The basal ganglia are subcortical nuclei that control voluntary actions, and they are affected by a number of debilitating neurological disorders1,2,3,4. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum5,6—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 movement1,2. 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-specific6,7) and A2A-Cre (indirect-pathway-specific8,9) mice10. 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.
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We thank C. R. Gerfen for gifts of multiple bacterial artificial chromosome (BAC) transgenic mouse lines; L. L. Looger and the Howard Hughes Medical Institute (HHMI) for permission to use AAV GCaMP3 vectors and GCaMP3 mice; S. R. Ikeda for assistance with Ca2+ imaging in brain slices; G. Luo for mouse genotyping; C. Thaler for assistance with FLIM curve analysis; B. Mathur and M. Davis for assistance with brain slice electrophysiology and histology; and A. Martin for assistance with AAV vector injection. This work was supported by the Division of Intramural Clinical and Biological Research of the NIAAA, European Research Council STG 243393, an International Early Career Scientist grant from the Howard Hughes Medical Institute to R.M.C., a National Research Foundation of Korea grant (2011-0029485, 2012-0004003) and Smart IT Convergence System Research Center (SIRC-2011-0031866) from the Korean government (MEST) to S.B.J., and by an Ellison Medical Foundation grant (AG-NS-0944-12) to X.J.
In-Vivo optical recording of striatal neural activity in an animal performing a two-lever free choice operant task
A food pellet was delivered into the food magazine when the animal had made a total of 10 lever-presses, regardless of left or right lever.
Action potential-triggered GCAMP3 fluorescence transient in a striatal SPN evoked by current injection
A 400 pA, 487.5 ms square pulse current was injected through a patch pipette in tight-seal cell-attached configuration to evoke a burst of action potentials. See Supplementary Fig.10a,b for more detailed description.
Action potential-triggered GCAMP3 fluorescence transient in a striatal SPN evoked by synaptic stimulation
A train of 3 pulses at 200 uA, 100 Hz was delivered by a concentric bipolar electrode to evoke a burst of action potentials. See Supplementary Fig.11a, b for more detailed description.
About this article
Nature Communications (2018)