Operant House: A versatile open-source platform for automated operant conditioning testing of mice in home cages

Operant conditioning is a powerful method for probing cognitive functions, yet its widespread use is constrained by low throughput, labor-intensive procedures, and high costs. Here, we developed "Operant House," a low-cost, programmable device equipped with a touchscreen, retractable levers, and a water-reward port, designed to enable automated operant conditioning with minimal experimenter intervention in individually housed mice within their home cages. Although individual home-cage testing requires careful attention to animal welfare, the system permits continuous monitoring through live camera observation and recorded videos. As proof of concept, we implemented two cognitive protocols: a delayed non-match-to-position (DNMTP) test for assessing working memory and a two-choice spatial discrimination (TCSD) test involving working-memory-related processes and behavioral flexibility. Because working memory impairment is one of the earliest clinical features of Alzheimer's disease (AD), we further applied these protocols to a knock-in mouse model carrying familial AD-associated amyloid precursor protein mutations (AppNL-G-F mice). Using this model, we detected significant working memory deficits as early as 5 months of age. At this age, we also detected subtle and spatially heterogeneous synaptic alterations in the prefrontal cortex, whereas conventional electrophysiological measures were largely preserved. Together, these findings highlight the Operant House as a cost-effective, scalable platform for assessing higher cognitive functions in mice, offering an accessible tool for investigating neurological and neuropsychiatric disease models.