Scientific Understanding of Consciousness
Basal Ganglia Direct and Indirect Pathways
Nature 494, 238–242 (14 February 2013)
Concurrent activation of striatal direct and indirect pathways during action initiation
Section on In Vivo Neural Function, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, Maryland 20892-9412, USA
Guohong Cui, Xin Jin, Michael D. Pham, David M. Lovinger & Rui M. Costa
Department of Electronics Engineering, Ewha Womans University, Seoul 120-750, Korea
Sang Beom Jun
Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
Section on Cellular Biophotonics, Laboratory for Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda 20892-9412, Maryland, USA
Steven S. Vogel
Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, Maryland 20892-9412, USA
David M. Lovinger
Champalimaud Neuroscience Programme at Instituto Gulbenkian de Ciência and Champalimaud Centre for the Unknown, Lisbon 1400-038, Portugal
Rui M. Costa
The basal ganglia are subcortical nuclei that control voluntary actions, and they are affected by a number of debilitating neurological disorders. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum—the so-called direct and indirect pathways—have opposing effects on movement: activity of direct-pathway SPNs is thought to facilitate movement, whereas activity of indirect-pathway SPNs is presumed to inhibit movement. This model has been difficult to test owing to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals. Here we develop a novel in vivo method to specifically measure direct- and indirect-pathway SPN activity, using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCaMP3 in the dorsal striatum of D1-Cre (direct-pathway-specific) and A2A-Cre (indirect-pathway-specific) mice. Using fibre optics and time-correlated single-photon counting (TCSPC) in mice performing an operant task, we observed transient increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function and may have implications for understanding the origin of motor symptoms in basal ganglia disorders.
Excitatory inputs to striatum arise from cortical and thalamic structures, while striatal inhibitory output diverges, with some neurons projecting directly to basal ganglia output nuclei (striatonigral SPNs) and others to intermediate nuclei (striatopallidal SPNs), giving rise to the direct and the indirect pathways that propagate throughout the basal ganglia.
Despite advances in our understanding of basal ganglia circuitry, the functional relationship between these two pathways and the generation of actions is still under debate.
Although the predominant model proposes an ‘opposing’ scheme primarily based on the polarity of neural transmission in these two pathways and their final convergence onto basal ganglia output nuclei, more recent models propose coordinated activation of both pathways during action selection. Some propose, for example, that activation of the direct pathway could facilitate output of the desired motor programs but that activation of the indirect pathway would inhibit competing motor programs. Others suggest that coordinated activity of direct and indirect pathway is critical for the appropriate timing and synchrony of basal ganglia circuits during movement.
Disambiguating between these models requires monitoring and comparing the activity of direct- and indirect-pathway SPNs in behaving animals. However, current in vivo imaging methods are not ideal for exploring the activity of subcortical structures in freely moving animals owing to limitations in the penetration depth (<1 mm) and the general requirement for head restraint during measurement.
To circumvent these issues and achieve optical recording of neural activity from striatum in freely moving animals, we developed an in vivo photometry method using time-correlated single-photon counting (TCSPC)-based fibre optics.
In summary, we have developed a new in vivo fibre-optic technique for monitoring the activity of specific cell types deep in the brain, and have provided the first definitive evidence that direct- and indirect-pathway striatal neurons are co-activated during movement initiation, and are inactive when the animal is not moving. These data call into question the predominant current model of basal ganglia function, which postulates that there should be more activity in the direct pathway during movement than during immobility, and more activity in the indirect pathway during immobility than during movement. We also observed that neuronal activation in both pathways preceded movement initiation (with a latency appropriate for movement control). Finally, we showed that activity in both pathways predicted the occurrence of specific movements within 500 ms of transient initiation. Although these data do not support a pro-kinetic versus anti-kinetic dichotomy in direct and indirect pathways, they are consistent with other models that propose that the coordinated activation of both pathways is important for action selection, or for the precise timing of basal ganglia output.
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