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

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) 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-HTR) and 4 (5-HTR). Pharmacological activation of 5-HTR or 5-HTR attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DRN-dCA1 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.