Circuit-specific selective vulnerability in the DMN persists in the face of widespread amyloid burden

The relationship between brainwide functional decline and accumulation of pathological protein aggregates in Alzheimer’s disease (AD) is complex and not well understood. A set of highly interconnected cortical regions known as the default mode network (DMN) exhibits selective vulnerability to both functional decline and amyloid beta (Aβ) plaques in early AD. One possibility is that early Aβ accumulation in the DMN drives vulnerability. However, it is unknown whether there is something intrinsic to neuronal projections within the DMN that biases these circuits towards dysfunction. Here we directly test this hypothesis using long-term recordings of the spiking activity of ensembles of single units in freely behaving mice characterized by global cortical and hippocampal Aβ burden (APP/PS1). Specifically, we track the interactions of a population of neurons within a DMN region and two additional populations that comprise monosynaptic targets, one within and the other outside the DMN. In addition, we record single neurons in hippocampus and examine interactions between in-DMN and out-DMN cortical circuits triggered on hippocampal sharp-wave ripples, stereotyped hippocampal events that contribute to memory consolidation in the cortex. We examine the statistics of local activity as well as inter-regional communication in a region, genotype, and brain-state dependent manner. Our data reveal dysfunction restricted to in-DMN projecting circuits. In contrast, communication along neuronal projections that originate in the DMN but target out-DMN populations are equivalent in APP/PS1 and WT mice. Circuit dysfunction is most evident throughout sleep as well as within sharp-wave ripples. Our results indicate that cells in the DMN exhibit differential intrinsic vulnerability to amyloid injury dependent on their projection targets.