Cognitive Dysfunction In Aged Mice Research Articles

Mechanism research on microRNA-669f-5p/deoxycytidylate deaminase axis mediating sevoflurane-induced cognitive dysfunction in aged mice.

To investigate the role of the microRNA (miRNA)-669f-5p/deoxycytidylate deaminase (Dctd) axisin sevoflurane inducing cognitive dysfunction in aged mice. Sixty-six C57BL/6J mice were used in the experiment model and were randomly divided into the sevoflurane group and the control group. The mice in the sevoflurane group were anesthetised with 3.4% sevoflurane, whereas those in the control group were air-treated for the same period. The study was then performed using bioinformatics sequencing, as well as in vitro and in vivo validation. The mice in the sevoflurane group showed significant cognitive impairments in terms of a decrease in both spatial learning and memory abilities. Experimental doses of miR-669f-5p agonist exhibited no obvious effect on cognitive function following sevoflurane inhalation, but inhibiting the expression of miR-669f-5p could alleviate the impairments. Based on the results of the bioinformatics sequencing, miR-669f-5p/Dctd and the toll-like receptor (TLR) signalling pathway could be the key miRNA, gene and pathway leading to postoperative cognitive dysfunction following sevoflurane inhalation. The aged mice showed significantly increased expression of miR-669f-5p in the hippocampus following sevoflurane inhalation, and upregulating/inhibiting its expression could increase/decrease TLR expression in the hippocampus. Furthermore, miR-669f-5p could reduce the expression of the Dctd gene by binding to its 3'untranslated region. The miR-669f-5p/Dctd axis plays an important role in sevoflurane inducing cognitive dysfunction in aged mice, providing a new direction for further development of therapeutic strategies concerning the prevention and treatment of cognitive dysfunction associated with sevoflurane anaesthesia.

Dysregulation of the Gut Microbiota Contributes to Sevoflurane-Induced Cognitive Dysfunction in Aged Mice by Activating the NLRP3 Inflammasome.

Postoperative cognitive dysfunction (POCD), a common complication in elderly patients after surgery, seriously affects patients' quality of life. Long-term or repeated inhalation of sevoflurane can cause neuroinflammation, which is a risk factor for POCD. However, the underlying mechanism needs to be further explored. Recent research had revealed a correlation between neurological disorders and changes in the gut microbiota. Dysfunction of the gut microbiota is involved in the occurrence and development of central nervous system diseases. Here, we found that cognitive dysfunction in aged mice induced by sevoflurane exposure (3%, 2 hours daily, for 3 days) was related to gut microbiota dysbiosis, while probiotics improved cognitive function by alleviating dysbiosis. Sevoflurane caused a significant decrease in the abundance of Akkermansia (P<0.05), while probiotics restored the abundance of Akkermansia. Compared to those in the control group, sevoflurane significantly increased the expression of NLRP3 inflammasome-associated proteins in the gut and brain in the sevoflurane-exposed group, thus causing neuroinflammation and synaptic damage, which probiotics can mitigate (con vs. sev, P < 0.01; p+sev vs. sev, P < 0.05). In conclusion, for the first time, our study revealed that dysbiosis of the gut microbiota caused by sevoflurane anesthesia contributes to the NLRP3 inflammasome-mediated neuroinflammation and cognitive dysfunction from the perspective of the gut-brain axis. Perhaps postoperative cognitive impairment in elderly patients can be alleviated or even prevented by regulating the gut microbiota. This study provides new insights and methods for the prevention and treatment of cognitive impairment induced by sevoflurane.

Hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice

BackgroundPostoperative Cognitive Dysfunction (POCD) has attracted increased attention, but its precise mechanism remains to be explored. This study aimed to figure out whether HDAC6 could regulate NLRP3-induced pyroptosis by modulating the functions of HSP70 and HSP90 in microglia to participate in postoperative cognitive dysfunction in aged mice. MethodsAnimal models of postoperative cognitive dysfunction in aged mice were established by splenectomy under sevoflurane anesthesia. Morris water maze was used to examine the cognitive function and motor ability. Sixteen-months-old C57BL/6 male mice were randomly divided into six groups: control group (C group), sham surgery group (SA group), splenectomy group (S group), splenectomy + HDAC6 inhibitor ACY-1215 group (ACY group), splenectomy + HDAC6 inhibitor ACY-1215 + HSP70 inhibitor Apoptozole group (AP group), splenectomy + solvent control group (SC group). The serum and hippocampus of mice were taken after mice were executed. The protein levels of HDAC6, HSP90, HSP70, NLRP3, GSDMD-N, cleaved-Caspase-1 (P20), IL-1β were detected by western blotting. Serum IL-1β, IL-6 and S100β were measured using ELISA assay, and cell localization of HDAC6 was detected by immunofluorescence. In vitro experiments, BV2 cells were used to validate whether this mechanism worked in microglia. The protein levels of HDAC6, HSP90, HSP70, NLRP3, GSDMD-N, P20, IL-1β were detected by western blotting and the content of IL-1β in the supernatant was measured using ELISA assay. The degree of acetylation of HSP90, the interaction of HSP70, HSP90 and NLRP3 were analyzed by coimmunoprecipitation assay. ResultsSplenectomy under sevoflurane anesthesia in aged mice could prolong the escape latency, reduce the number of crossing platforms, increase the expression of HDAC6 and activate the NLRP3 inflammasome to induce pyroptosis in hippocampus microglia. Using ACY-1215 could reduce the activation of NLRP3 inflammasome, the pyroptosis of microglia and the degree of spatial memory impairment. Apoptozole could inhibit the binding of HSP70 to NLRP3, reduce the degradation of NLRP3 and reverse the protective effect of HDAC6 inhibitors. The results acquired in vitro experiments closely resembled those in vivo, LPS stimulation led to the pyroptosis of BV2 microglia cells and the release of IL-1β due to the activation of the NLRP3 inflammasome, ACY-1215 showed the anti-inflammatory effect and Apoptozole exerted the opposite effect. ConclusionsOur findings suggest that hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice.

Astrocyte-derived exosomes-transported miRNA-26a-5p ameliorates sevoflurane-induced cognitive dysfunction in aged mice

Prolonged sevoflurane anesthesia is the primary factor contributing to the development of perioperative neurocognitive disorders (PND). Recent studies have highlighted neuronal apoptosis and abnormal dendritic structures as crucial features of PND. Astrocytes-derived exosomes (ADEs) have been identified as carriers of microRNAs (miRNAs), playing a vital role in cell-to-cell communication through transmitting genetic material. Nevertheless, the specific mechanisms by which miRNAs in ADEs contribute to sevoflurane-induced cognitive deficit are currently unknown. Through a series of in vivo and in vitro experiments, we demonstrated that ADEs contributed to improved neurocognitive outcomes by reducing neuronal apoptosis and promoting dendritic development. Our miRNA microarray analysis revealed a significant increase in the expression level of miR-26a-5p within ADEs. Furthermore, we identified NCAM as the downstream target gene of miR-26a-5p. Subsequent gain- and loss-of-function experiments were conducted to validate the role of the miR-26a-5p/NCAM axis. Finally, we found that the AKT/GSK3-β/CRMP2 signaling pathway was involved in regulating neurons through exosomal miR-26a-5p. Taken together, our findings suggest that the treatment with miR-26a-5p in ADEs can improve neurocognitive outcomes induced by long-term sevoflurane anesthesia, suggesting a promising approach for retarding the progress of PND.

Susceptibility to acute cognitive dysfunction in aged mice is underpinned by reduced white matter integrity and microgliosis

Age is a significant but heterogeneous risk factor for acute neuropsychiatric disturbances such as delirium. Neuroinflammation increases with aging but the determinants of underlying risk for acute dysfunction upon systemic inflammation are not clear. We hypothesised that, with advancing age, mice would become progressively more vulnerable to acute cognitive dysfunction and that neuroinflammation and neuronal integrity might predict heterogeneity in such vulnerability. Here we show region-dependent differential expression of microglial transcripts, but a ubiquitously observed primed signature: chronic Clec7a expression and exaggerated Il1b responses to systemic bacterial LPS. Cognitive frailty (vulnerability to acute disruption under acute stressors LPS and double stranded RNA; poly I:C) was increased in aged animals but showed heterogeneity and was significantly correlated with reduced myelin density, synaptic loss and severity of white matter microgliosis. The data indicate that white matter disruption and neuroinflammation may be key substrates of the progressive but heterogeneous risk for delirium in aged individuals.

