A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum.

The striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (∼ four- to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.Significance StatementPlacing the subthalamostriatal projection within schemes of basal ganglia circuit organization is challenging because of the diversity of cell types within striatum. Here, we shed new light on the structural and electrophysiological substrates by which STN neurons can exert direct and biased influences on the striatal microcircuit. We discovered that STN innervation of parvalbumin-expressing interneurons is relatively enriched and impactful as compared to innervation of other types of striatal neuron. Accordingly, the STN joins a growing list of subcortical structures that, although not considered 'canonical' sources of inputs to striatum, selectively target striatal interneurons. Our results are important in supporting the concept that the glutamatergic subthalamostriatal projection is positioned to fulfil diverse and likely unique roles within basal ganglia circuits.