Vulnerability of short-term memory in a mouse model of Alzheimer’s disease

Interference from distracting stimuli renders short-term memory vulnerable. While behavioral evidence suggests short-term memory deficits in Alzheimer's disease (AD), the underlying neural mechanisms remain poorly understood. Using a mouse model of AD (APP-KI), we identified increased susceptibility of short-term memory to sensory perturbations. Simultaneous two-photon calcium imaging across eight cortical regions during a delayed-response task showed that distractors disrupted neural selectivity at both single-neuron and population levels in APP-KI mice. Recurrent neural network models replicating the neural activity of APP-KI mice exhibited decreased stability, consistent with reduced functional connectivity across the dorsal cortex. Furthermore, analyses of multi-regional corticocortical communication revealed reduced spatiotemporal degeneracy in activity transmission within the dorsal cortex of APP-KI mice, which could account for their attenuated robustness during sensorimotor transformations. Collectively, these findings identify reduced functional connectivity and impaired spatiotemporal degeneracy as central mechanisms of short-term memory deficits in the APP-KI mouse model of AD.