Necroptosis involved in sevoflurane-induced cognitive dysfunction in aged mice by activating NMDA receptors increasing intracellular calcium

Perioperative neurocognitive disorders are a common surgical and postanesthesia complication. Necroptosis contributes to the emergence of various neurological disorders. We conjecture that cognitive impairment is associated with necroptosis of hippocampal neurons, which is mediated by NMDA receptors leading to cytoplasmic calcium imbalance. C57BL/6 J male mice ( 18 months) were randomly divided into the C ( control group), S ( sevoflurane group), S+M ( sevoflurane plus the NMDA receptor antagonist memantine group) and S+N ( sevoflurane plus necrostatin-1) group. We exposed the mice to 3% sevoflurane for 2 h a day for three consecutive days in the S, S+M and S+N groups. Memantine ( 20 mg/kg) or Nec-1 ( 10 mg/kg) was injected intraperitoneally 1 h before sevoflurane anesthesia in the S+M or S+N group. We used the animal behavior tests to evaluate the cognitive function. Pathological damage, the rate of necroptosis, [Ca2+]i, and the expression of necroptosis-related proteins were evaluated. The cognitive function tests, pathological damage, the rate of necroptosis, the expression of necroptosis-related proteins, NMDAR2A and NMDAR2B were significantly different in the S group ( P < 0.05). Alleviated pathological damage, decreased the rate of necroptosis and down-regulated the expression of necroptosis-related proteins occurred in the S+M and S+N group ( P < 0.05). The lower elevated [Ca2+]i, expression of NMDAR2A and NMDAR2B were found in the S+M group. Our findings highlighted sevoflurane-induced cognitive dysfunction is associated with an imbalance in cytoplasmic calcium homeostasis by activating NMDA receptors, which causes hippocampus neurons to undergo necroptosis and ultimately affects cognitive performance in aged mice.

Role and mechanism of esketamine in improving postoperative cognitive dysfunction in aged mice through the TLR4/MyD88/p38 MAPK pathway.

Postoperative cognitive dysfunction (POCD) is a significant concern for the elderly population worldwide. This study explored the effects of esketamine on aged mice with POCD and investigate its mechanism of action involving the TLR4/MyD88/MAPK pathway. We administrated esketamine, along with lipopolysaccharide or anisomycin, to the aged POCD mouse models. We assessed their cognitive function using the Morris water maze test. Additionally, we evaluated histopathological changes/neuronal apoptosis in the mouse hippocampal CA1 area through HE/TUNEL stainings. Furthermore, we measured IL-1β/IL-6/TNF-α/TLR4/MyD88/MAPK (p-p38/p38) levels in mouse hippocampal tissues using ELISA/RT-qPCR/Western blotting. Lastly, we analyzed the interaction between TLR4 and MyD88 using a co-immunoprecipitation assay. Our findings showed that esketamine effectively mitigated POCD in aged mice. This was evident from the improved cognitive performance observed in the Morris water maze test, characterized by reduced escape latency/increased number of platform crossing/a higher percentage of time spent in the target quadrant. Furthermore, esketamine exhibited a protective effect against neuronal apoptosis and reduced the levels of inflammatory factors. These findings suggest that esketamine exerts an anti-inflammatory effect by downregulating TLR4/MyD88, thereby attenuating the inflammatory response associated with POCD. Additionally, esketamine suppressed the p38 MAPK pathway by inhibiting the TLR4/MyD88 signaling cascade. Esketamine demonstrated its efficacy in improving postoperative inflammation and cognitive impairment in aged mice by inhibiting the TLR4/MyD88 pathway. The activation of p38 MAPK signaling diminished the beneficial effects of esketamine in aged POCD mice. Collectively, the underlying mechanism of esketamine in mitigating POCD in aged mice involves the suppression of the TLR4/MyD88/p38 MAPK pathway.

