A 5-HTergic DRN vCA1 circuit and Alzheimer's disease

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PROJECT SUMMARY Despite the tremendous efforts in Alzheimer’s disease (AD) research, we have not made much progress in understanding the pathophysiology of AD or inhibiting/correcting AD-related behavioral symptoms. The recent FDA-approved aducanumab demonstrated significant efficacy in reducing amyloid β (Aβ). Still, it showed a limited effect in improving AD-related memory impairments. The specific neural circuits that mediate these cognitive processes but are altered progressively in the AD brains may serve as a treatment target after the removal of Aβ plaques. In my previous studies, I demonstrated that dorsal Raphe nucleus (DRN) serotonin (5- HT) neurons provide monosynaptic inputs to the hippocampal ventral CA1 (vCA1). Further, genetic ablation of 5-HT synthesis selectively in these vCA1-projecting DRN neurons impaired spatial memory in young mice. In addition, genetic deletion of the 5-HT 2C receptor (5-HT2CR) in the vCA1 led to spatial memory deficits in young mice. I also observed that lorcaserin, a selective agonist of 5-HT2CR, can ameliorate spatial memory deficits in a 6-month-old knock-in AD mouse model (APPNL-G-F), associated with restoration of synaptic plasticity in vCA1 neurons. Together, I developed a hypothesis that a 5-HTergic DRN to vCA1 circuit regulates spatial memory via 5-HT2CR, a therapeutic target for memory symptoms in Alzheimer’s disease. The K99 phase will focus on the upstream node of this circuit, the vCA1-projecting 5-HT neurons. Fiber photometry experiments will be used to monitor the real-time activity of these vCA1-projecting 5-HT neurons, as well as 5-HT release in the vCA1, corresponding to memory acquisition and retrieval behaviors. The intersectional retrograde chemogenetic approach will be used to further test whether inhibition of the vCA1-projecting 5-HT neurons would inhibit memory function and whether activating these neurons would rescue memory impairments in APPNL-G-F mice and aged mice. During the R00 phase, I will utilize the techniques and the problem-solving experience I acquire from the K99 phase to test the functional significance of the downstream 5-HT2CR-expressing vCA1 neurons. I will use fiber photometry to monitor the activity of 5-HT2CR-expressing vCA1 neurons during the memory test and will use the chemogenetic approach to assess the functional relevance of these neurons in memory function. In addition, I will also test the combination treatment of Aβ-lowering (aducanumab) and 5-HT2CR agonism (lorcaserin) in APPNL-G-F mice and aged mice. The proposed studies will advance our knowledge of the circuitry mechanisms underlying memory function and evaluate the possibility of 5-HT2CR agonism as a novel therapeutic target for AD in combination with Aβ-reducing medications. In addition, the K99 phase will provide an ideal training opportunity to equip me with essential techniques, knowledge, and problem-solving skills. These will prepare me for the R00 phase of research and an independent research career focusing on circuitry mechanisms of different behaviors.