biostudies-literatureRamos AU.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)NIMH NIH HHSNARSAD, Stanley, and S-R/RUSKU.S. Department of Health & Human Services | NIH | National Institute of Mental Health2967-2978https://www.ebi.ac.uk/biostudies/studies/S-EPMC11449656biostudies-literatureUnknown29(10)We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamateMolecular psychiatryNuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility.PMC11449656MH-107730MH-105660MH-094268 Silvio O. Conte centerP50 MH094268R01 MH105660R01 MH107730Tsujimura TPalen TSaitoh TNamkung HSawa AZhang MCarloni ENiwa MTakimoto ECalva CIshizuka KSrivastava RSlusher BSKariya TRamos AHayashida AIkemoto SHayes LNElkins NRais RSaito AfalseNuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility.We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate2024-01-01T00:00:00Z2024 Oct2025-04-22T21:40:56.737Z2025-04-06T03:42:22.118ZS-EPMC114496563861510210.1038/s41380-024-02553-1