| Autor: |
Adriana Ramos, Koko Ishizuka, Ho Namkung, Lindsay N. Hayes, Atsushi Saito, Arisa Hayashida, Rupali Srivastava, Noah Elkins, Trexy Palen, Elisa Carloni, Tsuyoshi Tsujimura, Coleman Calva, Satoshi Ikemoto, Rana Rais, Barbara S. Slusher, Minae Niwa, Toshiaki Saitoh, Eiki Takimoto, Akira Sawa |
| Rok vydání: |
2022 |
| Popis: |
We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute 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. Furthermore, hyperactivation of the prelimbic layer 5 excitatory neurons, which are known to be a neuronal substrate of cognitive inflexibility, was also normalized by the pharmacological and microglia-specific genetic interventions. The RR compound may offer a mechanism-driven, translational opportunity against stress-induced cognitive inflexibility. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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