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Role for the M1 Muscarinic Acetylcholine Receptor in Top-Down Cognitive Processing Using a Touchscreen Visual Discrimination Task in Mice
journal contribution
posted on 2015-10-21, 00:00 authored by R. W. Gould, D. Dencker, M. Grannan, M. Bubser, X. Zhan, J. Wess, Z. Xiang, C. Locuson, C. W. Lindsley, P. J. Conn, C. K. JonesThe 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.
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MiceThe M 1 muscarinic acetylcholine receptorm 1 mAChR knockoutallosteric modulator BQCApairwise discrimination taskDiscrimination TaskM 1 mAChR potentiationdiscrimination taskpharmacotherapeutic targetM 1 KOM 1touchscreen discrimination taskM 1 mAChRacquisitionschizophrenia show impairmentsM 1 potentiationM 1 KO miceperformance deficitsM 1 Muscarinic Acetylcholine Receptor
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