title: Role for the M1 Muscarinic Acetylcholine Receptor in Top-Down Cognitive Processing Using a Touchscreen Visual Discrimination Task in Mice.
abstract: The M1 muscarinic acetylcholine receptor (mAChR) subtype has been implicated in the underlying mechanisms of learning and memory and represents an important potential pharmacotherapeutic target for the cognitive impairments observed in neuropsychiatric disorders such as schizophrenia. Patients with schizophrenia show impairments in top-down processing involving conflict between sensory-driven and goal-oriented processes that can be modeled in preclinical studies using touchscreen-based cognition tasks. The present studies used a touchscreen visual pairwise discrimination task in which mice discriminated between a less salient and a more salient stimulus to assess the influence of the M1 mAChR on top-down processing. M1 mAChR knockout (M1 KO) mice showed a slower rate of learning, evidenced by slower increases in accuracy over 12 consecutive days, and required more days to acquire (achieve 80% accuracy) this discrimination task compared to wild-type mice. In addition, the M1 positive allosteric modulator BQCA enhanced the rate of learning this discrimination in wild-type, but not in M1 KO, mice when BQCA was administered daily prior to testing over 12 consecutive days. Importantly, in discriminations between stimuli of equal salience, M1 KO mice did not show impaired acquisition and BQCA did not affect the rate of learning or acquisition in wild-type mice. These studies are the first to demonstrate performance deficits in M1 KO mice using touchscreen cognitive assessments and enhanced rate of learning and acquisition in wild-type mice through M1 mAChR potentiation when the touchscreen discrimination task involves top-down processing. Taken together, these findings provide further support for M1 potentiation as a potential treatment for the cognitive symptoms associated with schizophrenia.
authors.forename: R W
authors.initials: RW
authors.lastname: Gould
authors.affiliation: Laboratory of Neuropsychiatry, Psychiatric Center Copenhagen , DK-2100 Copenhangen, Denmark.
authors.forename: D
authors.initials: D
authors.lastname: Dencker
authors.forename: M
authors.initials: M
authors.lastname: Grannan
authors.forename: M
authors.initials: M
authors.lastname: Bubser
authors.forename: X
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: J
authors.initials: J
authors.lastname: Wess
authors.forename: Z
authors.initials: Z
authors.lastname: Xiang
authors.forename: C
authors.initials: C
authors.lastname: Locuson
authors.forename: C W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: P J
authors.initials: PJ
authors.lastname: Conn
authors.forename: C K
authors.initials: CK
authors.lastname: Jones
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018678:Cholinergic Agents / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000175:diagnosis* / Q000235:genetics*; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010364:Pattern Recognition, Visual / Q000502:physiology*; D010775:Photic Stimulation; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000378:metabolism*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D014110:Touch / Q000502:physiology
chemical_list: D018678:Cholinergic Agents; D015363:Quinolones; D012333:RNA, Messenger; D043643:Receptor, Muscarinic M1
keywords: BQCA; M1 knockout mice; M1 muscarinic acetylcholine receptors; Positive allosteric modulators; top-down processing; touchscreen cognition