Functional integrity of mesolimbic-hippocampal circuits is associated with anhedonia in individuals with early life stress

Abstract

Anhedonia reflects a transdiagnostic deficit in a range of processes that impact reward and motivation. While human neuroimaging has mainly focused on striatal-related alterations in anhedonia, animal models suggest hippocampal [HPC] novelty processing regulates mesolimbic dopamine activity, implicating mesolimbic-HPC alterations in anhedonia. Childhood trauma, which disproportionately impacts HPC structure and function, may exacerbate this vulnerability. The present study of 37 males and 55 females examined whether HPC alterations interact with childhood trauma to predict anhedonia in humans. Using fMRI in a sample enriched for anhedonia, we assessed three HPC-related processes: resting-state connectivity with mesolimbic targets in the ventral tegmental area [VTA] and nucleus accumbens [NAc], task-based HPC novelty response, and task-based HPC modulation of VTA activation reflecting novelty-evoked facilitation of target detection. Significant interactions emerged for anticipatory anhedonia: reduced HPC-NAc connectivity, reduced novelty response, and weaker HPC→VTA modulation were each associated with greater anticipatory anhedonia among individuals with high childhood trauma. Moreover, LASSO regression confirmed these interactions as unique predictors. These findings suggest that early life adversity interacts with alterations in HPC-mesolimbic signaling to contribute to individual differences in anhedonia, highlighting the HPC as a potential target of motivation-related deficits in striatum. Significance Statement The ability to process rewarding stimuli and initiate goal-directed behavior is critical for human functioning. While human neuroimaging has highlighted the role of striatal function in these processes, animal evidence suggests that hippocampal modulation of mesolimbic dopamine signaling is critical for motivated behavior. The present study translates this framework to humans, demonstrating that hippocampal-mesolimbic functional integrity interacts with childhood trauma to predict individual differences in anticipatory anhedonia (i.e., impairments in one's ability to anticipate and pursue rewards). These findings implicate the hippocampus as a potential upstream contributor to motivational deficits and highlight early life stress as a key context in which mesolimbic circuit dysfunction becomes behaviorally relevant.