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 glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. 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.

我们报告了一种在分子水平上导致压力引起的认知僵化的机制。在亚急性细胞应激下的小鼠模型中，引发了规则转换任务的缺陷，核甘油醛脱氢酶（N-GAPDH）级联在前边缘皮层的小胶质细胞中被特异性激活。通过使用一种化合物（RR 化合物）进行药物干预，认知缺陷得以正常化，该化合物选择性地阻断 N-GAPDH 级联的启动，而不影响糖酵解活性。通过针对 N-GAPDH 级联的小胶质细胞特异性遗传干预也观察到了正常化。在机制水平上，小胶质细胞高迁移率族盒（HMGB）的分泌增加，HMGB 已知与 NMDA 型谷氨酸受体结合并调节。因此，还观察到前边缘第 5 层兴奋性神经元（认知僵化的神经基础）的过度激活。通过药理学和小胶质细胞特异性遗传干预，小胶质细胞 HMGB 信号传导的上调和神经元过度激活得以正常化。综上所述，我们展示了皮质小胶质细胞和小胶质细胞-神经元相互作用在压力引起的认知僵化中的关键作用。我们强调小胶质细胞中的 N-GAPDH 级联，它介导压力诱导的认知改变。