It has long been understood that people who are under constant (“chronic”) and acute traumatic stress are at high risk of developing anxiety and depressive disorders. Over the last 10-20 years, increasing efforts have been devoted to studying not only the neural and circuit mechanisms that are involved in the stress response, but also how chronic and traumatic stress appear to impact a subset of individuals much more than others, while another subset of individuals appears to be largely resilient in the face of such stressors. There is much to be learned from both kinds of people.

A team of researchers led by Mazen A. Kheirbek, Ph.D., a member of BBRF’s Scientific Council and a 2010 BBRF Young Investigator, recently reported in the journal Nature the results of experiments in mice that help to explain individual differences in responses to traumatic stress. The findings are the culmination of a project supported by a 2021 BBRF Young Investigator grant awarded to Frances Xia, Ph.D., first author on the new paper, who, like Dr. Kheirbek, is at the University of California, San Francisco.

The team focused on the neural underpinnings of anhedonia, the diminished drive to seek, value, and learn about rewards, which is a core feature of major depressive disorder. How does anhedonia drive behavior in those who experience it? “We investigated the neural code of anhedonia,” the researchers said, “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taking advantage of the fact that when mice are exposed to traumatic social stress, susceptible animals become socially withdrawn and anhedonic, whereas others remain resilient.”

Besides blunting positive emotional responses to what should be pleasurable experiences, anhedonia also profoundly affects behavior, diminishing the drive to seek rewards and causing deficits in reward learning (a basis for motivated behavior) and being able to judge the relative value of specific rewards.

Mice, with brains that are in evolutionary terms structurally and functionally very similar to the human brain, can model anhedonia by being exposed to stress; some animals show resilience to prolonged stress while susceptible mice socially withdraw and become anhedonic, showing less motivation to attain high-value rewards. It was in such mice that the team conducted its experiments, along with control animals for comparative purposes.

Two crucial nodes in a brain network responsible for generating emotional and motivated behavior are the basolateral section of the amygdala (BLA) and a ventral portion of the hippocampus (called vCA1), which are reciprocally connected. The BLA plays a role in detecting threats and in anxiety-related behavior. It guides decision-making by generating representations of specific rewards that are linked with probable outcomes. For its part, vCA1 encodes stimuli that predict rewards and helps drive behaviors that involve physically moving toward rewards.

Important in the new research is the hypothesis that all of these reward-related functions of the BLA and vCA1 are affected by changes in an individual’s emotional state. The team’s experiments sought to reveal how animals’ reward-related internal states are represented in the BLA and vCA1—how large populations of neurons in these brain areas behave in concert to give rise to these mental pictures. How do these representations then shape reward-related behaviors? This was the initial target of the experiments.

In mice that were exposed to traumatic social stress, the team used a sophisticated recording technology to simultaneously monitor the activity of large numbers of neurons in the BLA and vCA1, and used “population decoders” to derive patterns of activity from this data. In these patterns they found “distinctive neural signatures” of susceptibility and resilience to traumatic stress.

When stressed mice actively sought rewards, BLA activity in resilient individuals showed clear discrimination between different reward choices. Representing these differences is a critical part of the process by which the animal decides whether and which rewards to pursue. The mechanism, in effect, supports the possibilities of choosing and acting.

In contrast, the neural signature in stress-susceptible mice exhibited what the researchers called a “rumination-like signature.” Rumination is often seen in people with depression who mull over choices at great length and often in a repetitive loop, making it difficult if not impossible to make choices. This is one way of explaining why people with anhedonia don’t feel able to get motivated and do not tend to pursue rewards, even those that can be expected to bring pleasure. This rumination-like neural activity was manifest in the BLA of susceptible mice by neurons encoding an intention to switch among various choices or to stay on a previously chosen reward. Overall, the team was able to conclude that “susceptible mice exhibit an aberrant reward decision-making process, resulting in anhedonia.”

Another phase of the experiments sought to elucidate in individual stressed animals that were not engaged in a task or exposed to a rewarding stimulus how activity patterns in the resting BLA and vCA1 differed—if at all—in susceptible and resilient individuals. Such “spontaneous” neural activity in the BLA in susceptible mice showed a greater number of distinct neural “population states” relative to the same activity in resilient mice. Such patterns in the BLA enabled the team to infer whether a particular individual did or did not have a history of stress—suggesting that the signatures identified might be useful as biomarkers.

Finally, the team addressed whether there might be a way of altering BLA or vCA1 activity to reduce, for example, a susceptible animal’s vulnerability to anhedonia as a result of traumatic stress. Using genetic and chemical methods to manipulate inputs sent from the vCA1 to the BLA in susceptible mice, the researchers were able to reverse dysfunctional neural dynamics in the BLA, which had the effect of amplifying dynamics associated with resilience, and resulting in the reversal of anhedonic behavior in these susceptible individuals.

The team said its work “provides crucial evidence for a role of the vCA1-BLA circuit in modulating stress-induced” behaviors. By demonstrating that “boosting vCA1-BLA communication can normalize neural dynamics associated with susceptibility” and thus promoting resilience in the BLA, the results shed light on how anhedonia arises in the brain.

The team suggests the vCA1-BLA circuit is a “promising target for neuromodulation in mood disorder treatments” and opens new possibilities for other future therapeutic approaches.