TREM2 and CD163 Ameliorate Microglia-Mediated Inflammatory Environment in the Aging Brain.

Aging decreases cognitive functions, especially learning and memory. Neuroinflammation is mediated by microglia and occurs in age-related neurodegenerative diseases. The expression profiles in a dataset of cognitively normal controls (GSE11882) were obtained from the Gene Expression Omnibus (GEO) database. Microarray data were used to explore the expression of age-related genes in the human hippocampus. A total of 120 differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein-protein interaction (PPI) network was constructed. A total of 18 key genes were identified by the plugin cytoHubba in Cytoscape software. Two genes with a positive impact on cognition during aging were teased out: triggering receptor expressed on myeloid cells 2 (TREM2) and a scavenger receptor (CD163). Finally, the results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) verified that the mRNA expression of these two genes was significantly upregulated in aged mice. Moreover, the levels of the inflammatory factors IL-1ß and IL-6 were significantly increased. TREM2 and CD163 may be upregulated to alleviate the inflammatory environment resulting from microglial activation in the aging brain, thereby delaying cognitive decline.

Identification of hub genes associated with cognition in the hippocampus of Alzheimer's Disease.

Alzheimer's Disease (AD) is a neurodegenerative disease featured by cognitive impairment. This bioinformatic analysis was used to identify hub genes related to cognitive dysfunction in AD. The gene expression profile GSE48350 in the hippocampus of AD patients aged >70 years was obtained from the Gene Expression Omnibus (GEO) database. A total of 96 differentially expressed genes (DEGs) were identified, and subjected to Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses; a protein-protein interaction (PPI) network was constructed. The DEGs were enriched in synapse-related changes. A protein cluster was teased out of PPI. Furthermore, the cognition ranked the first among all the terms of biological process (BP). Next, 4 of 10 hub genes enriched in cognition were identified. The function of these genes was validated using APP/PS1 mice. Cognitive performance was validated by Morris Water Maze (MWM), and gene expression by RT-qPCR, Cholecystokinin (CCK), Tachykinin precursor 1 (TAC1), Calbindin 1 (CALB1) were downregulated in the hippocampus. These genes can provide new directions in the research of the molecular mechanism of AD.

Sevoflurane plays a reduced role in cognitive impairment compared with isoflurane: limited effect on fear memory retention.

Isoflurane and sevoflurane are both inhalation anesthetics, but in clinical application, sevoflurane has been considered to be less suitable for long-term anesthesia because of its catabolic compounds and potential nephrotoxicity. Nevertheless, recent studies have shown that these two inhalation anesthetics are similar in hepatorenal toxicity, cost, and long-term anesthetic effect. Moreover, sevoflurane possibly has less cognitive impact on young mice. In this study, C57BL/6 mice aged 8-10 weeks were exposed to 1.2% isoflurane or 2.4% sevoflurane for 6 hours. Cognitive function and memory were examined in young mice using the novel object recognition, contextual fear conditioning, and cued-fear extinction tests. Western blot assay was performed to detect expression levels of D1 dopamine receptor, catechol-O-methyltransferase, phospho-glycogen synthase kinase-3ß, and total glycogen synthase kinase-3ß in the hippocampus. Our results show that impaired performance was not detected in mice exposed to sevoflurane during the novel object recognition test. Contextual memory impairment in the fear conditioning test was shorter in the sevoflurane group than the isoflurane group. Long-term sevoflurane exposure did not affect memory consolidation, while isoflurane led to memory consolidation and reduced retention. Downregulation of hippocampal D1 dopamine receptors and phosphorylated glycogen synthase kinase-3ß/total glycogen synthase kinase-3ß and upregulation of catechol-O-methyltransferase may be associated with differing memory performance after exposure to isoflurane or sevoflurane. These results confirm that sevoflurane has less effect on cognitive impairment than isoflurane, which may be related to expression of D1 dopamine receptors and catechol-O-methyltransferase and phosphorylation of glycogen synthase kinase-3ß in the hippocampus. This study was approved by the Institutional Animal Care and Use Committee, Nanjing University, China on November 20, 2017 (approval No. 20171102).

GLYX-13 pretreatment ameliorates long-term isoflurane exposure-induced cognitive impairment in mice.

