Enhanced flexibility of place discrimination learning by targeting striatal cholinergic interneurons
Open accessAbstract
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.
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CHRM4 has been associated with schizophrenia and implicated in cognitive flexibility and dopamine release.
“the muscarinic acetylcholine M4 receptor (CHRM4) has been associated with schizophrenia22 and implicated in cognitive flexibility23 and dopamine release24.”
From Oxytocin pathway gene networks in the human brain (2019) · cites this paper as [23]
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- Authors
- Okada, K., Nishizawa, K., Fukabori, R., Kai, N., Shiota, A., Ueda, M., Tsutsui, Y., Sakata, S., Matsushita, N., & Kobayashi, K.
- Affiliations
- Hiroshima University (JP)
- Fukushima Medical University (JP)
- PhoenixBio (Japan) (JP)
- Fukushima University (JP)
- Ehime University Hospital (JP)
- Corresponding author
- Kobayashi, Kazuto
- ORCID
- Venue
- Nature Communications
- Published
- 2014-05-06
- Volume
- 5
- Issue
- 1
- Pages
- 3778-3778
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2075268859
- Cited by
- 90
- References
- 59
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 12 · 2020: 11 · 2019: 5 · 2018: 10 · 2017: 10 · 2016: 5 · 2015: 5
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (221S0003, 26112002, 25280051, 26119519, 25870583)
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- behavioral flexibility, striatal cholinergic interneurons, dorsomedial striatum, dorsolateral striatum, M4 muscarinic receptor, M1 muscarinic receptor, reward contingency
- MeSH terms
- Animals, Conditioning, Classical, Corpus Striatum, Discrimination Learning, Interneurons, Locomotion, Receptors, Muscarinic, Rats, Rats, Transgenic, Gene Knockdown Techniques
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