2. Academic Validation
  3. Dorsal raphe nucleus-hippocampus serotonergic circuit underlies the depressive and cognitive impairments in 5×FAD male mice

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

  • Transl Neurodegener. 2024 Jul 24;13(1):34. doi: 10.1186/s40035-024-00425-w.
Meiqin Chen 1 2,  Chenlu Wang 3,  Yinan Lin 3,  Yanbing Chen 2,  Wenting Xie 2,  Xiaoting Huang 2,  Fan Zhang 1,  Congrui Fu 1,  Kai Zhuang 2,  Tingting Zou 2,  Dan Can 2,  Huifang Li 2,  Shengxi Wu 4,  Ceng Luo 4,  Jie Zhang 5 6 7 8
Affiliations

Affiliations

  • 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 The Key Laboratory of Neural and Vascular Biology, Ministry of Education, College of Basic Medicine, Hebei Medical University, Shijiazhuang, 050017, China. jiezhang@xmu.edu.cn.
  • 6 Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, 361102, China. jiezhang@xmu.edu.cn.
  • 7 Department of Neurology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China. jiezhang@xmu.edu.cn.
  • 8 Institute of Neuroscience, Fujian Medical University, Fuzhou, 350004, China. jiezhang@xmu.edu.cn.
PMID: 39044270 DOI: 10.1186/s40035-024-00425-w
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.

Keywords

5-HT neurons; Alzheimer’s disease; Cognitive impairment; Depressive symptoms; Dorsal hippocampal CA1; Dorsal raphe nucleus; Serotonin receptor.

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