Friday, March 03, 2023

Empathy lost and regained in a mouse model of dementia

A PNAS Journal Club article by Carolyn Beans points to work by Yao and colleagues that shows that a loss of empathy that is especially problematic for those experiencing frontotemporal dementia (FTD...a rare condition that often develops earlier in life than other types of dementia) can be linked to slowed activity in a particular brain region of a mouse model of FTD. When Yao and colleagues experimentally increased brain activity, empathy returned. Here is the technical abstract of Yao and collaborators:


• Mice display dmPFC-dependent emotional contagion and other-directed consolation
• Emotional contagion and other-directed consolation are blunted in aged c9FTD mice
• Aged c9FTD mice exhibit reduced pyramidal neuron excitability in the dmPFC
• Enhancing dmPFC activity rescues empathy loss in aged c9FTD mice
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.

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