Role for the M1 Muscarinic Acetylcholine Receptor in Top-Down Cognitive Processing Using a Touchscreen Visual Discrimination Task in Mice.
Role for the M1 Muscarinic Acetylcholine Receptor in Top-Down Cognitive Processing Using a Touchscreen Visual Discrimination Task in Mice.
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DOI：
10.1021/acschemneuro.5b00123
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发表时间：
2015-10-21
影响因子：
5
通讯作者：
Jones CK
中科院分区：
文献类型：
--
作者：
Gould RW;Dencker D;Grannan M;Bubser M;Zhan X;Wess J;Xiang Z;Locuson C;Lindsley CW;Conn PJ;Jones CK
M1毒蕈碱型乙酰胆碱受体（mAChR）亚型与学习和记忆的潜在机制有关，是神经精神疾病（如精神分裂症）中观察到的认知障碍的重要潜在药理学靶点。精神分裂症患者表现出自上而下的处理障碍，涉及感觉驱动和目标导向过程之间的冲突，可以在临床前研究中使用基于触摸屏的认知任务进行建模。本研究采用触摸屏视觉成对辨别任务，其中小鼠区分不太突出和更突出的刺激，以评估M1 mAChR对自上而下处理的影响。M1 mAChR基因敲除（M1 KO）小鼠表现出较慢的学习速度，证明了在连续12天的准确性缓慢增加，并需要更多的天来获得（达到80%的准确性）与野生型小鼠相比，这个辨别任务。此外，M1阳性变构调节剂BQCA提高了野生型小鼠学习这种辨别的速度，但在连续12天测试前每天给予BQCA时，M1 KO小鼠则没有。重要的是，在同等显著性的刺激之间的区别，M1 KO小鼠没有表现出受损的收购和BQCA没有影响野生型小鼠的学习或收购的速度。这些研究首次证明了使用触摸屏认知评估的M1 KO小鼠的性能缺陷，以及当触摸屏辨别任务涉及自上而下处理时，通过M1 mAChR增强野生型小鼠的学习和获取率。总之，这些发现为M1增强作为精神分裂症相关认知症状的潜在治疗提供了进一步的支持。
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.