Impairments of spatial memory retrieval via medial mammillary body dysfunction in Alzheimer's disease model

Alzheimer's disease (AD) patients and AD mouse models usually have cognitive impairments, such as significant spatial memory deficits, which are coupled with dysregulation in the structure and function of neural circuits. The medial mammillary body (MM) is associated with spatial memory, and its dysfunction emerges in early AD. However, the link between spatial memory deficits and MM dysfunction remains unclear. Here, by combining c-Fos mapping with optogenetic stimulation, we found the MM was involved in the retrieval of object-location memory. Furthermore, using viral tracing, we demonstrated the axonopathy of MM neurons in the thalamus in the early stages of AD mouse model. Fiber photometry revealed that neuronal activity of MM neurons showed distinct responses to objects in different locations. However, neuronal activity was significantly reduced during the object-location memory retrieval phase in AD mice. Activating MM neurons in AD mice through optogenetic manipulation rescues the object-location memory impairment. Together, our results highlight the importance of MM dysfunction in AD, which may serve as a foundation for further exploration of new targets in AD.