Regulation of parkinsonian motor behaviors by optogenetic control of basal ganglia circuitry

By Alexxai V. Kravitz, Benjamin Freeze, Philip R. L. Parker, Kenneth Kay, Myo Thwin, Karl Deisseroth, A. Kreitzer. Nature, 2010

1,741 citations recorded by the source corpus.

Neural circuits of the basal ganglia are critical for motor planning and action selection. Two parallel basal ganglia pathways have been described, and have been proposed to exert opposing influences on motor function. According to this classical model, activation of the ‘direct’ pathway facilitates movement and activation of the ‘indirect’ pathway inhibits movement. However, more recent anatomical and functional evidence has called into question the validity of this hypothesis. Because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown. Here we report direct activation of basal ganglia circuitry in vivo, using optogenetic control of direct- and indirect-pathway medium spiny projection neurons (MSNs), achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of bacterial artificial chromosome transgenic mice expressing Cre recombinase under control of regulatory elements for the dopamine D1 or D2 receptor. Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia and decreased locomotor initiations. In contrast, activation of direct-pathway MSNs reduced freezing and increased locomotion. In a mouse model of Parkinson’s disease, direct-pathway activation completely rescued deficits in freezing, bradykinesia and locomotor initiation. Taken together, our findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behaviour and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.

View Paper: https://www.semanticscholar.org/paper/fbdd8f8f4271dd1b77171d82024d35f633c70bea

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Citations in the corpus

Dopamine release in the basal ganglia (2011, background): “Given the role of D1-receptor-expressing striatal medium spiny neurons (MSNs) in facilitating movement via the direct (striatonigral) pathway and corresponding role of D2-receptor-expressing MSNs in movement suppression via the indirect (striatopallidal) pathway (Kravitz et al., 2010; Gerfen and Sur”
Dopamine, Affordance and Active Inference (2012, background): “Key examples here include the opposing effects of the direct and indirect pathways [128,129] and the opposing influences of dopamine on synaptic plasticity [56].”
Modulation of striatal projection systems by dopamine (2011, unknown): “Additional support for this model has recently come from an elegant application of optogenetics to selectively activate direct and indirect pathway SPNs in mouse model of PD (Kravitz et al., 2010).”
Functional neuroanatomy of the basal ganglia. (2012, unknown): “Kravitz et al. (2010) showed that selective stimulation of MSNs expressing D 2 R (indirect circuit) provoked movement arrest, whereas activation of MSNs expressing D 1 R led to movement activation .”
Closed-loop and activity-guided optogenetic control. (2015, unknown): “…et al., 2012), 16-site neural probes with a single waveguide (Cho et al., 2010), commercially available 16-recording-site, single-fiber probes (Kravitz et al., 2010), and Utah arrays modified to include a tapered optrode (Zhang et al., 2009), yielding various single-input, multiple output…”
Computational models of basal-ganglia pathway functions: focus on functional neuroanatomy (2013, background): “Functional evidence for this hypothesis comes from an optogenetic study, where stimulation of striatal MSNs of the indirect pathways resulted in decreased motor initiation and increased bradykinesia (Kravitz et al., 2010).”
Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement (2011, unknown): “While genetically-modified mice have enabled substantial advances in neuroscience and have made possible new approaches for circuit analysis with optogenetics (Tsai et al., 2009; Gradinaru et al., 2009; Lobo et al., 2010; Kravitz et al., 2010; Witten et al., 2010; Tye et al., 2011), a generalizable ”
FROM REINFORCEMENT LEARNING MODELS OF THE BASAL GANGLIA TO THE PATHOPHYSIOLOGY OF PSYCHIATRIC AND NEUROLOGICAL DISORDERS (2011, background): “Although the original version of this account was based on a somewhat oversimplified view of basal ganglia anatomy and function, recent findings strongly support this distribution of function between the direct (or Go) and indirect (or NoGo) pathway”
Opponent actor learning (OpAL): modeling interactive effects of striatal dopamine on reinforcement learning and choice incentive. (2014, background): “Striatal MSNs originating in the direct (striatonigral) pathway predominantly express dopamine D1 receptors and act to facilitate actions (Kravitz et al., 2010).”