Accumulating evidence indicates that inhalation anesthetics induce or increase the risk of cognitive impairment. GLYX-13 (rapastinel) acts on the glycine site of N-methyl-D-aspartate receptors (NMDARs) and has been shown to enhance hippocampus-dependent learning and memory function. However, the mechanisms by which GLYX-13 affects learning and memory function are still unclear. In this study, we investigated these mechanisms in a mouse model of long-term anesthesia exposure. Mice were intravenously administered 1 mg/kg GLYX-13 at 2 hours before isoflurane exposure (1.5% for 6 hours). Cognitive function was assessed using the contextual fear conditioning test and the novel object recognition test. The mRNA expression and phosphorylated protein levels of NMDAR pathway components, N-methyl-D-aspartate receptor subunit 2B(NR2B)-Ca2+/calmodulin dependent protein kinase II (CaMKII)-cyclic adenosine monophosphate response element binding protein (CREB), in the hippocampus were evaluated by quantitative RT-PCR and western blot assay. Pretreatment with GLYX-13 ameliorated isoflurane exposure-induced cognitive impairment and restored NR2B, CaMKII and CREB mRNA and phosphorylated protein levels. Intracerebroventricular injection of KN93, a selective CaMKII inhibitor, significantly diminished the effect of GLYX-13 on cognitive function and NR2B, CaMKII and CREB levels in the hippocampus. Taken together, our findings suggest that GLYX-13 pretreatment alleviates isoflurane-induced cognitive dysfunction by protecting against perturbation of the NR2B/CaMKII/CREB signaling pathway in the hippocampus. Therefore, GLYX-13 may have therapeutic potential for the treatment of anesthesia-induced cognitive dysfunction. This study was approved by the Experimental Animal Ethics Committee of Drum Tower Hospital affiliated to the Medical College of Nanjing University, China (approval No. 20171102) on November 20, 2017.

Photoacoustic treatment mitigates cognitive dysfunction in a model of sleep-wake rhythm disturbance.

Sleep-wake rhythm disturbances, which are characterized by abnormal sleep timing or duration, are associated with cognitive dysfunction. Photoacoustic treatments including light and sound stimulation have been found to be effective in modulating sleep patterns and improving cognitive behavior in abnormal sleep-wake pattern experiments. In this study, we examined whether light and sound interventions could reduce sleep-wake pattern disturbances and memory deficits in a sleep rhythm disturbance model. We established a model of sleep rhythm disturbance in C57BL/6J mice via a sleep deprivation method involving manual cage tapping, cage jostling, and nest disturbance. We used a Mini Mitter radio transmitter device to monitor motor activity in the mice and fear conditioning tests to assess cognitive function. Our results indicated that an intervention in which the mice were exposed to blue light (40-Hz flickering frequency) for 1 hour during their subjective daytime significantly improved the 24-hour-acrophase shift and reduced the degree of memory deficit induced by sleep deprivation. However, interventions in which the mice were exposed to a 40-Hz blue light at offset time or subjective night time points, as well as 2 Hz-blue light at 3 intervention time points (subjective day time, subjective night time, and offset time points), had no positive effects on circadian rhythm shift or memory deficits. Additionally, a 2000-Hz sound intervention during subjective day time attenuated the 24-hour-acrophase shift and memory decline, while 440-Hz and 4000-Hz sounds had no effect on circadian rhythms. Overall, these results demonstrate that photoacoustic treatment effectively corrected abnormal sleep-wake patterns and cognitive dysfunction associated with sleep-deprivation-induced disturbances in sleep-wake rhythm. All animal experiments were approved by the Experimental Animal Ethics Committee of Drum Tower Hospital Affiliated to the Medical College of Nanjing University, China (approval No. 20171102) on November 20, 2017.

Effect of neuromuscular blockade on transcranial electric motor evoked potentials during surgical correction for idiopathic scoliosis under total intravenous anesthesia.

Transcranial electric motor evoked potentials (TCeMEPs) play an important role in reducing the risk of iatrogenic paraplegia. TCeMEPs could be obviously suppressed by neuromuscular blockade (NMB). The aims of this study were to examine the effects of NMB on TCeMEPs and to determine an appropriate level of partial neuromuscular blockade (pNMB) for TCeMEPs during surgical correction of idiopathic scoliosis under total intravenous anesthesia (TIVA). All patients were maintained with TIVA. The pNMB levels were classified into five phases: one or two train-of-four (TOF) counts (TOF1); three TOF counts, or T4/T1 (TOFR, T1,4, first or four twitch height of TOF) ≤ 15% (TOF2); TOFR at 16-25% (TOF3); TOFR at 26-50% (TOF4); and TOFR at 51-75% (TOF5). No neuromuscular blockade (nNMB) was achieved when TOFR was more than 75%. The absolute and relative latency, amplitude and area under curve (AUC), efficacy of TCeMEPs and rate of unexpected movement were compared among these phases. Neither the amplitude and AUC nor the efficacy of TCeMEPs were affected at TOF4-5 of abductor halluces muscles TCeMEPs (AH-TCeMEPs) or at TOF3-5 of tibialis anterior muscles TCeMEPs (TA-TCeMEPs) compared with nNMB. However, the rate of unexpected movement was increased significantly at TOF5 and nNMB compared with TOF1 and TOF4. The application of pNMB with TOFR aimed at 26-50% for AH-TCeMEPs or 16-50% for TA-TCeMEPs seems to be an appropriate regimen for TCeMEPs during surgical correction for idiopathic scoliosis under TIVA.