oxytocin in the dmPFC enables consolation and restores neurophysiology. I will learn advanced patch-clamp electrophysiology skills and optogenetics before the transition to the K00 phase. The nervous system undergoes numerous changes during aging. However, little is known about how the electrical properties and associated molecular signatures of neurons change across the lifespan and in disease. There is a crucial need to understand how alternations in these functions are disrupted in and contribute to disease. The goal of the K00 phase is to identify age-dependent mechanisms contributing to lost empathy in bvFTD. I will characterize age-dependent neuronal firing patterns and associated molecular signatures in wild-type and bvFTD mice engaged in empathy behaviors and will restore impaired empathetic behavior by targeting identified neurophysiological and molecular alternations. I will learn and use in vivo electrophysiology, single- cell RNA-seq, and patch-seq. Completion of the F99 and K00 aims will fill critical gaps in our understanding of th...