Frontal Brain Injury Reduces Sensitivity to Reward-Predictive Cues and Remodels the Nucleus Accumbens.

Traumatic brain injuries (TBIs) are more than mere lesions and generate a persistent secondary pathology. This, combined with functional reorganization of circuits post-injury, may explain the increased risk for psychiatric disorders in patients with TBI. In the current studies, we demonstrate that frontal TBI changed the Pavlovian behavioral response to reinforcer-predicting cues and reduced the motivational value of cues. TBI also chronically impaired decision-making on a gambling-like task with reinforcer-paired cues. To investigate how these changes occur, we evaluated the nucleus accumbens (NAc) core. At a subacute time point (14 days), we confirmed reduced input to the NAc with optogenetics and evaluated electrophysiological and transcriptional changes. TBI increased neuronal excitability and the single nucleus RNA sequencing profile indicated a substantial stress and inflammatory response, but also high indicators of plasticity, particularly in D1- and D2-positive medium spiny neurons. To evaluate how these subacute changes transitioned to chronic NAc dysfunction, we measured immunohistochemical surrogates of activity post-mortem and recorded calcium activity from the NAc after TBI during Pavlovian conditioning. TBI reduced histological markers of activity and reduced cue-evoked calcium activity. Overall, these data indicate that substantial reorganization of the NAc occurs following frontal brain injury. A primary effect of this is to reduce the salience of environmental cues linked to outcomes. The inability to properly process outcomes could contribute to broader psychiatric symptoms after TBI, including impairments in decision-making, behavioral flexibility, and impulsivity but also presents a potential treatment target.