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Cell-type specific vulnerability to Alzheimer’s neurodegeneration in a subcortical limbic circuit node

Circuit mechanisms governing susceptibility to Alzheimer’s neurodegeneration and memory impairments is poorly understood. The mammillary body (MB), a subcortical node of the medial limbic circuit, exhibits early Alzheimer’s Disease (AD) pathology. Using single-cell RNA-sequencing, we identified two neuronal subtypes residing in specific MB compartments, Lateral MB (LM) and Medial MB (MM). LM and MM neurons harbored distinct molecular markers, projection targets, and electrophysiological properties. LM neurons are susceptible to neurodegeneration and neuronal dysfunction in both mice and humans with AD pathology. Slice electrophysiology revealed LM neurons were hyperactive several months before memory impairments emerged, and hyperactivity was exacerbated in the symptomatic stage of AD mice. Bidirectionally modulating LM neuronal activity suggested LM hyperactivity was necessary and sufficient to drive memory deficits. Our findings causally link dysregulated LM neurons to memory deficits in AD and suggest neurodegeneration is a result of genetically distinct, projection-specific cellular dysfunction.