SUMMARY
We report a molecular mechanism that controls brain response to stress and regulates adaptive behavior. In a mouse model under subacute stress, activation of the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade occurs selectively in cortical microglia. This stress response causally underlies cognitive inflexibility in mouse behaviors, which is proven by pharmacological intervention or microglia-specific genetic intervention targeting the initial steps of the N-GAPDH cascade. We performed ChIP-Seq against N-GAPDH and for the first time demonstrate how N-GAPDH influences the genome-wide transcriptional landscape under stress. Through this analysis, we obtained evidence that High-Mobility Group Box (HMGB) downstream of the N-GAPDH cascade, connected with the NMDA receptor, is responsible for the regulation of the adaptive behavior. Furthermore, the activation of this N-GAPDH-HMGB cascade is reflected by augmented autofluorescence in peripheral blood cells. Consistent with these observations, we clinically demonstrated an association between augmented lymphoblast autofluorescence and impaired cognitive flexibility in patients with schizophrenia.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Figure 7C corrected
