Segregated supramammillary-dentate gyrus circuits modulate cognitive and affective function in healthy and Alzheimer's disease model mice.

While progressive cognitive decline is the defining feature of Alzheimer's disease (AD), many patients also develop prominent neuropsychiatric symptoms, including anxiety and depression. The circuit-level mechanisms underlying these distinct symptom domains remain poorly understood, and treatments that address both cognitive and noncognitive aspects of AD are limited. Here, we identify anatomically, molecularly, and functionally distinct subpopulations of supramammillary (SuM) neurons that project to either the dorsal or ventral dentate gyrus (dDG or vDG). These distinct SuM neurons and their SuM-DG subcircuits selectively regulate memory and emotion, respectively. In AD model mice, SuM neurons targeting dDG or vDG display aberrant activity during memory or emotional processing, and importantly, targeted optogenetic activation of SuM-dDG or SuM-vDG pathways selectively restores cognitive or affective function. These findings reveal SuM-DG subcircuits as parallel modulators of cognitive and emotional states and highlight their potential as therapeutic targets for addressing the multifaceted symptomatology of AD.