Neuroinflammation is being increasingly recognized as a vital factor in the development of various neurological and neuropsychiatric diseases. Lipopolysaccharides (LPS), an outer membrane component of gram-negative bacteria, can trigger innate immune responses, resulting in neuroinflammation and subsequent cognitive deficits. The expression of glutamate receptors (GluRs) on glial cells can induce glial activation. Therefore, we hypothesized that repeated LPS exposure can increase GluR levels, promoting microglial activation and ultimately affecting synaptic plasticity and cognitive function. In this study, C57/BL6 mice were repeatedly exposed to LPS to construct a neuroinflammation animal model. The levels of GluRs, inflammatory cytokines, ionized calcium-binding adaptor molecule 1, postsynaptic density protein 95, synaptophysin 38, NMDA receptor 2 A, and NMDA receptor 2B (GluN2B) were measured in the hippocampi. Furthermore, dendritic spine density in the CA1 hippocampal region was determined. Repeated LPS exposure induced cognitive impairments and microglial activation and increased GluR1 and GluR2 levels. This was accompanied by a significant decrease in GluN2B expression and dendritic spine density in the hippocampi. However, CFM-2, an α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate receptor antagonist, reversed these anomalies. Furthermore, minocycline, a microglial inhibitor, reversed these anomalies and downregulated GluR2 but not GluR1 expression. In summary, we demonstrated that GluR2 plays an essential role in microglia-induced neuroinflammation, resulting in synaptic plasticity and cognitive impairment induced by repeated exposure to LPS.

Postintensive care syndrome (PICS) is defined as a new or worsening impairment in cognition, mental health, and physical function after critical illness and persisting beyond hospitalization, which is associated with reduced quality of life and increased mortality. Recently, we have developed a clinically relevant animal model of PICS based on two-hit hypothesis. However, the underlying mechanism remains unclear. Accumulating evidence has demonstrated that hippocampal GABAergic interneuron dysfunction is implicated in various mood disorders induced by stress. Thus, this study investigated the role of hippocampal GABAergic interneurons and relevant neural activities in an animal model of PICS. In addition, we tested whether fluoxetine treatment early following combined stress can prevent these anatomical and behavioral pathologies. In the present study, we confirmed our previous study that this PICS model displayed reproducible anxiety- and depression like behavior and cognitive impairments, which resembles clinical features of human PICS. This behavioral state is accompanied by hippocampal neuroinflammation, reduced parvalbumin (PV) expression, and decreased theta and gamma power. Importantly, chronic fluoxetine treatment reversed most of these abnormities. In summary, our study provides additional evidence that PV interneuron-mediated hippocampal network activity disruption might play a key role in the pathology of PICS, while fluoxetine offers protection via modulation of the hippocampal PV interneuron and relevant network activities.

目的 研究海马F-肌动蛋白聚合在老年小鼠围术期神经认知障碍(PND)中的作用并探讨其可能的作用机制.方法 20月龄雄性C57BL/6小鼠72只,随机均分为四组:对照+溶质组(CV组)、对照+jasplakinolide(F-肌动蛋白聚合诱导剂)组(CJ组)、模型+溶质组(PV组)及模型+jas-plakinolide组(PJ组),每组18只.采用异氟醚麻醉+腹腔探查术建立PND模型.手术麻醉开始前2 h和行为学训练后即刻左侧脑室注射jasplakinolide(0.5μg/1.5μl)(CJ组和PJ组)或等容量溶质(97.5％生理盐水+2.5％DMSO)(CV组和PV组).手术麻醉后第2天行场景性条件恐惧实验训练、第3天行场景性条件恐惧实验测试僵直时间百分比.行为学测试结束后90 min取脑组织.采用Western blot检测海马F-actin、G-actin、突触体和神经元膜上GluR1和GluR2含量;采用高尔基染色检测海马CA1区神经元树突棘数目和分型;采用免疫荧光检测海马CA1区c-fos数目.结果 条件性恐惧实验训练阶段,四组僵直时间百分比差异无统计学意义.与CV组比较,PV组在手术麻醉后第3天场景性条件恐惧实验测试中的僵直时间百分比明显下降,海马F-actin/G-actin数值、突触体和神经元膜上GluR1和GluR2含量明显降低,CA1区神经元树突棘总数、丝状伪足和蘑菇型数目以及c-fos数目明显减少(P<0.05).与PV组比较,PJ组僵直时间百分比明显上升,海马F-actin/G-actin数值、突触体和神经元膜上GluR1和GluR2含量明显升高,CA1区神经元树突棘总数、丝状伪足和蘑菇型数目以及c-fos数目明显增多(P<0.05).结论 F-肌动蛋白聚合诱导剂jasplakinolide可改善老年小鼠术后的场景性恐惧记忆损害,其作用机制可能与促进树突棘重塑和AMPA受体转运上膜,增加神经元活动有关.

