Author:
Chen Meiqin,Wang Chenlu,Lin Yinan,Chen Yanbing,Xie Wenting,Huang Xiaoting,Zhang Fan,Fu Congrui,Zhuang Kai,Zou Tingting,Can Dan,Li Huifang,Wu Shengxi,Luo Ceng,Zhang Jie
Abstract
Abstract
Background
Depressive symptoms often occur in patients with Alzheimer's disease (AD) and exacerbate the pathogenesis of AD. However, the neural circuit mechanisms underlying the AD-associated depression remain unclear. The serotonergic system plays crucial roles in both AD and depression.
Methods
We used a combination of in vivo trans-synaptic circuit-dissecting anatomical approaches, chemogenetic manipulations, optogenetic manipulations, pharmacological methods, behavioral testing, and electrophysiological recording to investigate dorsal raphe nucleus serotonergic circuit in AD-associated depression in AD mouse model.
Results
We found that the activity of dorsal raphe nucleus serotonin neurons (DRN5-HT) and their projections to the dorsal hippocampal CA1 (dCA1) terminals (DRN5-HT-dCA1CaMKII) both decreased in brains of early 5×FAD mice. Chemogenetic or optogenetic activation of the DRN5-HT-dCA1CaMKII neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B (5-HT1BR) and 4 (5-HT4R). Pharmacological activation of 5-HT1BR or 5-HT4R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DRN5-HT-dCA1CaMKII neural circuit to improve synaptic plasticity.
Conclusions
These findings provide a new mechanistic connection between depression and AD and provide potential pharmaceutical prevention targets for AD.
Funder
National Natural Science Foundation of China
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education
Project of Sichuan Department of Science and Technology
Publisher
Springer Science and Business Media LLC