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

• Published in: Translational neurodegeneration 2024-07, Vol.13 (1), p.34-21, Article 34
• Main Authors: Chen, Meiqin, Wang, Chenlu, Lin, Yinan, Chen, Yanbing, Xie, Wenting, Huang, Xiaoting, Zhang, Fan, Fu, Congrui, Zhuang, Kai, Zou, Tingting, Can, Dan, Li, Huifang, Wu, Shengxi, Luo, Ceng, Zhang, Jie
• Format: Article
• Language: English
• Subjects: 5-HT neurons; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - psychology; Alzheimer’s disease; Animals; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - physiopathology; Cognitive Dysfunction - psychology; Cognitive impairment; Depression - genetics; Depression - metabolism; Depression - psychology; Depressive symptoms; Disease Models, Animal; Dorsal hippocampal CA1; Dorsal raphe nucleus; 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
• ISSN: 2047-9158; 2047-9158
• DOI: 10.1186/s40035-024-00425-w

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. 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. We found that the activity of dorsal raphe nucleus serotonin neurons (DRN ) and their projections to the dorsal hippocampal CA1 (dCA1) terminals (DRN -dCA1 ) both decreased in brains of early 5×FAD mice. Chemogenetic or optogenetic activation of the DRN -dCA1 neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B (5-HT R) and 4 (5-HT R). Pharmacological activation of 5-HT R or 5-HT R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DRN -dCA1 neural circuit to improve synaptic plasticity. These findings provide a new mechanistic connection between depression and AD and provide potential pharmaceutical prevention targets for AD.