title: Enhanced flexibility of place discrimination learning by targeting striatal cholinergic interneurons.
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.
authors.affiliation: Department of Behavioural Sciences, Graduate School of Integrated Arts & Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Okada
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Nishizawa
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Fukabori
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kai
authors.affiliation: PhoenixBio, Co., Ltd, Utsunomiya 321-0973, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shiota
authors.affiliation: PhoenixBio, Co., Ltd, Utsunomiya 321-0973, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Faculty of Symbiotic Systems Science, Fukushima University, Fukushima 960-1296, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tsutsui
authors.affiliation: Department of Behavioural Sciences, Graduate School of Integrated Arts & Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Sakata
authors.affiliation: Translational Research Center, Ehime University Hospital, Toon 791-0295, Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Matsushita
authors.affiliation: 1] Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan [2] Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D003214:Conditioning, Classical; D003342:Corpus Striatum / Q000166:cytology*; D004193:Discrimination Learning; D055785:Gene Knockdown Techniques; D007395:Interneurons / Q000166:cytology*; D008124:Locomotion; D051381:Rats; D055647:Rats, Transgenic; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*
chemical_list: D011976:Receptors, Muscarinic