Acetylcholine deficiency disrupts extratelencephalic projection neurons in the prefrontal cortex in a mouse model of Alzheimer’s disease

Qingtao Sun, Jianping Zhang, Anan Li, Mei Yao, Guangcai Liu, Siqi Chen, Yue Luo, Zhi Wang, Hui Gong, Xiangning Li () and Qingming Luo ()
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Qingtao Sun: Huazhong University of Science and Technology
Jianping Zhang: Hainan University
Anan Li: Huazhong University of Science and Technology
Mei Yao: Huazhong University of Science and Technology
Guangcai Liu: Huazhong University of Science and Technology
Siqi Chen: Huazhong University of Science and Technology
Yue Luo: Huazhong University of Science and Technology
Zhi Wang: Huazhong University of Science and Technology
Hui Gong: Huazhong University of Science and Technology
Xiangning Li: Huazhong University of Science and Technology
Qingming Luo: Hainan University

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract Short-term memory deficits have been associated with prefrontal cortex (PFC) dysfunction in Alzheimer’s disease (AD) and AD mouse models. Extratelencephalic projection (ET) neurons in the PFC play a key role in short-term working memory, but the mechanism between ET neuronal dysfunction in the PFC and short-term memory impairment in AD is not well understood. Here, using fiber photometry and optogenetics, we found reduced neural activity in the ET neurons in the medial prefrontal cortex (mPFC) of the 5×FAD mouse model led to object recognition memory (ORM) deficits. Activation of ET neurons in the mPFC of 5×FAD mice rescued ORM impairment, and inhibition of ET neurons in the mPFC of wild type mice impaired ORM expression. ET neurons in the mPFC that project to supramammillary nucleus were necessary for ORM expression. Viral tracing and in vivo recording revealed that mPFC ET neurons received fewer cholinergic inputs from the basal forebrain in 5×FAD mice. Furthermore, activation of cholinergic fibers in the mPFC rescued ORM deficits in 5×FAD mice, while acetylcholine deficiency reduced the response of ET neurons in the mPFC to familiar objects. Taken together, our results revealed a neural mechanism behind ORM impairment in 5×FAD mice.

Date: 2022
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DOI: 10.1038/s41467-022-28493-4

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