Program in Biomedical Science and Engineering, Department of Biomedical Science, College of Medicine, Inha University, Incheon, South Korea.
Department of Physiology and Biophysics, College of Medicine, Inha University, Incheon, South Korea.
Am J Physiol Cell Physiol. 2024 Mar 1;326(3):C978-C989. doi: 10.1152/ajpcell.00691.2023. Epub 2024 Feb 5.
Sleep deprivation (SD) is widely acknowledged as a significant risk factor for cognitive impairment. In this study, intraperitoneal caffeine administration significantly ameliorated the learning and memory (L/M) deficits induced by SD and reduced aggressive behaviors in adult zebrafish. SD led to a reduction in protein kinase A (PKA) phosphorylation, phosphorylated-cAMP response element-binding protein (p-CREB), and c-Fos expression in zebrafish brain. Notably, these alterations were effectively reversed by caffeine. In addition, caffeine mitigated neuroinflammation induced by SD, as evident from suppression of the SD-mediated increase in glial fibrillary acidic protein (GFAP) and nuclear factor-κB (NF-κB) activation. Caffeine restored normal -GlcNAcylation and -GlcNAc transferase (OGT) levels while reversing the increased expression of -GlcNAcase (OGA) in zebrafish brain after SD. Intriguingly, rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, effectively mitigated cognitive deficits, restored p-CREB and c-Fos levels, and attenuated the increase in GFAP in brain induced by SD. In addition, rolipram reversed the decrease in -GlcNAcylation and OGT expression as well as elevation of OGA expression following SD. Treatment with H89, a PKA inhibitor, significantly impaired the L/M functions of zebrafish compared with the control group, inducing a decrease in -GlcNAcylation and OGT expression and, conversely, an increase in OGA expression. The H89-induced changes in -GlcNAc cycling and L/M dysfunction were effectively reversed by glucosamine treatment. H89 suppressed, whereas caffeine and rolipram promoted -GlcNAc cycling in Neuro2a cells. Our collective findings underscore the interplay between PKA signaling and -GlcNAc cycling in the regulation of cognitive function in the brain, offering potential therapeutic targets for cognitive deficits associated with SD. Our observation highlights the intricate interplay between cAMP/PKA signaling and -GlcNAc cycling, unveiling a novel mechanism that potentially governs the regulation of learning and memory functions. The dynamic interplay between these two pathways provides a novel and nuanced perspective on the molecular foundation of learning and memory regulation. These insights open avenues for the development of targeted interventions to treat conditions that impact cognitive function, including SD.
睡眠剥夺（SD）被广泛认为是认知障碍的一个重要危险因素。在这项研究中，腹腔内给予咖啡因可显著改善 SD 诱导的学习和记忆（L/M）缺陷，并减少成年斑马鱼的攻击行为。SD 导致斑马鱼大脑中蛋白激酶 A（PKA）磷酸化、磷酸化 cAMP 反应元件结合蛋白（p-CREB）和 c-Fos 表达减少。值得注意的是，这些变化被咖啡因有效逆转。此外，咖啡因减轻了 SD 引起的神经炎症，抑制了 SD 介导的胶质纤维酸性蛋白（GFAP）和核因子-κB（NF-κB）激活的增加。咖啡因恢复了正常的 N-乙酰葡萄糖胺化和 N-乙酰葡萄糖胺转移酶（OGT）水平，同时逆转了 SD 后斑马鱼大脑中 N-乙酰葡萄糖胺酶（OGA）表达的增加。有趣的是， rolipram，一种选择性磷酸二酯酶 4（PDE4）抑制剂，有效减轻了认知缺陷，恢复了 p-CREB 和 c-Fos 水平，并减轻了 SD 引起的大脑中 GFAP 的增加。此外，rolipram 逆转了 SD 后 N-乙酰葡萄糖胺化和 OGT 表达的降低以及 OGA 表达的升高。与对照组相比，PKA 抑制剂 H89 显著损害了斑马鱼的 L/M 功能，导致 N-乙酰葡萄糖胺化和 OGT 表达降低，而 OGA 表达升高。用葡萄糖胺处理可有效逆转 H89 引起的 N-乙酰葡萄糖胺循环和 L/M 功能障碍。H89 抑制，而咖啡因和 rolipram 促进 Neuro2a 细胞中的 N-乙酰葡萄糖胺循环。我们的综合研究结果强调了 PKA 信号转导和 N-乙酰葡萄糖胺循环在大脑认知功能调节中的相互作用，为与 SD 相关的认知缺陷提供了潜在的治疗靶点。我们的观察结果突出了 cAMP/PKA 信号转导和 N-乙酰葡萄糖胺循环之间的复杂相互作用，揭示了一种潜在的调节学习和记忆功能的新机制。这两种途径之间的动态相互作用为学习和记忆调节的分子基础提供了一个新的、细致入微的视角。这些见解为开发针对影响认知功能的疾病的靶向干预措施开辟了途径，包括 SD。
