Neural Mechanisms of Empathy Loss in Frontotemporal Dementia - Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative diseases caused by focal and progressive atrophy of frontal and/or temporal lobes and is the leading cause of dementia before the age of 60 and the second most common form of dementia after Alzheimer’s disease (AD). There is no cure. Among several variants within the FTD spectrum, the behavioral variant (bvFTD) is the most prevalent, accounting for nearly 50% of all FTD cases. bvFTD is characterized by marked changes in personality, impaired judgement and social conduct, and blunted emotion and affect, including a loss of empathy, which represents arguably the most distressing and defining feature of bvFTD. The underlying neural mechanisms are unknown. About 40-50% of FTD cases are familial and associated with mutations of over a dozen genes with diverse molecular and cellular functions, among which GGGGCC (G4C2) hexanucleotide repeat expansions (HREs) in the chromosome 9 open reading frame 72 (C9orf72, or C9) gene is the most common genetic cause of FTD. We established an bvFTD mouse model of empathy loss and observed that aged somatic transgenic mice expressing G4C2 HREs in C9orf72 exhibited blunted affect-sharing and failed to comfort distressed conspecifics by affiliative touch. Our preliminary studies found that a marked reduction of pyramidal neuron excitability in the dorsomedial prefrontal cortex (dmPFC) in aged mutant mice underlies their lost empathy. Remarkably, restoring dmPFC neuronal excitability rescued the empathy deficits in mutant mice, even at advanced ages when substantial cortical atrophy had occurred. These results establish dmPFC hypoexcitability as a potential pathophysiological basis of empathy loss in bvFTD. The goals of this R01 application are to define the prefrontal circuits mediating empathy-driven consolation behavior (Aim 1), delineate the intrinsic, synaptic, and circuit mechanisms of lost empathy in C9-bvFTD mouse models (Aim 2), and explore therapeutic strategies that can rescue, reverse, and prevent empathy loss in mutant mice (Aim 3). The proposed studies are fundamentally important and highly significant because they have the immediate potential to uncover novel pathogenic mechanisms and treatment strategies for FTD and related dementia.
