Dorsomedial prefrontal hypoexcitability underlies lost empathy in frontotemporal dementia

Hannah L. Phillips, Huihui Dai, So Yoen Choi, Karen Jansen-West, Alexis S. Zajicek, Luke Daly, Leonard Petrucelli, Fen Biao Gao, Wei Dong Yao

Research output: Contribution to journalArticlepeer-review


Empathic function is essential for the well-being of social species. Empathy loss is associated with various brain disorders and represents arguably the most distressing feature of frontotemporal dementia (FTD), a leading form of presenile dementia. The neural mechanisms are unknown. We established an FTD mouse model deficient in empathy and observed that aged somatic transgenic mice expressing GGGGCC repeat expansions in C9orf72, a common genetic cause of FTD, exhibited blunted affect sharing and failed to console distressed conspecifics by affiliative contact. Distress-induced consoling behavior activated the dorsomedial prefrontal cortex (dmPFC), which developed profound pyramidal neuron hypoexcitability in aged mutant mice. Optogenetic dmPFC inhibition attenuated affect sharing and other-directed consolation in wild-type mice, whereas chemogenetically enhancing dmPFC excitability rescued empathy deficits in mutant mice, even at advanced ages when substantial cortical atrophy had occurred. These results establish cortical hypoexcitability as a pathophysiological basis of empathy loss in FTD and suggest a therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)797-806.e6
Issue number6
StatePublished - Mar 15 2023


  • affiliative behavior
  • behavioral variant FTD
  • C9orf72
  • consolation
  • dorsomedial prefrontal cortex
  • empathy
  • frontotemporal dementia
  • hypoexcitability
  • observational fear

ASJC Scopus subject areas

  • Neuroscience(all)


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