A non-canonical cholinergic pathway from the dorsal tail of the striatum to the auditory cortex

For decades canonical models proposed that striatal influences on cortex are conveyed indirectly, through inhibitory projections from the striatum to the globus pallidus, which in turn controls thalamic output to the cortex. Accordingly, information flow between the cortex and the striatum has traditionally been considered unidirectional. Here, we demonstrate a direct striato-cortical projection, revising this view. Using anatomical, electrophysiological and optogenetic techniques in mice, we identified a population of striatal cholinergic neurons (SC-ChAT) in the dorsal tail of the striatum that directly project to auditory, somatosensory and motor cortices. Auditory SC-ChAT axons extend across all cortical layers, preferentially targeting layer 6 neurons via fast nicotinic receptor-mediated transmission of acetylcholine. Functionally, these inputs increase spike probability and advance action potential onset, exerting precise control over the output of cortical pyramidal neurons and demonstrating that the striatum not only receives cortical input but also directly modulates cortical processing.