Enhanced flexibility of place discrimination learning by targeting striatal cholinergic interneurons

Kana Okada, Kayo Nishizawa, Ryoji Fukabori, Nobuyuki Kai, Akira Shiota, Masatsugu Ueda, Yuji Tsutsui, Shogo Sakata, Natsuki Matsushita and Kazuto Kobayashi ()
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Kana Okada: Graduate School of Integrated Arts & Sciences, Hiroshima University
Kayo Nishizawa: Institute of Biomedical Sciences, Fukushima Medical University School of Medicine
Ryoji Fukabori: Institute of Biomedical Sciences, Fukushima Medical University School of Medicine
Nobuyuki Kai: Institute of Biomedical Sciences, Fukushima Medical University School of Medicine
Akira Shiota: PhoenixBio, Co., Ltd
Masatsugu Ueda: PhoenixBio, Co., Ltd
Yuji Tsutsui: Faculty of Symbiotic Systems Science, Fukushima University
Shogo Sakata: Graduate School of Integrated Arts & Sciences, Hiroshima University
Natsuki Matsushita: Translational Research Center, Ehime University Hospital
Kazuto Kobayashi: Institute of Biomedical Sciences, Fukushima Medical University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Behavioural flexibility is mediated through the neural circuitry linking the prefrontal cortex and basal ganglia. Here we conduct selective elimination of striatal cholinergic interneurons in transgenic rats by immunotoxin-mediated cell targeting. Elimination of cholinergic interneurons from the dorsomedial striatum (DMS), but not from the dorsolateral striatum, results in enhanced reversal and extinction learning, sparing the acquisition of place discrimination. This enhancement is prevented by infusion of a non-selective muscarinic acetylcholine receptor agonist into the DMS either in the acquisition, reversal or extinction phase. In addition, gene-specific silencing of M4 muscarinic receptor by lentiviral expression of short hairpin RNA (shRNA) mimics the place reversal learning promoted by cholinergic elimination, whereas shRNA-mediated gene silencing of M1 muscarinic receptor shows the normal performance of reversal learning. Our data indicate that DMS cholinergic interneurons inhibit behavioural flexibility, mainly through the M4 muscarinic receptor, suggesting that this role is engaged to the stabilization of acquired reward contingency and the suppression of response switch to changed contingency.

Date: 2014
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DOI: 10.1038/ncomms4778

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