Understanding the neural code of stress to control anhedonia

Frances Xia, Valeria Fascianelli, Nina Vishwakarma, Frances Grace Ghinger, Andrew Kwon, Mark M. Gergues, Lahin K. Lalani, Stefano Fusi and Mazen A. Kheirbek ()
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Frances Xia: University of California, San Francisco
Valeria Fascianelli: Columbia University
Nina Vishwakarma: University of California, San Francisco
Frances Grace Ghinger: University of California, San Francisco
Andrew Kwon: University of California, San Francisco
Mark M. Gergues: University of California, San Francisco
Lahin K. Lalani: University of California, San Francisco
Stefano Fusi: Columbia University
Mazen A. Kheirbek: University of California, San Francisco

Nature, 2025, vol. 637, issue 8046, 654-662

Abstract: Abstract Anhedonia, the diminished drive to seek, value, and learn about rewards, is a core feature of major depressive disorder1–3. The neural underpinnings of anhedonia and how this emotional state drives behaviour remain unclear. Here we investigated the neural code of anhedonia by taking advantage of the fact that when mice are exposed to traumatic social stress, susceptible animals become socially withdrawn and anhedonic, whereas others remain resilient. By performing high-density electrophysiology to record neural activity patterns in the basolateral amygdala (BLA) and ventral CA1 (vCA1), we identified neural signatures of susceptibility and resilience. When mice actively sought rewards, BLA activity in resilient mice showed robust discrimination between reward choices. By contrast, susceptible mice exhibited a rumination-like signature, in which BLA neurons encoded the intention to switch or stay on a previously chosen reward. Manipulation of vCA1 inputs to the BLA in susceptible mice rescued dysfunctional neural dynamics, amplified dynamics associated with resilience, and reversed anhedonic behaviour. Finally, when animals were at rest, the spontaneous BLA activity of susceptible mice showed a greater number of distinct neural population states. This spontaneous activity allowed us to decode group identity and to infer whether a mouse had a history of stress better than behavioural outcomes alone. This work reveals population-level neural dynamics that explain individual differences in responses to traumatic stress, and suggests that modulating vCA1–BLA inputs can enhance resilience by regulating these dynamics.

Date: 2025
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DOI: 10.1038/s41586-024-08241-y

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