TY - JOUR
T1 - Understanding the neural code of stress to control anhedonia
AU - Xia, Frances
AU - Fascianelli, Valeria
AU - Vishwakarma, Nina
AU - Ghinger, Frances Grace
AU - Kwon, Andrew
AU - Gergues, Mark M.
AU - Lalani, Lahin K.
AU - Fusi, Stefano
AU - Kheirbek, Mazen A.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - Anhedonia, the diminished drive to seek, value, and learn about rewards, is a core feature of major depressive disorder1, 2–3. 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taking advantage of the fact that when mice are exposed to traumatic social stress, susceptible animals become socially withdrawn and anhedonic, whereas others remain resilient.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.
AB - Anhedonia, the diminished drive to seek, value, and learn about rewards, is a core feature of major depressive disorder1, 2–3. 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taking advantage of the fact that when mice are exposed to traumatic social stress, susceptible animals become socially withdrawn and anhedonic, whereas others remain resilient.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.
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U2 - 10.1038/s41586-024-08241-y
DO - 10.1038/s41586-024-08241-y
M3 - Article
C2 - 39633053
AN - SCOPUS:85211222771
SN - 0028-0836
JO - Nature
JF - Nature
M1 - 2419
ER -