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

Neural systems have evolved to generate approach-avoidance decisions by evaluating potential rewards and threats. This core ability is disrupted in anxiety disorders, marked by an imbalance between approach and avoidance due to threat-generalization to non-threatening situations, impairing daily life. The regulation of approach-avoidance behavior involves complex interactions between the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC). The mPFC is often linked to flexible behavior and approach strategies when threats are minimal, while BLA is thought to mediate aversive stimuli, increasing vigilance and avoidance tendencies. How these opposing pathways integrate to regulate behavioral output remains unclear. Both the mPFC and the BLA send unidirectional excitatory inputs to the dorsomedial striatum (DMS). This convergence suggests that the DMS may serve as a key integrator, influencing approach-avoidance decisions depending on the emotional state of the individual. Using a chemogenetic approach, we selectively activated or inhibited mPFC-DMS and BLA-DMS inputs in CD1 male mice and assessed approach-avoidance conflict in the elevated plus maze (EPM). Activation of PFC-DMS or inhibition of BLA-DMS projections significantly increased approach. Conversely, BLA-DMS activation significantly increased avoidance, while mPFC-DMS inhibition had no effect. These results confirm that mPFC-DMS and BLA-DMS pathways exert opposing bidirectional control in anxiety regulation, suggesting a crucial role for DMS in balancing approach-avoidance behavior. Ongoing work is investigating the contribution of DMS outputs to substantia nigra (SN) and globus pallidus (GP) to these effects. Our preliminary data show that optogenetic stimulation of DMS-SN projections has an anxiogenic effect in the EPM. These findings offer new circuit-level insights into the neural mechanisms underlying anxiety disorders.