The subiculum (SUB), a hippocampal formation structure, is among the earliest brain regions impacted in Alzheimer's disease (AD). Toward 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 the hippocampal subregions (CA1, CA2, CA3), medial septum and diagonal band, retrosplenial cortex, SUB, postsubiculum (postSUB), visual cortex, auditory cortex, somatosensory cortex, entorhinal cortex, thalamus, perirhinal cortex (Prh), ectorhinal cortex, and temporal association cortex. 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 with control mice. Significant sex differences for SUB inputs are found in 5xFAD mice for CA1, CA2, CA3, postSUB, Prh, lateral entorhinal cortex, and medial entorhinal cortex: all of these areas are critical for learning and memory. Notably, we find significant changes at different ages for visual cortical inputs to SUB. While the visual function is not ordinarily considered defective in AD, these specific connectivity changes reflect that altered visual circuitry contributes 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.

下托 (SUB) 是一种海马结构，是最早受到阿尔茨海默病 (AD) 影响的大脑区域之一。为了更好地理解基于 AD 电路的机制，我们通过定量比较年龄匹配的对照和不同年龄的 5xFAD 小鼠的 SUB 兴奋性神经元的电路连接，在 5xFAD 小鼠模型中使用单突触狂犬病追踪将突触电路输入映射到背侧 SUB。两性。输入映射的大脑区域包括海马亚区（CA1、CA2、CA3）、内侧隔膜和对角线带、压后皮质、SUB、后下皮质（postSUB）、视觉皮层、听觉皮层、体感皮层、内嗅皮层、丘脑、周围皮层（ Prh)、内嗅皮层和颞联合皮层。我们发现，与对照小鼠相比，5xFAD 小鼠海马亚区域和其他大脑区域的 SUB 突触前输入的连接强度和模式存在性别和年龄依赖性变化。在 5xFAD 小鼠的 CA1、CA2、CA3、postSUB、Prh、外侧内嗅皮层和内侧内嗅皮层中发现 SUB 输入存在显着的性别差异：所有这些区域对于学习和记忆都至关重要。值得注意的是，我们发现不同年龄段的 SUB 视觉皮层输入有显着变化。虽然 AD 患者的视觉功能通常不被认为有缺陷，但这些特定的连接变化反映出视觉回路的改变会导致学习和记忆缺陷。我们的工作为 AD 进展过程中 SUB 导向的神经回路机制提供了新的见解，并支持神经回路破坏是 AD 的一个显着特征的观点。