A direct GABAergic output from the basal ganglia to frontal cortex

Anatomical and functional analyses reveal the existence of two types of globus pallidus externus neurons that directly control cortex, suggesting a pathway by which dopaminergic drugs used to treat neuropsychiatric disorders may act in the basal ganglia to modulate cortex. Basal ganglia/frontal cortex linkage Current models postulate that the basal ganglia — nerve cells clustered in the caudate nucleus, putamen and globus pallidus at the base of the forebrain in vertebrates — exert their effects on the cerebral cortex indirectly via inhibition of thalamus, and that this circuitry controls movement and reward learning. Bernardo Sabatini and colleagues now describe a previously unrecognized direct anatomical connection from the globus pallidus externus to the frontal cortex, and show that it functionally modulates cortical activity. The activity of this pathway is sensitive to dopamine receptor signalling, suggesting a potentially novel mechanism for the action of dopaminergic drugs used to treat neuropsychiatric disorders. The basal ganglia are phylogenetically conserved subcortical nuclei necessary for coordinated motor action and reward learning 1 . Current models postulate that the basal ganglia modulate cerebral cortex indirectly via an inhibitory output to thalamus, bidirectionally controlled by direct- and indirect-pathway striatal projection neurons (dSPNs and iSPNs, respectively) 2 , 3 , 4 . The basal ganglia thalamic output sculpts cortical activity by interacting with signals from sensory and motor systems 5 . Here we describe a direct projection from the globus pallidus externus (GP), a central nucleus of the basal ganglia, to frontal regions of the cerebral cortex (FC). Two cell types make up the GP–FC projection, distinguished by their electrophysiological properties, cortical projections and expression of choline acetyltransferase (ChAT), a synthetic enzyme for the neurotransmitter acetylcholine (ACh). Despite these differences, ChAT + cells, which have been historically identified as an extension of the nucleus basalis, as well as ChAT − cells, release the inhibitory neurotransmitter GABA (γ-aminobutyric acid) and are inhibited by iSPNs and dSPNs of dorsal striatum. Thus, GP–FC cells comprise a direct GABAergic/cholinergic projection under the control of striatum that activates frontal cortex in vivo . Furthermore, iSPN inhibition of GP–FC cells is sensitive to dopamine 2 receptor signalling, revealing a pathway by which drugs that target dop