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Nat Commun. 2017 Feb 1;8:14304. doi: 10.1038/ncomms14304.

Dysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation.

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  • 1Department of Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582, Japan.
  • 2Research Fellow of Japan Society for the Promotion of Science (RPD), Tokyo 102-0083, Japan.
  • 3Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
  • 4Department of Physiology, National Defense Medical College, Saitama 359-8513, Japan.
  • 5Department of Anatomy and Embryology, University of Hokkaido, Hokkaido 060-8638, Japan.
  • 6Center for Learning and Memory, Department of Neuroscience, The University of Texas at Austin, Austin, Texas 78712, USA.
  • 7Division of System Neurophysiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.


Impaired motivation is present in a variety of neurological disorders, suggesting that decreased motivation is caused by broad dysfunction of the nervous system across a variety of circuits. Based on evidence that impaired motivation is a major symptom in the early stages of Huntington's disease, when dopamine receptor type 2-expressing striatal medium spiny neurons (D2-MSNs) are particularly affected, we hypothesize that degeneration of these neurons would be a key node regulating motivational status. Using a progressive, time-controllable, diphtheria toxin-mediated cell ablation/dysfunction technique, we find that loss-of-function of D2-MSNs within ventrolateral striatum (VLS) is sufficient to reduce goal-directed behaviours without impairing reward preference or spontaneous behaviour. Moreover, optogenetic inhibition and ablation of VLS D2-MSNs causes, respectively, transient and chronic reductions of goal-directed behaviours. Our data demonstrate that the circuitry containing VLS D2-MSNs control motivated behaviours and that VLS D2-MSN loss-of-function is a possible cause of motivation deficits in neurodegenerative diseases.

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