In Vivo Fiber Photometry Reveals Signature of Future Stress Susceptibility in Nucleus Accumbens.

Recognizing why chronic stress causes only a subset of individuals to become depressed is critical to understanding depression on a basic level and, also, to developing treatments that increase resilience. Stress-induced alterations in the activity of reward-related brain regions, such as the nucleus accumbens (NAc), are linked to the pathophysiology of depression. However, it has been difficult to determine if differences in stress susceptibility are pre-existing or merely an effect of chronic stress. The NAc consists largely of medium spiny neurons (MSNs), distinguished by their predominant expression of either D1 or D2 dopamine receptors. Mice that develop depressive-like symptoms after chronic social defeat stress show distinct changes in the activity of these two cell subtypes. Until now it has not been possible to determine whether such effects are merely a consequence of stress or in fact precede stress and, thus, have utility in pre-identifying stress-susceptible individuals. The goal of this study was to define a cell-type specific signature of stress susceptibility and resilience. Using fiber photometry calcium imaging, we recorded calcium transients in NAc D1- and D2-MSNs in awake behaving mice and found that D1-MSN activity is a predictive marker of depression susceptibility: prior to stress, mice that will later become resilient had increased baseline D1- MSN activity, and increased calcium transients specific to social interaction. Differences in D2- MSN activity were not specific to social interaction. Our findings identify a pre-existing mechanism of stress-induced susceptibility, creating the potential to target preventative interventions to the most relevant populations.