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
  • 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. [email protected].
  • 6. Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, 361102, China. [email protected].
  • 7. Department of Neurology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China. [email protected].
  • 8. Institute of Neuroscience, Fujian Medical University, Fuzhou, 350004, China. [email protected].
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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