Xiaogang Li

Histidine triad nucleotide-binding protein 1 (HINT1), implicated in psychiatric disorders, is highly expressed in the nucleus accumbens (NAc). Although previous work has linked HINT1 to aggression and anxiety, its specific role and mechanism remain unclear. This study aimed to delineate HINT1 distribution in the NAc and its regulatory function in aggressive and anxiety-like behaviors. Using immunofluorescence, we mapped HINT1 expression in wild-type (WT) mouse NAc. Behavioral and molecular analyses were performed on Hint1-knockout (KO) and WT littermates. Adeno-associated virus (AAV) vectors were then used to knock down (KD) or overexpress (OE) Hint1 in the NAc of WT mice for further validation. HINT1 was expressed in medium spiny neurons (MSN), microglia, oligodendrocytes and cholinergic interneurons (ChINs) in the NAc. The Hint1-KO mice exhibited increased aggression, accompanied by elevated levels of dopamine D1 receptor (D₁R), CREB, ΔFOSB, and heightened p-PKA and p-CREB in the NAc. AAV-mediated KD of Hint1enhanced both aggressive and anxiety-like behaviors, whereas OE produced no significant behavioral changes. Molecular upregulation in KD mice mirrored KO alterations but was absent in OE mice. These findings indicate that NAc HINT1 inhibits aggression, likely via suppression of the D₁R-PKA-CREB-ΔFOSB pathway, although its role in anxiety-like behavior requires further investigation. Our findings indicate that HINT1 in the NAc inhibits aggressive behavior. Loss of Hint1 likely leads to enhanced aggression through aberrant activation of the D₁R-PKA-CREB-ΔFOSB pathway. The role of HINT1 in anxiety-like behavior and its underlying mechanisms warrants further investigation.