The Effects of Vitamin D on Movement and Cognitive Function in Senile Mice After Sevoflurane Anaesthesia

ABSTRACT Background Vitamin D (VD) is a neuroactive steroid involved in many brain functions, such as neurotrophic, neuroimmune control and neurotransmission, which affects the growth and function of the brain. The purpose of this study is to explore the effect of VD on motor and cognitive function of aged mice after sevoflurane anesthesia. Method We established sevoflurane anesthesia model and VD(-) and VD(+) mice model. The VD concentration of mice in each group was determined by enzyme-linked immunosorbent assay (ELISA). An open-field test was used to evaluate the mice’s capacity for movement and exploration. A Y-maze test was used to gauge the mice’s short-term memory. The primary purpose of the water-maze experiment was to examine mice’s long-term spatial memory. Results The ELISA results showed that the model was successfully constructed. In the open-field test, VD increased the exercise distance of mice (P < .05). In the Y-maze experiment, VD improved short-term memory impairment in mice (P < .05). In the water-maze test, VD increased the activity time and platform crossing number of mice in the target quadrant. (P < .05). Conclusion Sevoflurane anesthesia caused cognitive dysfunction in aged mice, including reduced learning ability, memory loss, lower motor and exploratory abilities and depression, and VD deficiency aggravated these impairments. By supplementing with VD, learning ability and long-term memory were enhanced, motor and exploratory abilities were improved, and depression levels were reduced. Anxiety was also improved.

Dexmedetomidine attenuates the neuroinflammation and cognitive dysfunction in aged mice by targeting the SNHG14/miR‑340/NF‑κB axis.

Neuroinflammation plays a key role in the pathogenesis of postoperative cognitive dysfunction (POCD). Results of our previous study demonstrated that dexmedetomidine (Dex) attenuates neuroinflammation in BV2 cells treated with lipopolysaccharide (LPS) by targeting the microRNA (miR)-340/NF-κB axis. However, the molecular mechanisms by which Dex improves POCD remain unclear. In the present study, the association between long non-coding (lnc)RNA small nucleolar RNA host gene 14 (SNHG14) and miR-340 in BV2 microglial cells was determined using a dual-luciferase reporter assay. In addition, SNHG14, miR-340 and NF-κB expression levels were measured in LPS-treated BV-2 cells and hippocampal tissues of mice with POCD, and an enzyme-linked immunosorbent assay was used to determine the levels of proinflammatory mediators. Results of the present study demonstrated that SNHG14 exhibited potential as a target of miR-340. In addition, SNHG14 knockdown increased the levels of miR-340 and reduced the levels of NF-κB in LPS-treated BV2 cells. In addition, Dex treatment significantly reduced the levels of SNHG14 and NF-κB, and elevated the levels of miR-340 in the hippocampus of aged mice with POCD. Moreover, Dex treatment notably decreased the expression levels of TNF-α, IL-1β, IL-2, IL-6, IL-8 and IL-12 in the hippocampus of aged mice with POCD by upregulating miR-340. The spatial memory impairments in aged mice with POCD were also notably increased following Dex treatment via upregulation of miR-340. Collectively, results of the present study demonstrated that Dex may protect microglia from LPS-induced neuroinflammation in vitro and attenuate hippocampal neuroinflammation in aged mice with POCD in vivo via the SNHG14/miR-340/NF-κB axis. The present study may provide further insights into the mechanisms underlying Dex in the treatment of POCD.

Gastrodin ameliorates postoperative cognitive dysfunction in aged mice by promoting nuclear translocation of Nrf2 through activation of AMPK

