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Functional Integrity of Mesolimbic-Hippocampal Circuits Is Associated with Anhedonia in Individuals with Early Life Stress

Year: 2026

Type: article

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, least absolute shrinkage and selection operator 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.

Source: Journal of Neuroscience

DOI: 10.1523/jneurosci.0274-26.2026