Decoding stress susceptibility from activity in amygdala-ventral hippocampal network

Mood disorders are characterized by behavioral changes arising from network-level alterations, with the amygdala (AMY)-ventral hippocampus (vHPC) pathway being a central component. Anhedonia, the reduced ability to feel pleasure, is a core feature of mood disorders. However, how stress-induced changes in motivation to seek and consume rewards are represented in the activity patterns in the AMY and vHPC remains unclear. Furthermore, how these activity patterns can inform pathway-specific manipulations to rescue anhedonic behavior remains to be explored. Here, we used Neuropixels probes to record AMY and vHPC single units in mice following chronic social defeat stress (CSDS) to assess how stress modulates representations of reward choice and reward-seeking behavior. First, we explored whether anhedonia is linked to reduced discriminability of reward values in vHPC and AMY. Surprisingly, we found that vHPC and AMY neurons in CSDS mice showed enhanced reward choice sensitivity in comparison to controls. Furthermore, we could decode future reward choices from vHPC and AMY activity in mice susceptible to CSDS, seconds before mice made their choice, suggesting inflexibility in reward representations. This was accompanied by reduced sensitivity to reward delivery. We next explored how neural activity differs between groups before mice were task-engaged. We found that the neural representations in AMY of susceptible mice have higher embedding dimensionality with fewer correlated states, suggesting that even in the absence of behavior, AMY activity patterns can differentiate mice of varying stress susceptibility levels. Inter-regionally, AMY-vHPC coordinated activity was correlated with sucrose preference, suggesting that reduced AMY-vHPC interaction may underlie anhedonia. To correct this, we chemogenetically activated the vHPC-AMY pathway, which enhanced vHPC-AMY correlated activity and rescued anhedonic behavior. Together, our results show that reward choice representations in the AMY and vHPC are altered in susceptible mice, and these changes may be responsible for ultimately driving anhedonic behavior following stress.