BackgroundPerioperative neurocognitive disorder (PND) remains a prevalent complication following anesthesia and surgery. Recent studies have revealed the therapeutic potential of gastrodin (GAS) in treating cognitive disturbances. This study delves deeper into the mechanisms through which GAS impacts PND. MethodsMale C57BL/6 mice (18 months old) underwent laparotomies and were administered GAS orally daily for three weeks preceding surgery and one week post-surgery. Thirty minutes before GAS administration, an intraperitoneal injection of Compound C was given. In vitro, H2O2-incubated SH-SY-5Y cells, with or without Nrf2-siRNA transfection, were set up and subjected to GAS or Compound C treatments. Cell viability was assessed via MTT assays, and apoptosis levels were assessed through flow cytometry. Cognitive function was evaluated using the Morris water maze, novel object recognition, and Y-maze tests. Oxidative stress markers, including MDA, SOD, GSH, GSH-px, and intracellular ROS (determined through immunofluorescence), were quantified. The expression of the genes Caspase3, Bax, Bcl-2, GST, and NQO1 was gauged using real-time RT-PCR. Brain, cortex and hippocampal pathologies were examined with hematoxylin-eosin (HE) and NeuN/TUNEL costaining. Finally, Nrf2 and p-AMPK were analyzed using Western blotting (WB) and immunofluorescence assays. ResultsGAS improved cognitive dysfunction in PND mice and reduced oxidative stress, neuro-apoptosis, and ROS levels both in vivo and in vitro experiment. In vivo, Immunofluorescence and Western blot outcomes indicated that postoperative p-AMPK and Nrf2 levels in the hippocampus were mitigated but were augmented by GAS. In vitro studies revealed GAS's protective effect against H2O2-induced oxidative stress and apoptosis and its upregulation of p-AMPK and Nrf2 in SH-SY-5Y cells. Notably, this protective effect was negated when Nrf2 siRNA was introduced. ELISA and PCR results highlighted the role of GAS in enhancing GST and NQO1 activity in both the mice hippocampus and SH-SY-5Y cells. Compound C, an AMPK inhibitor, both in vitro and in vivo, reversed the beneficial effects of GAS on Nuc-Nrf2/Cyt-Nrf2 expression and counteracted the positive influence of GAS on cognitive functions in PND mice. ConclusionGAS facilitates the nuclear translocation of Nrf2 via AMPK activation, offering a therapeutic avenue for alleviating postoperative cognitive impairments in mice, with a significant reduction in oxidative stress.

The role of PERK-eIF2α-ATF4-CHOP pathway in sevoflurane induced neuroapoptosis and cognitive dysfunction in aged mice

Postoperative cognitive dysfunction (POCD) is a common surgical complication that causes additional pain in patients and affects their quality of life. To address this problem, emerging studies have focused on the POCD. Recent studies have shown that aging and anesthetic exposure are the two major risk factors for developing POCD. However, few reports described the exact molecular mechanisms underlying POCD in elderly patients. In the previous studies, the endoplasmic reticulum (ER) stress and neuroapoptosis in the hippocampus were associated with inducing POCD; however, no further information on the related signaling pathways could be disclosed. The PERK-eIF2α-ATF4-CHOP pathway is identified as the main regulatory pathway involved in ER stress and cell apoptosis. Therefore, we assume that the occurrence of POCD induced by sevoflurane inhalation may potentially result from ER stress and neuroapoptosis in the hippocampus of aged mice mediated by the PERK-eIF2α-ATF4-CHOP pathway. In our study, we found a relationship between sevoflurane inhalation concentration and memory decline in aged mice, with a ‘ceiling effect’. We have confirmed that POCD induced by sevoflurane results from ER stress and neuroapoptosis in the hippocampus of aged mice, which is regulated by the over-expression of PERK-eIF2α-ATF4-CHOP pathway. Furthermore, we also showed that the dephosphorylation inhibitor of eIF2α (salubrinal) could down-regulate PERK-eIF2α-ATF4-CHOP pathway expression to inhibit ER stress and enhance the cognitive function of aged mice. In general, our study has elucidated one of the molecular mechanisms of sevoflurane-related cognitive dysfunction in aged groups and provided new strategies for treating sevoflurane-induced POCD.

Microglial priming induced by loss of Mef2C contributes to postoperative cognitive dysfunction in aged mice

Postoperative cognitive dysfunction (POCD) is a common postoperative central nervous system (CNS) complication with a higher occurrence among aged individuals than among young individuals. The aim of this study was to explore the mechanisms by which POCD preferentially affects older individuals. We found here that exploratory laparotomy induced cognitive function decline in aged mice but not in young mice and that this decline was accompanied by inflammatory activation of microglia in the hippocampus. Furthermore, microglial depletion by feeding of a standard diet containing a colony stimulating factor 1 receptor (CSF1R) inhibitor (PLX5622) markedly protected aged mice from POCD. Notably, the expression of myocyte-specific enhancer 2C (Mef2C), an immune checkpoint that limits overactivation of microglia, was downregulated in aged microglia. Knocking down Mef2C induced a microglial priming phenotype in young mice, resulting in postoperative increases in the hippocampal levels of the inflammatory factors IL1-β, IL-6 and TNF-α that could impair cognition; these findings were consistent with the observations in aged mice. In vitro, BV2 cells lacking Mef2C released higher levels of inflammatory cytokines upon stimulation with lipopolysaccharide (LPS, a bacterial toxin) than Mef2C-sufficient cells. Moreover, upregulation of Mef2C in aged mice restrained postoperative microglial activation, attenuating the neuroinflammatory response and cognitive impairment. These results reveal that during aging, loss of Mef2C leads to microglial priming, amplifying postsurgical neuroinflammation and contributing to the vulnerability of elderly patients to POCD. Thus, targeting the immune checkpoint Mef2C in microglia may be a potential strategy for the prevention and treatment of POCD in aged individuals.

