Immunometabolic dysregulation drives selective executive cognitive dysfunction in male db/db mice

Type 2 diabetes (T2D) is associated with cognitive impairment, with executive functions such as cognitive flexibility being particularly vulnerable. Growing evidence suggests that chronic inflammatory and metabolic stress contributes to diabetes -related brain dysfunction, yet behavioral assessment in animal models is often confounded by anxiety, altered motivation, and reduced response vigor. In this study, we used a translational touchscreen-based operant platform to distinguish associative learning from executive cognitive flexibility in db/db mice, a well-established genetic model of T2D, and to evaluate the effects of the non-erythropoietic erythropoietin derived peptide ARA 290. Male db/db mice and age matched db/m heterozygote lean controls were tested using pairwise visual discrimination to assess associative learning and reversal learning to probe cognitive flexibility. Metabolic function was evaluated using glucose and insulin tolerance tests, while immune and metabolic effects of ARA 290 were evaluated by flow cytometry and RNA-seq. Db/db mice displayed delayed task engagement and longer response latencies during pretraining and acquisition, yet maintained intact associative learning accuracy. In contrast, they exhibited pronounced impairments in cognitive flexibility during reversal learning, characterized by increased perseveration and reduced adaptation to changed reward contingencies. Treatment with ARA 290 improved insulin sensitivity and altered circulating monocyte proportions but did not rescue deficits in executive cognitive flexibility. RNA-seq of the hippocampus revealed enrichment of immune pathways consistent with chronic low-grade inflammation, providing molecular context for the observed behavioral phenotype. Together, these findings demonstrate that T2D selectively impairs executive cognitive flexibility while sparing basic associative learning, and that improvement in peripheral metabolic function and altered monocyte proportions are insufficient to restore executive cognition. This work highlights the value of touchscreen-based paradigms for resolving distinct cognitive domains in metabolic disease and highlights the need to target brain specific immunometabolic mechanisms to address diabetes-associated cognitive dysfunction.