Background: Accumulating evidence has demonstrated that aging is associated with an exaggerated response to surgical trauma together with cognitive impairments. This has significant implications for the development of clinical phenotype such as perioperative neurocognitive disorders (PND), which is a common complication following surgery, especially for the elderly. However, the mechanism by which aging brain is vulnerable to surgical trauma remains to be elucidated. Objective: To test whether age-related alterations in hippocampal network activities contribute to increased risk of PND following surgery. Methods: Thirty-two adult and seventy-two aged male C57BL/6 mice undergone sevoflurane anesthesia and exploratory laparotomy were used to mimic human abdominal surgery. For the interventional study, mice were treated with minocycline. Behavioral tests were performed post-surgery with open field, novel object recognition and fear conditioning tests, respectively. The brain tissues were then harvested and subjected to biochemistry studies. Local field potential (LFP) recording was performed in another separate experiment. Results: Aged mice displayed signs of neuroinflammation, as reflected by significantly increased proinflammatory mediators in the hippocampus. Also, aged mice displayed persistently decreased oscillation activities under different conditions, both before and after surgery. Further correlation analysis suggested that theta power was positively associated with time with novel object, while γ oscillation activity was positively associated with freezing time to context. Of note, downregulation of neuroinflammation by microglia inhibitor minocycline reversed some of these abnormities. Conclusion: Our study highlights that age-related hippocampal oscillation dysregulation increases the risk of PND incidence, which might provide diagnostic/prognostic biomarkers for PND and possible other neurodegenerative diseases.

PDK1 (3-Phosphoinositide dependent protein kinase-1) is a member in the PI3K (phosphatidylinositol 3 kinase) pathway and is implicated in neurodevelopmental disease with microcephaly. Although the role of PDK1 in neurogenesis has been broadly studied, it remains unknown how PDK1 may regulate oligogenesis in the central nervous system (CNS). To address this question, we generated oligodendrocyte (OL) lineage cells specific PDK1 conditional knockout (cKO) mice. We find that PDK1 cKOs display abnormal white matter (WM), massive loss of mature OLs and severe defect in myelination in the CNS. In contrast, these mutants exhibit normal neuronal development and unchanged apoptosis in the CNS. We demonstrate that deletion of PDK1 severely impairs OL differentiation. We show that genetic or pharmacological inhibition of PDK1 causes deficit in the mammalian target of rapamycin (mTor) signaling and down-regulation of Sox10. Together, these results highlight a critical role of PDK1 in OL differentiation during postnatal CNS development.

The roles of lncRNAs in cardiac diseases have received increasing attention. The biological role of taurine upregulated gene 1 (TUG 1) in hypoxia-induced damage of cardiomyocytes is still poorly defined. Our study aimed to investigate the function of TUG 1 in hypoxia-treated cardiomyocytes and the possible underlying mechanism. TUG 1 and miR-133a expression levels in hypoxia-cultured human AC16 cardiomyocytes were examined by RT-qPCR. The role of TUG 1 and miR-133a in cell proliferation was assayed by CCK-8 assay. AC16 cell apoptosis was assessed by flow cytometry and caspase-3/7 activity assay. The expression levels of cleaved poly ADP ribose polymerase (PARP) and cleaved caspase-3 were evaluated by Western blot analysis. We found that TUG 1 expression was elevated, while miR-133a expression was reduced under hypoxic condition in AC16 cells. TUG 1 silencing and miR-133a restoration relieved hypoxia-induced reduction of proliferation as well as repressed hypoxia-induced AC16 cell apoptosis, while the opposite effects were observed after TUG 1 overexpression and miR-133a inhibition. We identified that TUG 1 acted as a competing endogenous RNA to suppress miR-133a expression. Mechanistically, miR-133a overturned TUG 1 overexpression-mediated inhibition of proliferation and promotion on apoptosis in AC16 cells under hypoxic condition. Conversely, inhibition of miR-133a abolished TUG 1 knockdown-mediated promotion of proliferative ability and repression of apoptosis in hypoxia-cultured AC16 cells. In conclusion, TUG 1 knockdown relieved hypoxia-induced reduction of proliferation and repressed hypoxia-induced AC16 cell apoptosis by up-regulating miR-133a expression.

Sepsis-associated encephalopathy (SAE) is a potentially irreversible acute cognitive dysfunction with unclear mechanism. Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase which normally opposes synaptic strengthening by regulating key signaling molecules involved in synaptic plasticity and neuronal function. Thus, we hypothesized that abnormal STEP signaling pathway was involved in sepsis-induced cognitive impairment evoked by lipopolysaccharides (LPS) injection. The levels of STEP, phosphorylation of GluN2B (pGluN2B), the kinases extracellular signal-regulated kinase 1/2 (pERK), cAMP-response element binding protein (CREB), synaptophysin, brain derived neurotrophic factor (BDNF), and post-synaptic density protein 95 (PSD95) in the hippocampus, prefrontal cortex, and striatum were determined at the indicated time points. In the present study, we found that STEP levels were significantly increased in the hippocampus, prefrontal cortex, and striatum following LPS injection, which might resulted from the disruption of the ubiquitin-proteasome system. Notably, a STEP inhibitor TC-2153 treatment alleviated sepsis-induced memory impairment by increasing phosphorylation of GluN2B and ERK1/2, CREB/BDNF, and PSD95. In summary, our results support the key role of STEP in sepsis-induced memory impairment in a mouse model of SAE, whereas inhibition of STEP may provide a novel therapeutic approach for this disorder and possible other neurodegenerative diseases.