Microglia participate in postoperative cognitive dysfunction by mediating the loss of inhibitory synapse through the complement pathway

BackgroundElderly patients after surgery are prone to cognitive decline known as postoperative cognitive dysfunction (POCD). Several studies have shown that the microglial activation and the increase of complement protein expression in hippocampus induced by surgery may be related to the pathogenesis of POCD. The purpose of this study was to determine whether microglia and complement system were involved in cognitive dysfunction in aged mice. MethodsThe POCD model was established by exploratory laparotomy in 15-month-old male C57BL/6J mice and animal behavioral tests were performed to test hippocampal-dependent memory capacity. Minocycline was used to suppress the activation of microglia, and complement 3 receptor inhibitor was used to suppress the association between microglia and complement 3. Western blot and immunofluorescence were used to detect the microglial activation, complement protein, and synaptic protein expressions. ResultsOperation induced hippocampal-dependent memory impairment (P < 0.01), which was accompanied by microglial activation (P < 0.01). There was also a significant reduction in inhibitory synaptic protein expression in the hippocampus of mice in the surgery group (P < 0.01). However, minocycline, a microglia inhibitor, rescued all the above changes. In addition, C3RI intervention inhibited the phagocytosis of inhibitory synapses by microglia (P < 0.05) and improved the cognitive function of mice (P < 0.01). ConclusionMicroglia participate in postoperative cognitive dysfunction by mediating inhibitory synaptic loss through the complement pathway.

Exogenous recombinant Hsp70 attenuates sevoflurane anesthesia-induced cognitive dysfunction in aged mice.

Postoperative cognitive dysfunction (POCD) is a severe postoperative neurological sequela in elderly patients, and there is currently no standard treatment for POCD. In this study, whether recombinant human heat shock protein 70 (rHsp70) could alleviate sevoflurane-induced cognitive impairment in aged mice is investigated. To determine the prophylactic effect of rHsp70 in sevoflurane-induced cognitive dysfunction, aged mice were pretreated with different concentrations of rHsp70 (29.4, 58.8, and 117.6μg/kg; intranasal injected; N=12) every day for 1 week; then, 3% sevoflurane was utilized to anesthetize the aged mice. Cognitive function, neurotoxicity, and serum and hippocampal Hsp70 levels in aged mice undergoing sevoflurane anesthesia were assessed by the Morris water maze test and enzyme-linked immunosorbent assay. The effects of rHsp70 on inflammatory response were assessed by proinflammatory cytokine production and nuclear factor-κB (NF-κB) activation assays. We found that aged mice exposed to sevoflurane showed reduced learning and memory ability and reduced Hsp70 expression, which were both restored by rHsp70 pretreatment. RHsp70 also reversed sevoflurane-induced up-regulated Bax and Bcl-2 expression and interleukin-1, IL-6, and monocyte chemoattractant protein-1 overproduction. Finally, rHsp70 pretreatment suppressed sevoflurane-induced NF-κB activation. Our study indicated that rHsp70 was sufficient to suppress sevoflurane-induced cognitive decline and neurotoxicity. Our important finding warrants further study on the clinical application of rHsp70 in elderly patients undergoing anesthesia.

Activation of astrocyte Gq pathway in hippocampal CA1 region attenuates anesthesia/surgery induced cognitive dysfunction in aged mice

