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

doi:10.1186/s40035-024-00425-w

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.

Authors

Meiqin Chen^{1

2}, Chenlu Wang³, Yinan Lin³, Yanbing Chen², Wenting Xie², Xiaoting Huang², Fan Zhang¹, Congrui Fu¹, Kai Zhuang², Tingting Zou², Dan Can², Huifang Li², Shengxi Wu⁴, Ceng Luo⁴, 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].

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_1BR) and 4 (5-HT₄R). Pharmacological activation of 5-HT_1BR or 5-HT₄R 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.

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

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Alzheimer Disease* / psychology
Animals
Cognitive Dysfunction* / genetics
Cognitive Dysfunction* / metabolism
Cognitive Dysfunction* / physiopathology
Cognitive Dysfunction* / psychology
Depression* / genetics
Depression* / metabolism
Depression* / psychology
Disease Models, Animal*
Dorsal Raphe Nucleus* / metabolism
Hippocampus / metabolism
Male
Mice
Mice, Transgenic*
Neural Pathways / metabolism
Neural Pathways / physiopathology
Optogenetics
Serotonergic Neurons* / metabolism
Serotonergic Neurons* / physiology
Serotonin / metabolism

Substances

Serotonin

Abstract

MeSH terms

Substances

Grants and funding