The basal ganglia (BG) control action selection, motor programs, habits, and goal-directed learning. The striatum, the principal input structure of BG, is predominantly composed of medium-sized spiny neurons (MSNs). Arising from these spatially intermixed MSNs, two inhibitory outputs form two main efferent pathways, the direct and indirect pathways. Striatonigral MSNs give rise to the activating, direct pathway MSNs and striatopallidal MSNs to the inhibitory, indirect pathway (iMSNs). BG output nuclei integrate information from both pathways to fine-tune motor procedures and to acquire complex habits and skills. Therefore, balanced activity between both pathways is crucial for harmonious functions of the BG. Despite the increase in knowledge concerning the role of glutamate NMDA receptors (NMDA-Rs) in the striatum, understanding of the specific functions of NMDA-R iMSNs is still lacking. For this purpose, we generated a conditional knock-out mouse to address the functions of the NMDA-R in the indirect pathway. At the cellular level, deletion of GluN1 in iMSNs leads to a reduction in the number and strength of the excitatory corticostriatopallidal synapses. The subsequent scaling down in input integration leads to dysfunctional changes in BG output, which is seen as reduced habituation, delay in goaldirected learning, lack of associative behavior, and impairment in action selection or skill learning. The NMDA-R deletion in iMSNs causes a decrease in the synaptic strength of striatopallidal neurons, which in turn might lead to a imbalanced integration between direct and indirect MSN pathways, making mice less sensitive to environmental change. Therefore, their ability to learn and adapt to the environment-based experience was significantly affected.

The basal ganglia are known to control actions and modulate movements. Neuronal activity in the two efferent pathways of the dorsal striatum, a major input to the basal ganglia, is critical for appropriate behavioral control. Previous evidence has led to divergent conclusions on the respective engagement of both pathways during actions. We used calcium imaging to evaluate how neurons in the direct and indirect pathways in the dorsal striatum encode behaviors during self-paced spontaneous explorations in an open field. We observed that the two striatal pathways exhibit distinct tuning properties during spontaneous behaviors. We applied supervised learning algorithms and found that direct pathway neurons encode behaviors through their activation, whereas indirect pathway neurons exhibit behavior-specific silencing. These properties remain stable for weeks. Our findings highlight a complementary encoding of behaviors in the two striatal pathways that supports an updated model, reconciling previous conflicting conclusions on motor encoding in the striatum.

No abstract