Dorsal raphe nucleus–hippocampus serotonergic circuit underlies the depressive and cognitive impairments in 5×FAD male mice
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
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 (DRN 5-HT ) and their projections to the dorsal hippocampal CA1 (dCA1) terminals (DRN 5-HT -dCA1 CaMKII ) both decreased in brains of early 5×FAD mice. Chemogenetic or optogenetic activation of the DRN 5-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). Pharmacological activation of 5-HT 1B R or 5-HT 4 R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DRN 5-HT -dCA1 CaMKII 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.