BACKGROUND: Exposure to adversity, including unpredictable environments, during early life is associated with neuropsychiatric illness in adulthood. One common factor in this sequela is anhedonia, the loss of responsivity to previously reinforcing stimuli. To accelerate the development of new treatment strategies for anhedonic disorders induced by early-life adversity, animal models have been developed to capture critical features of early-life stress and the behavioral deficits that such stressors induce. We have previously shown that rats exposed to the limited bedding and nesting protocol exhibited blunted reward responsivity in the probabilistic reward task, a touchscreen-based task reverse translated from human studies. METHODS: To test the quantitative limits of this translational platform, we examined the ability of Bayesian computational modeling and probability analyses identical to those optimized in previous human studies to quantify the putative mechanisms that underlie these deficits with precision. Specifically, 2 parameters that have been shown to independently contribute to probabilistic reward task outcomes in patient populations, reward sensitivity and learning rate, were extracted, as were trial-by-trial probability analyses of choices as a function of the preceding trial. RESULTS: Significant deficits in reward sensitivity, but not learning rate, contributed to the anhedonic phenotypes in rats exposed to early-life adversity. CONCLUSIONS: The current findings confirm and extend the translational value of these rodent models by verifying the effectiveness of computational modeling in distinguishing independent features of reward sensitivity and learning rate that complement the probabilistic reward tasks signal detection end points. Together, these metrics serve to objectively quantify reinforcement learning deficits associated with anhedonic phenotypes.

Background

Alterations in reward processing are a central feature of depression and may be influenced by inflammation. Indeed, inflammation is associated with deficits in reward-related processes in animal models and with dysregulation in reward-related neural circuitry in humans. However, the downstream behavioral manifestations of such impairments are rarely examined in humans.

Methods

The influenza vaccination was used to elicit a mild inflammatory response in 41 healthy young adults (age range: 18-22, 30 female). Participants provided blood samples and completed behavioral measures of three key aspects of reward-reward motivation, reward learning, and reward sensitivity-before and 1 day after receiving the influenza vaccine.

Results

The influenza vaccine led to mild but significant increases in circulating levels of the pro-inflammatory cytokine interleukin-6 (IL-6) (p <  .001). Consistent with hypotheses, increases in IL-6 predicted lower reward motivation (p =  .029). However, contrary to hypotheses, increases in IL-6 predicted increased performance on a reward learning task (p =  .043) and were not associated with changes in reward sensitivity (p's > .288).

Conclusions

These findings contribute to an emerging literature on the nuanced associations between inflammation and reward and demonstrate that even mild alterations in inflammation are associated with multiple facets of reward processing.

Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted.