Journal Article

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

Kravitz, Alexxai V., Freeze, Benjamin S., Deisseroth, Karl, Kay, Kenneth, Thwin, Myo T., Kreitzer, Anatol C., Parker, Philip R. L.

2010

Overview

Control of parkinsonian behaviour The basal ganglia are a collection of interconnected brain areas thought to be crucial for motor planning, sequencing and execution. It has long been thought that motor control is achieved through the balanced activity of two parallel and anatomically distinct pathways, acting on the basal ganglia with opposing effects, but these pathways have never been functionally verified. Kravitz et al . have tested this hypothesis directly using optogenetic activation of different populations of mouse striatal neurons, and they both trace functional connectivity and demonstrate opposing effects on motor behaviour. Selective activation of the 'direct' pathway increased locomotion and rescued motor deficits in a parkinsonian model, whereas activation of the 'indirect' pathway suppressed motor behaviour. It has long been thought that motor control is achieved through the balanced activity of two distinct pathways through the basal ganglia that have opposing effects, but this has never been functionally verified. These authors directly test this hypothesis with optogenetic activation of different populations of mouse striatal neurons, and not only trace functional connectivity but demonstrate opposing effects on motor behaviour in a parkinsonian model. Neural circuits of the basal ganglia are critical for motor planning and action selection 1 , 2 , 3 . Two parallel basal ganglia pathways have been described 4 , and have been proposed to exert opposing influences on motor function 5 , 6 , 7 . 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 8 , 9 , 10 . 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 11 , 12 , 13 , 14 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/2632/1323 / 631/443/376 / 631/601/18 / 692/699/375/346/1718 / Animals / Artificial chromosomes / Basal ganglia / Basal Ganglia - cytology / Basal Ganglia - pathology / Basal Ganglia - physiology / Basal Ganglia - physiopathology / Behavior / Biological and medical sciences / Care and treatment / Channelrhodopsins / Chromosomes, Artificial, Bacterial - genetics / Data collection / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Disease Models, Animal / Dopamine / Freezing / Gait / Genetic aspects / Humanities and Social Sciences / Hypokinesia - complications / Hypokinesia - genetics / Hypokinesia - physiopathology / Integrases - genetics / Integrases - metabolism / letter / Light / Medical examination / Medical sciences / Mice / Mice, Transgenic / Models, Neurological / Motor Activity - physiology / multidisciplinary / Neostriatum - cytology / Neostriatum - pathology / Neostriatum - physiology / Neostriatum - physiopathology / Neural Pathways - cytology / Neural Pathways - pathology / Neural Pathways - physiology / Neural Pathways - physiopathology / Neurology / Neurons / Neurons - cytology / Neurons - pathology / Neurons - physiology / Oxidopamine / Parkinson Disease - complications / Parkinson Disease - genetics / Parkinson Disease - pathology / Parkinson Disease - physiopathology / Parkinson's disease / Principal components analysis / Psychomotor Performance / Receptors, Dopamine - genetics / Rodents / Science / Science (multidisciplinary)