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taking advantage of the fact that when mice are exposed to traumatic social stress, susceptible animals become socially withdrawn and anhedonic, where they cease to seek high-value rewards, while others remain resilient.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.
ABSTRACT
The neural dynamics that underlie divergent anhedonic responses to stress remain unclear. Here, we identified neuronal dynamics in an amygdala-hippocampal circuit that distinguish stress resilience and susceptibility. In a reward-choice task, basolateral amygdala (BLA) activity in resilient mice showed enhanced discrimination of upcoming reward choices. In contrast, a rumination-like signature emerged in the BLA of susceptible mice; a linear decoder could classify the intention to switch or stay on a previously chosen reward. Spontaneous activity in the BLA of susceptible mice was higher dimensional than controls, reflecting the exploration of a larger number of distinct neural states. Manipulation of vCA1-BLA inputs rescued dysfunctional neural dynamics and anhedonia in susceptible mice, suggesting that targeting this pathway can enhance BLA circuit function and ameliorate of depression-related behaviors.
ABSTRACT
The hippocampus can be divided into distinct segments that make unique contributions to learning and memory. The dorsal segment supports cognitive processes like spatial learning and navigation while the ventral hippocampus regulates emotional behaviors related to fear, anxiety and reward. In the current study, we determined how pyramidal cells in ventral CA1 respond to spatial cues and aversive stimulation during a context fear conditioning task. We also examined the effects of high and low frequency stimulation of these neurons on defensive behavior. Similar to previous work in the dorsal hippocampus, we found that cells in ventral CA1 expressed high-levels of c-Fos in response to a novel spatial environment. Surprisingly, however, the number of activated neurons did not increase when the environment was paired with footshock. This was true even in the subpopulation of ventral CA1 pyramidal cells that send direct projections to the amygdala. When these cells were stimulated at high-frequencies (20 Hz) we observed feedforward inhibition of basal amygdala neurons and impaired expression of context fear. In contrast, low-frequency stimulation (4 Hz) did not inhibit principal cells in the basal amygdala and produced an increase in fear generalization. Similar results have been reported in dorsal CA1. Therefore, despite clear differences between the dorsal and ventral hippocampus, CA1 neurons in each segment appear to make similar contributions to context fear conditioning.
