Dorsal raphe nucleus-hippocampus serotonergic circuit underlies the depressive and cognitive impairments in 5×FAD male mice  

作　　者：Meiqin Chen Chenlu Wang Yinan Lin Yanbing Chen Wenting Xie Xiaoting Huang Fan Zhang Congrui Fu Kai Zhuang Tingting Zou Dan Can Huifang Li Shengxi Wu Ceng Luo Jie Zhang 

机构地区：[1]The Key Laboratory of Neural and Vascular Biology,Ministry of Education,College of Basic Medicine,Hebei Medical University,Shijiazhuang 050017,China [2]Institute of Neuroscience,College of Medicine,Xiamen University,Xiamen 361102,China [3]Department of Anesthesiology,First Affiliated Hospital of Xiamen University,Xiamen 361000,China [4]Department of Neurobiology,School of Basic Medicine,Fourth Military Medical University,Xi’an 710032,China [5]Department of Neurology,Sichuan Provincial People’s Hospital,School of Medicine,University of Electronic Science and Technology of China,Chengdu 610054,China [6]Institute of Neuroscience,Fujian Medical University,Fuzhou 350004,China

出　　处：《Translational Neurodegeneration》2024年第1期619-639,共21页转化神经变性病(英文)

基　　金：supported by the National Natural Science Foundation of China(81925010,91849205,U1905207,92149303 to J.Z.);the National Key Research and Development Program of China(2021YFA1101402 to J.Z.);the Key laboratory of Neural and Vascular Biology,Ministry of Education of China(NV20230010,NV20230014);the Project of Sichuan Department of Science and Technology(2021YFS0385).

摘　　要：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(DR^(N5-HT))and their projections to the dorsal hippocampal CA1(dCA1)terminals(DR^(N5-HT)-dCA1^(CaMKII))both decreased in brains of early 5×FAD mice.Chemogenetic or optogenetic activation of the DR^(N5-HT)-dCA1^(CaMKII) neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B(5-HT_(1B)R)and 4(5-HT_(4)R).Pharmaco-logical activation of 5-HT1BR or 5-HT4R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DR^(N5-HT)-dCA1^(CaMKII) neural circuit to improve synaptic plasticity.Conclusions These findings provide a new mechanistic connection between depression and AD and provide poten-tial pharmaceutical prevention targets for AD.

关 键 词：Alzheimer’s disease Depressive symptoms Cognitive impairment 5-HT neurons Dorsal raphe nucleus Dorsal hippocampal CA1 Serotonin receptor 

分 类 号：R749.4[医药卫生—神经病学与精神病学]