Balancing approach and avoidance: circuit mechanisms for anxiety regulation in the dorsomedial striatum

Neural systems have evolved to generate adaptive approach–avoidance decisions by evaluating potential rewards and threats. This fundamental ability is disrupted in anxiety disorders, which are characterized by excessive or generalized avoidance that interferes with daily functioning. The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) are key regions in regulating this behavioral equilibrium. While the mPFC is associated with flexible, goal-directed, and approach-oriented behavior when threat levels are low, the BLA mediates aversive learning, promoting vigilance and avoidance [1]. However, how these opposing influences interact within downstream structures to shape behavioral output remains largely unresolved. Both the BLA and mPFC send converging excitatory projections to the dorsomedial striatum (DMS) [2], a basal ganglia region classically involved in action selection and reinforcement learning but implicated also in innate avoidance responses [3]. This anatomical convergence suggests that the DMS could act as a critical integrator of emotional and motivational signals, coordinating approach–avoidance decisions according to internal state and environmental context [4,5]. Using chemogenetic and optogenetic approaches, we selectively manipulated BLA-DMS and mPFC-DMS projections in CD1 male mice and we assessed anxiety-related behavior in the elevated plus maze (EPM) and open field (OF) tests. Chemogenetic activation of mPFC-DMS or inhibition of BLA-DMS projections significantly increased open-arm exploration in the EPM, reflecting an anxiolytic effect (mPFC-DMS: p=0,0175; unpaired t-test; Vheicle=7, CNO=10. BLA-DMS: p=0,0426; unpaired t-test; Vehicle=7, CNO=9). Conversely, activation of BLA-DMS projections enhanced avoidance and produced an anxiogenic phenotype, whereas inhibition of mPFC-DMS inputs did not alter behavior (BLA-DMS: p=0,0174; unpaired t-test; Vehicle=7, CNO=7. mPFC-DMS: p= 0,9358; unpaired t-test; Vheicle=10, CNO=8). These findings demonstrate that mPFC-DMS and BLA-DMS pathways exert opposing, bidirectional control over anxiety-like behavior. Optogenetic stimulation further confirmed the anxiolytic role of the mPFC-DMS circuit. Real-time activation of this pathway reduced anxiety-like behavior in EPM, increasing approach of open arms during laser ON periods compared to laser OFF (2-way ANOVA repeated measure, laser epochs, p<0,0001; treatment, p=0,0435; treatment x laser epochs, p= 0,0234; EYFP=7, CNO=7). We next examined whether DMS efferent pathways mediate these behavioral effects. Optogenetic stimulation of DMS projections to the substantia nigra (SN) and internal globus pallidus (GPi) produced anxiogenic effects in the EPM (DMS-GPi: 2-way ANOVA repeated measure, laser epochs, p<0,0001; treatment, p=0,2575; treatment x laser epochs, p= 0,0276; EYFP=9, CNO=10. DMS-SN: 2-way ANOVA repeated measure, laser epochs, p<0,0026; treatment, p=0,0760; treatment x laser epochs, p= 0,0327; EYFP=8, CNO=10 ). Together, these data identify the DMS as a central node that integrates opposing cortical and amygdalar inputs to regulate approach–avoidance behavior. By coordinating information flow from BLA and mPFC and projecting to basal ganglia output structures, the DMS exerts a key role in balancing emotional reactivity and behavioral flexibility. These results provide new circuit-level insights into the neural mechanisms underlying anxiety and open perspectives for targeting striatal pathways in anxiety disorders.