A choice disinhibition paradigm to reveal neural correlates of behavioral disinhibition in Frontotemporal dementia

Behavioral disinhibition is a hallmark symptom of behavioral variant frontotemporal dementia (bvFTD). There is no cure or strategy to slow progression, mainly due to little understanding of how disinhibition occurs and the mechanisms underlying self-control. To date, disinhibition has not been demonstrated in an FTD model. We designed a paradigm to assess disinhibition, separating general cognitive capacity, and found that aged mutant mice display increased impulsive choice but have intact cognition, suggestive of early-mid- stage bvFTD-associated symptoms. Further, the neural mechanisms underlying self-control are dissociable from impulsive choice; CaMKIIlower case Greek alpha- and somatostatin-expressing neurons in the medial prefrontal cortex, but not the classical anterior cingulate cortex, were activated during self-control. Together, we demonstrate behavioral disinhibition in mutant mice and identified specific regions and cell types that underlie self-control. This paradigm is viable for future work dissecting neural circuits underling impulsive choice and self-control behavior in bvFTD and other neurological conditions.