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Anhedonia, the diminished drive to seek, value, and learn about rewards, is a core feature of major depressive disorder 1-3 . 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taking advantage of the fact that when mice are exposed to traumatic social stress, susceptible animals become socially withdrawn and anhedonic, whereas others remain resilient.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., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

A central goal of neuroscience is to understand how the brain transforms external stimuli and internal bodily signals into patterns of activity that underlie cognition, emotional states, and behavior. Understanding how these patterns of activity may be disrupted in mental illness is crucial for developing novel therapeutics. It is well appreciated that psychiatric disorders are complex, circuit-based disorders that arise from dysfunctional activity patterns generated in discrete cell types and their connections. Recent advances in large-scale, cell-type specific calcium imaging approaches have shed new light on the cellular, circuit, and network-level dysfunction in animal models for psychiatric disorders. Here, we highlight a series of recent findings over the last ~10 years from in vivo calcium imaging studies that show how aberrant patterns of activity in discrete cell types and circuits may underlie behavioral deficits in animal models for several psychiatric disorders, including depression, anxiety, autism spectrum disorders, and schizophrenia. These advances in calcium imaging in pre-clinical models demonstrate the power of cell-type-specific imaging tools in understanding the underlying dysfunction in cell types, activity patterns, and neural circuits that may contribute to disease and provide new blueprints for developing more targeted therapeutics and treatment strategies., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)