Long-range inputome of prefrontal GABAergic interneurons in the Alzheimer's disease mouse

INTRODUCTIONAlzheimer's disease (AD) is the most common neurodegenerative disease, characterized by damage to cortical circuits. However, the mechanisms underlying AD-associated changes in long-range circuits remain poorly understood. METHODSIn this study, we used viral tracing and fluorescence micro-optical sectioning tomography (fMOST) imaging to investigate whole-brain changes in the input circuit of the frontal cortex of 5xFAD mice. RESULTSPathological axonal degeneration was widely observed in upstream regions, including the cortex, hippocampus, and thalamus, across all AD brains examined. The proportion of input neurons projecting to parvalbumin-expressing neurons, compared to those projecting to somatostatin-expressing neurons, decreased in the hippocampus and basal forebrain. This decline was closely related to mouse age and the cell type of the presynaptic input neurons. DISCUSSIONThis study demonstrates the selective vulnerability of long-range circuits in the prelimbic area in AD at the mesoscopic level, thereby enhancing our understanding of circuit architecture degeneration across the brain. Highlights We used whole-brain imaging with single-cell resolution to generate brain-wide input maps of the Alzheimer's disease mouse model. The pathological changes in the input proportions showed relevance with the mouse age, distribution, and cell type of the presynaptic input neurons. Compared to the cell body and dendrites of the medial prefrontal cortex input neurons, the pathological changes in the axonal structure are more extensive.