Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Basal Ganglia to Frontal Cortex Direct Connection


Nature  521, 85–89 (07 May 2015)

A direct GABAergic output from the basal ganglia to frontal cortex

Arpiar Saunders,

Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA

Neurobiology Imaging Facility, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA

Image and Data Analysis Core, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA

Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, Maryland 20892, USA


The basal ganglia are phylogenetically conserved subcortical nuclei necessary for coordinated motor action and reward learning. 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). The basal ganglia thalamic output sculpts cortical activity by interacting with signals from sensory and motor systems. 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 dopamine receptors for the treatment of neuropsychiatric disorders can act in the basal ganglia to modulate frontal cortices.

iSPNs are the major dopamine 2 receptor (D2R)-expressing cells in the brain and project from dorsal striatum to GP, suggesting that the therapeutic effects of drugs that target D2Rs to treat schizophrenia, bipolar disorder and obsessive compulsive disorder may involve GP circuits. GP neurons are generally described as GABAergic, spontaneously active, and projecting to the thalamus and all nuclei of the basal ganglia. Thus the GP is thought to coordinate subcortical activity through inhibition. Nevertheless, there are ChAT+ neurons in and around GP that project to cortex and appear to be innervated by striatal projection neurons from dorsal striatum, despite the rarity of iSPN synapses at the ultra-structural level. In macaques, GP neurons with nucleus basalis-like firing properties respond to reward, a computation attributed to the basal ganglia. Furthermore, humans with GP lesions exhibit reduced metabolism in frontal cortices and psychiatric symptoms reminiscent of patients with frontotemporal lobe damage, consistent with loss of substantial extrinsic input. Therefore, we examined if the GP contains a projection system to FC that is functionally integrated into basal ganglia circuitry.

The existence of GP–FC cells suggests a major revision to basal ganglia models. Striatal direct and indirect pathways were proposed to exert opposite effects on cortical activity through bidirectional control of ascending thalamic drive. The GP–FC projections bypass thalamus, allowing dSPNs and iSPNs to modulate cortex in concert. Furthermore, the hyperdirect cortical projection through the STN excites GP–FC neurons directly, forming a two-synapse loop for recurrent cortical modulation. The effects of GP–FC neurons on cortex are complex, mediated by GABA and ACh acting on diverse postsynaptic targets. The context of GP–FC activity during behaviour, the specific identities of cortical targets, and the mechanisms and consequences of GABA/ACh co-release will be the subjects of further investigation.

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