To mechanistically link the high-glucose-mediated Bhlhe41 upregulation with cognitive impairment in type 2 diabetes, we specifically eliminated Bhlhe41 expression in hippocampal CA1 neurons by crossing db/m mice with Bhlhe41fl/+ mice (Appendix Fig. S1J) to generate db/db Bhlhe41fl/fl mice (Appendix Fig. S1K), and bilaterally infusing adeno-associated virus (AAV) containing either a control or CAMKII-Cre vector construct into the hippocampal CA1 region of db/db Bhlhe41fl/fl mice (Appendix Fig. S1L). Here, BHLHE41 is linked to type 2 diabetes mellitus.