Neuromodulation in the striatum

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PROJECT SUMMARY The striatum serves as the entry station of the basal ganglia. It mediates many critical brain functions, including motor control, decision making, learning, and reward. In particular, the dorsolateral striatum plays essential roles in locomotion execution and motor learning. The striatum outputs to two distinct pathways: a direct pathway that directly innervates the output nuclei of the basal ganglia, and an indirect pathway that projects to the basal ganglia output nuclei indirectly via related nuclei. These two pathways form a push-and-pull system, with the direct pathway promoting movement initiation, and the indirect pathway inhibiting movement. The balance of the push-and-pull system is critical to proper motor execution, and defective balance is associated with neurological disorders, such as Parkinson’s disease and Huntington’s disease. The balance of the two pathways is tightly regulated by neuromodulators. Dopamine is the most studied neuromodulator in the striatum. Locomotion intention is associated with increased dopamine release in the striatum. Dopamine enhances the direct pathway function by upregulate intracellular cAMP concentrations and the function of cAMP-dependent kinase in the projection neurons of this pathway, while suppressing the other pathway by inhibiting cAMP and cAMP-dependent kinase in the projection neurons of the indirect pathway. However, dopamine is not the only neuromodulator in the striatum. Other neuromodulators, such as adenosine, are also known to play roles in the striatum. Adenosine receptors are abundantly expressed in the striatum. However, it is not known whether and when adenosine is released during animal behavior, how it affects intracellular cAMP and cAMP-dependent kinase in the projection neurons of the two pathways, and how such effects mediate animal locomotion. Our proposal aims to answer these questions by using modern imaging or optical measurements of the activities of both extracellular adenosine concentrations and the cell type-specific activity of intracellular cAMP-dependent kinases in behaving mice during locomotion. Our results will add a previously underexplored dimension to the knowledge of neuromodulation in the striatum, which may deepen our understanding of the striatal function and dysfunction.