Metformin Restores Innate Fear Deficits in Young Adult Female APP/PS1 Mice via Basolateral Amygdala Activation

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by cognitive decline and neuropsychiatric symptoms, among which impaired fear responses are particularly notable. While studies have established that learned fear is compromised in AD, the status of innate fear in this context remains unclear. We found that young adult female APP/PS1 mice exhibited reduced freezing and avoidance responses to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) compared to their wild-type littermates, indicating an impaired innate fear response. Additionally, c-Fos-positive cells in the basolateral amygdala (BLA), a key region for fear processing, were significantly lower in the APP/PS1 mice. Notably, metformin treatment significantly restored TMT-induced freezing behavior and increased c-Fos-positive cells in the BLA, suggesting that it can reverse the innate fear deficit in this AD model. Mechanistically, chemogenetic inactivation of the BLA abolished the therapeutic effects of metformin on the innate fear deficit. Our study suggests metformin as a promising candidate for therapeutic intervention aimed at improving innate fear-related behavioral deficits in AD.