FUNCTIONAL AND STRUCTURAL ALTERATIONS IN THE MAMMILLARY BODIES IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

Dysfunction of the mammillary bodies (MB), a key hypothalamic relay within the hippocampal–diencephalic memory circuit, disrupts spatial and episodic memory. The MB are among the earliest brain structures affected by Alzheimer’s disease (AD) pathology, yet their subregional organization, functional contributions to memory, and selective vulnerability during disease progression remain poorly understood.
We combine behavioral, anatomical, molecular, and electrophysiological approaches to define subregion-specific roles of the MB in memory processing and AD-related degeneration using the 5xFAD mouse model. Contextual fear conditioning reveals that neuronal activity in the medial mammillary body (MMB) robustly correlates with fear memory retrieval performance. Molecular profiling identifies two distinct MMB subregions defined by complementary marker expression: a parvalbumin-positive pars dorsalis (MMd) and a dopamine D2 receptor-positive pars basalis (MMpb).
Quantitative histological analyses demonstrate significant differences in neuronal cell density across MB subregions that are preserved across genotypes, while revealing striking subregion-specific vulnerability to amyloidosis. In both young and aged 5xFAD mice, amyloid pathology preferentially accumulates in the MMd, whereas the MMpb is comparatively spared. Anatomical tracing shows that dorsal and ventral MMB receive hippocampal input, with dense projections from the dorsal subiculum to dorsal MMB and from the ventral subiculum to ventral MMB. Notably, the ventral subiculum–ventral MMB pathway exhibits reduced amyloidosis. Finally, analyses of intrinsic electrophysiological properties further support functional specialization across MB subregions.
Together, these findings reveal molecularly and functionally distinct mammillary body subregions with differential susceptibility to AD pathology, providing mechanistic insight into how selective degeneration of diencephalic memory circuits dysfunction.