Chemogenetic activation of the HPC-mPFC pathway improves cognitive dysfunction in lipopolysaccharide -induced brain injury.
Chemogenetic activation of the HPC-mPFC pathway improves cognitive dysfunction in lipopolysaccharide -induced brain injury.
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作者：
Ge C;Chen W;Zhang L;Ai Y;Zou Y;Peng Q
理由：尽管脓毒症相关脑病（SAE）是脓毒症患者常见的精神并发症，但其潜在机制尚不清楚。本研究探讨了海马(HPC) -内侧前额叶皮质（mPFC）通路在脂多糖性脑损伤认知功能障碍中的作用。方法：采用脂多糖（LPS, 5 mg/kg，腹腔注射）诱导SAE动物模型。我们首先通过逆行示踪剂和病毒表达确定了从HPC到mPFC的神经投射。注射活化病毒（pAAV-CaMKIIα-hM3Dq-mCherry），评估氯氮平- n -氧化物（CNO）存在下mPFC兴奋性神经元特异性活化对认知任务和焦虑相关行为的影响。通过mPFC中c- fos阳性神经元的免疫荧光染色评估HPC-mPFC通路的激活情况。Western blotting检测突触相关因子的蛋白水平。结果：我们成功地鉴定了C57BL/6小鼠HPC-mPFC的结构连接。lps诱导的脓毒症会导致认知障碍和焦虑样行为。HPC-mPFC通路的化学发生激活改善了lps诱导的认知功能障碍，但没有改善焦虑样行为。谷氨酸受体的抑制消除了HPC-mPFC的激活作用，阻断了HPC-mPFC通路的激活。谷氨酸受体介导的CaMKII/CREB/BDNF/TrKB信号通路影响HPC-mPFC通路在败血症诱导的认知功能障碍中的作用。结论：HPC-mPFC通路在脂多糖性脑损伤认知功能障碍中起重要作用。具体来说，谷氨酸受体介导的下游信号似乎是连接SAE中HPC-mPFC通路与认知功能障碍的重要分子机制。
Rationale: Although sepsis-associated encephalopathy (SAE) is a common psychiatric complication in septic patients, the underlying mechanisms remain unclear. Here, we explored the role of the hippocampus (HPC) - medial prefrontal cortex (mPFC) pathway in cognitive dysfunction in lipopolysaccharide-induced brain injury. Methods: Lipopolysaccharide (LPS, 5 mg/kg, intraperitoneal) was used to induce an animal model of SAE. We first identified neural projections from the HPC to the mPFC via a retrograde tracer and virus expression. The activation viruses (pAAV-CaMKIIα-hM3Dq-mCherry) were injected to assess the effects of specific activation of mPFC excitatory neurons on cognitive tasks and anxiety-related behaviors in the presence of clozapine-N-oxide (CNO). Activation of the HPC-mPFC pathway was evaluated via immunofluorescence staining of c-Fos-positive neurons in mPFC. Western blotting was performed to determine protein levels of synapse- associated factors. Results: We successfully identified a structural HPC-mPFC connection in C57BL/6 mice. LPS-induced sepsis induces cognitive impairment and anxiety-like behaviors. Chemogenetic activation of the HPC-mPFC pathway improved LPS-induced cognitive dysfunction but not anxiety-like behavior. Inhibition of glutamate receptors abolished the effects of HPC-mPFC activation and blocked activation of the HPC-mPFC pathway. The glutamate receptor-mediated CaMKII/CREB/BDNF/TrKB signaling pathway influenced the role of the HPC-mPFC pathway in sepsis-induced cognitive dysfunction. Conclusions: HPC-mPFC pathway plays an important role in cognitive dysfunction in lipopolysaccharide-induced brain injury. Specifically, the glutamate receptor-mediated downstream signaling appears to be an important molecular mechanism linking the HPC-mPFC pathway with cognitive dysfunction in SAE.
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