BK channel overactivity in NAc core D1R-expressing neurons elevates anxiety with age in mice

Anxiety disorders are the most common mental disorders in both younger and older adults. However, the current treatments for anxiety were developed based on younger adults and are not as effective in older adults. Therefore, investigating anxiety disorders in older adults would greatly benefit the mental well-being of the rapidly growing aged populations. This study finds that basal anxiety-like behaviors elevate with age in mice. This study further identifies an age-related increase in BK channel activity, which leads to a decrease in neuronal activity, in D1R-MSNs in the NAc core. These changes, when pharmacologically mimicked in young mice, reproduce the elevated anxiety-like behaviors that are normally seen in aged naïve mice. These changes, when pharmacologically normalized, reversed the elevated anxiety-like behaviors in aged mice. Accordingly, we conclude that the age-related increase in BK channel activity, and the consequent decrease in neuronal activity, in NAc core D1R-MSNs serves as a cellular physiological mechanism underlying the age-related elevation in basal anxiety-like behaviors in mice. Thus, this study provides a potential pharmacotherapeutic target for treating anxiety disorders specifically in older patients, the importance of which is highlighted by the high prevalence and high cost of anxiety disorders among the rapidly growing aged populations.