Concurrent Activation of Striatal Direct and Indirect Pathways During Action Initiation

1] 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 [2].
Nature (Impact Factor: 41.46). 01/2013; 494(7436). DOI: 10.1038/nature11846
Source: PubMed


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.

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Available from: Rui M Costa, Aug 28, 2014
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    • "As PDE10A expression is important for neuronal survival our findings are consistent with the pattern of volume loss that can be detected at later stages of Huntington's disease with MRI. Mutant huntingtin, by gaining a toxic effect on PDE10A (Hu et al., 2004; Leuti et al., 2013), would impair its function for regulating the striatonigral and striatopallidal downstream signalling cascades, which work in a coordinated manner for the fine-tuning of movement (Nishi et al., 2008; Girault, 2012; Cui et al., 2013). Imbalance of striatal output would lead to abnormal thalamo-cortical input, which contributes to the development of Huntington's disease symptoms (André et al., 2010). "
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    ABSTRACT: There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.
    Brain 07/2015; DOI:10.1093/brain/awv214 · 9.20 Impact Factor
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    • "A decrease in their firing rate during movement would thus fit well with the proposed role of the GPe in the classical ''indirect pathway,'' i.e., disinhibition of STN and output nuclei (Kravitz et al., 2010; Sano et al., 2013), which should ultimately inhibit unwanted actions or terminate action sequences (Gerfen and Surmeier, 2011). GABAergic striatopallidal neurons, which are active around movement onset (Cui et al., 2013; Isomura et al., 2013), are prime candidates for mediating the decreases in prototypic neuron firing during movement. Indeed, electrophysiological studies in vitro (Chuhma et al., 2011) and computational work (Nevado-Holgado et al., 2014) indicate that prototypic neurons receive comparatively large striatal inputs and are endowed with robust autonomous firing. "
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    ABSTRACT: Transcriptional codes initiated during brain development are ultimately realized in adulthood as distinct cell types performing specialized roles in behavior. Focusing on the mouse external globus pallidus (GPe), we demonstrate that the potential contributions of two GABAergic GPe cell types to voluntary action are fated from early life to be distinct. Prototypic GPe neurons derive from the medial ganglionic eminence of the embryonic subpallium and express the transcription factor Nkx2-1. These neurons fire at high rates during alert rest, and encode movements through heterogeneous firing rate changes, with many neurons decreasing their activity. In contrast, arkypallidal GPe neurons originate from lateral/caudal ganglionic eminences, express the transcription factor FoxP2, fire at low rates during rest, and encode movements with robust increases in firing. We conclude that developmental diversity positions prototypic and arkypallidal neurons to fulfil distinct roles in behavior via their disparate regulation of GABA release onto different basal ganglia targets. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neuron 04/2015; 34(2). DOI:10.1016/j.neuron.2015.03.007 · 15.05 Impact Factor
    • "The basal ganglia (BG) modulate movement through direct and indirect pathways (Obeso and Lanciego, 2011). Segregated into the direct and indirect pathways, dopaminergic D1 (D1R) and D2 recep- tors, respectively, regulate the activity of striatonigral and striatopallidal neurons, synergizing both pathways during the execution of movement (Cui et al., 2013). In a similar manner, the action of dopamine on pallidal and nigral terminals is important for the control of movement (Galvan and Wichmann , 2008). "
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    Synapse 12/2014; 69(3). DOI:10.1002/syn.21796 · 2.13 Impact Factor
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