Systemic inflammation and dorsolateral striatal activity converge to drive repetitive and compulsive-like behaviors caused by chronic stress

Repetitive and compulsive-like behaviors, characterized by excessive repetition and rigidity, are a key feature of many psychiatric and neurodevelopmental disorders. However, how chronic stress triggers these maladaptive behaviors and the underlying neuroimmune mechanisms remain unclear. Here, mice subjected to chronic unpredictable stress (CUS) exhibited pronounced repetitive and compulsive-like behaviors, as well as elevated serum levels of the pro-inflammatory cytokines IL-6 and TNF-α. Notably, the severity of the repetitive and compulsive-like behaviors was correlated with systemic cytokine concentrations of IL-6 and TNF-α, suggesting that chronic stress engages peripheral immune responses to drive behavioral pathology. Consistent with this association, peripheral neutralization of IL-6 and TNF-α attenuated the effects, whereas systemic inflammatory challenge was sufficient to induce repetitive and compulsive-like behaviors. Within the brain, CUS increased neuronal activity in the dorsolateral striatum (DLS) and nucleus accumbens shell (NAc-shell). Chemogenetic approaches revealed that decreased activity in the DLS or NAc-shell attenuated CUS-induced repetitive and compulsive-like behaviors, suggesting that both regions are involved in mediating these behaviors; however, only DLS activation was sufficient to drive repetitive and compulsive-like behaviors in non-CUS mice. Further circuit dissection identified the connections from the DLS to the external globus pallidus (GPe) to be critical to this behavior. Inhibition of DLS terminals or DLS neurons projecting to GPe reversed CUS-induced behavioral deficits; however, activating this pathway in non-CUS mice evoked the repetitive and compulsive-like phenotype. Collectively, our findings establish a peripheral-central axis whereby systemic inflammation and the activity of the DLS-GPe circuit drive repetitive and compulsive-like behaviors in the context of chronic stress. Importantly, this study uncovers potential neuroimmune and circuit-based strategies for therapeutic targets in the clinical treatment of stress-related repetitive and compulsive disorders.