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Neural mechanisms of behavioral variant frontotemporal dementia: identification, characterization, and normalization of disrupted prefrontal cortical circuits in mice
Kobeissi, Aya
Kobeissi, Aya
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2025-12-22
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AyaKobeissiDissertation2025.pdf
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Frontotemporal dementia (FTD) is a leading cause of early onset dementia and is characterized by progressive and focal atrophy of the frontal and/or temporal lobes. The most prevalent subtype is behavioral variant FTD (bvFTD), characterized by marked changes in personality, behavioral disinhibition, and the loss of empathic capacity, typically manifesting as a lack of compassion towards others. To date, there is no cure. Lost compassion and disinhibition are two of the most distressing features for people with bvFTD and their close kin, largely due to little understanding of the neural mechanisms that drive these behaviors and how they are impaired in disease. Therefore, there is a critical need to elucidate the mechanisms that underlie disinhibition and empathic behaviors, how these mechanisms are disrupted in bvFTD, and to develop targeted treatments. Despite genetic and pathogenic heterogeneity, similar behavioral symptoms arise in FTD suggesting dysfunction of the same neural circuits. In this dissertation, I performed comprehensive behavioral studies, pharmacology, viral cell and circuit manipulations, fiber photometry, and patch-clamp electrophysiology to identify a potential therapeutic strategy to alleviate loss of compassion in a bvFTD model. I established a mouse model of bvFTD harboring a highly toxic pathogenetic factor the abnormal formation of poly(GR) dipeptide repeat proteins, that recapitulates the core behavioral symptoms and identified care-related disinhibition in mutant mice. I identified that compassionate action is dissociable behaviorally and mechanistically from empathy and other empathic behaviors. Further, this compassion circuit is modulated by oxytocin (Oxt) action within a paraventricular nucleus to dorsomedial prefrontal cortical (dmPFC) pathway. Further, I found that hypofunction of this circuit in bvFTD mice underlies the loss of compassion, but not affect sharing or general behavior. Remarkably, a single, non-invasive intranasal dose of Oxt fully restores compassion in mutant mice by normalizing the intrinsic function of excitatory dmPFC neurons and restoring the balance of network excitation-inhibition, ultimately reactivating a hypofunctional dmPFC. Importantly, reactivation of the dmPFC via local pharmacology fully restored compassion and is likely a viable therapeutic strategy for people with bvFTD.
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