Identifying and modulating neural signatures of stress susceptibility and resilience enables control of anhedonia

TL;DR

This study identifies brain activity patterns linked to stress susceptibility and resilience in mice, offering a way to reverse anhedonia through targeted neural manipulation.

Contribution

The study discovers distinct neural signatures in the BLA and vCA1 that differentiate stress susceptibility and resilience, and shows how modulating these can reverse anhedonia.

Findings

Resilient mice show stronger BLA discrimination of reward choices, while susceptible mice exhibit rumination-like BLA activity.

Susceptible mice have higher-dimensional spontaneous BLA activity at rest, allowing accurate decoding of stress history.

Targeted vCA1-BLA manipulation rescues dysfunctional neural dynamics and reverses anhedonic behavior in susceptible mice.

Abstract

Anhedonia is a core aspect of major depressive disorder. Traditionally viewed as a blunted emotional state in which individuals are unable to experience joy, anhedonia also diminishes the drive to seek rewards and the ability to value and learn about them 1–4.The neural underpinnings of anhedonia and how this emotional state drives related behavioral changes remain unclear. Here, we investigated these questions by taking advantage of the fact that when mice are exposed to traumatic social stress, susceptible animals become socially withdrawn and anhedonic, where they cease to seek high-value rewards, while others remain resilient. By performing high density electrophysiological recordings and comparing neural activity patterns of these groups in the basolateral amygdala (BLA) and ventral CA1 (vCA1) of awake behaving animals, we identified neural signatures of susceptibility and resilience to anhedonia. When animals actively sought rewards, BLA activity in resilient mice showed stronger discrimination between upcoming reward choices. In contrast, susceptible mice displayed a rumination-like signature, where BLA neurons encoded the intention to switch or stay on a previously chosen reward. When animals were at rest, the spontaneous BLA activity of susceptible mice was higher dimensional than in controls, reflecting a greater number of distinct neural population states. Notably, this spontaneous activity allowed us to decode group identity and to infer if a mouse had a history of stress better than behavioral outcomes alone. Finally, targeted manipulation of vCA1 inputs to the BLA in susceptible mice rescued dysfunctional neural dynamics, amplified dynamics associated with resilience, and reversed their anhedonic behavior. This work reveals population-level neural signatures 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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