Ventral striatal islands of Calleja neurons bidirectionally mediate depression-like behaviors in mice

Abstract The ventral striatum, composed of the nucleus accumbens (NAc) and olfactory tubercle (OT), is a key reward center implicated in the pathophysiology of depression. Although the OT is known to regulate motivational and reward-related behaviors, its involvement in depression remains unexplored. We recently report that islands of Calleja, clusters of dopamine D3 receptor-expressing granule cells that are predominately situated in the OT, regulate self-grooming, a repetitive behavior manifested in mood disorders including depression. Here we show that chronic restraint stress (CRS) induces robust depression-like behaviors in mice and decreases excitability of OT D3 neurons. Ablation or inhibition of these neurons leads to depression-like behaviors, whereas their activation ameliorates CRS-induced depressive phenotypes. Moreover, activation of OT D3 neurons has a rewarding effect, which diminishes when grooming is blocked. Finally, we propose a model to explain how OT D3 neurons may influence dopamine release into the NAc via synaptic connections with OT spiny projection neurons (SPNs) that project to midbrain dopamine neurons. Our study reveals a novel role of OT D3 neurons in bidirectionally mediating depressive phenotypes, suggesting an attractive therapeutic target.