Monosynaptic rabies tracing reveals sex- and age-dependent dorsal subiculum connectivity alterations in an Alzheimer's disease mouse model

Abstract

The subiculum (SUB), a hippocampal formation structure, is among the earliest brain regions impacted in Alzheimer's disease (AD). Towards a better understanding of AD circuit-based mechanisms, we mapped synaptic circuit inputs to dorsal SUB using monosynaptic rabies tracing in the 5xFAD mouse model by quantitatively comparing the circuit connectivity of SUB excitatory neurons in age-matched controls and 5xFAD mice at different ages for both sexes. Input-mapped brain regions include hippocampal subregions (CA1, CA2, CA3), medial septum and diagonal band (MS-DB), retrosplenial cortex (RSC), SUB, post subiculum (postSUB), visual cortex (Vis), auditory cortex (Aud), somatosensory cortex (SS), entorhinal cortex (EC), thalamus, perirhinal cortex (Prh), ectorhinal cortex (Ect) and temporal association cortex (TeA). We find sex- and age-dependent changes in connectivity strengths and patterns of SUB presynaptic inputs from hippocampal subregions and other brain regions in 5xFAD mice compared to control mice. Significant sex differences for SUB inputs are found in 5xFAD mice for CA1, CA2, CA3, postSUB, Prh, LEC, and MEC: all areas critical for learning and memory. Notably, we find significant changes at different ages for visual cortical inputs to SUB. While visual function is not ordinarily considered defective in AD, these specific connectivity changes reflect altered visual circuitry contributing to learning and memory deficits. Our work provides new insights into SUB-directed neural circuit mechanisms during AD progression and supports the idea that neural circuit disruptions are a prominent feature of AD.Significance StatementAlzheimer's disease is a major health concern in the elderly, but the underlying neural circuit mechanisms of this disease remain unclear. The SUB is a critical brain region for relaying and integrating hippocampal and cortical information. In this study, we applied monosynaptic rabies viral tracing to study the circuit connectivity changes of SUB excitatory neurons in age-matched, gender-balanced control and 5xFAD mice. We identified age-progressive alterations of connectivity strengths and patterns of SUB neurons in AD model mice. The circuit alterations are differentially impacted in different genders for specific brain regions. Our new findings are supported by human AD literature and can help to identify potential new therapeutical circuit targets for AD treatments.