The elderly are particularly vulnerable to brain dysfunction after fracture surgery, but the mechanism underlying the cognitive decline due to anesthesia/surgery is not well understood. In this study, we observed hippocampus-dependent cognitive impairment in aged mice undergoing anesthesia and tibial fracture surgery, a common model of postoperative cognitive dysfunction in aged mice. We used Golgi staining and neuroelectrophysiological techniques to detect structurally and functionally impaired synaptic plasticity in hippocampal CA1 region of Postoperative cognitive dysfunction aged mice, respectively. Based on the 'third party synapse' hypothesis of astrocytes, we used glial fibrillary acidic protein to label astrocytes and found an increase in abnormal activation of astrocytes in the CA1 region of hippocampus. We hypothesize that abnormal astrocyte function is the driving force for impaired synaptic plasticity. So we used chemogenetic methods to intervene astrocytes. Injection of adeno-associated virus into the CA1 region of the hippocampus bilateral to aged mice resulted in the specific expression of the Gq receptor, a receptor specially designed to be activated only by certain drugs, within astrocytes. The results of novel object recognition and conditioned fear experiments showed that CNO activation of astrocyte Gq pathway could improve the learning and memory ability and the synaptic plasticity of Postoperative cognitive dysfunction aged mice was also improved. The results of this study suggest that activation of the Gq pathway in astrocytes alleviates Postoperative cognitive dysfunction induced by anesthesia and surgery in aged mice.

HDAC3 of dorsal hippocampus induces postoperative cognitive dysfunction in aged mice

Postoperative cognitive dysfunction (POCD) affects a substantial number of aged individuals. Although advanced age has been regarded as the only independent risk factor for cognitive decline following anesthesia and surgery, the exact cellular and molecular mechanisms remain poorly understood. Histone deacetylase 3 (HDAC3), an epigenetic regulator of memory plays an important role in age-dependent disease. In this study, we investigated the role of HDAC3 in POCD using a laparotomy mouse model. The results showed that the level of HDAC3 in the dorsal hippocampus (DH) was elevated in aged mice compared with young mice. The surgery impaired the spatial-temporal memory in aged mice, as indicated in the object location memory (OLM) and temporal order memory (TOM) tests. Model mice also exhibited increased expression of HDAC3 protein and decreased levels of dendritic spine density and synaptic plasticity-related proteins in the DH. Selectively blocking HDAC3 in the DH of aged mice reversed spatial-temporal memory impairment induced by surgery and restored dendritic spine density and synaptic plasticity-related proteins in the DH. Overexpression of HDAC3 by adeno-associated virus in the DH of young mice mimicked the behavioral deficits induced by anesthesia and surgery. Our results indicated that HDAC3 negatively regulates spatial-temporal memory in aged mice after anesthesia and surgery. Targeting HDAC3 might represent a potential therapy to avoid POCD.

Effect of Different Vitamin D Levels on Cognitive Function in Aged Mice After Sevoflurane Anesthesia.

Although the biological relationship between vitamin D (VD) deficiency and cognitive function has been recognized by many scholars, the theoretical mechanisms involved are still not well-understood. In this study, we demonstrated the role of VD in alleviating the cognitive dysfunction in aged mice caused by sevoflurane anesthesia. Forty female C57BL/6 mice aged 12 months were selected for the experiment. VD (-) and VD (+) mouse models and sevoflurane anesthesia models were established. Mice were randomly divided into normal elderly group (NC group), normal aged mice + sevoflurane anesthesia treatment group (NS group), aged VD (-) mice + sevoflurane anesthesia treatment group [VD (-) group], and aged VD (+) + sevoflurane anesthesia treatment group [VD (+) group]. To compare the emergence time after sevoflurane anesthesia in aged mice with different levels of VD and to test the cognitive function of four groups through the water maze. Inflammatory factor expression and cholinergic activity in hippocampus tissue of all mice were measured at the end of behavioral tests. These data show that, low levels of VD aggravated the delayed emergence and cognitive dysfunction in aged mice caused by sevoflurane anesthesia, while higher levels of VD mitigated this impairment by enhancing cholinergic activity and reducing inflammatory factor expression in the hippocampus.

Mineralocorticoid receptor agonist aldosterone rescues hippocampal neural stem cell proliferation defects and improves postoperative cognitive function in aged mice

Objectives Hippocampal neurogenesis is closely related to learning and memory, and hippocampal neurogenesis disorders are involved in the development of many neurodegenerative diseases. Mineralocorticoid receptor (MR) plays a vital role in regulating stress response, neuroendocrine and cognitive functions, and is involved in regulating the integrity and stability of neural networks. However, the potential role of MR in the pathogenesis of postoperative cognitive dysfunction (POCD) is unclear. Therefore, this study evaluated the effect and mechanism of MR activation on postoperative hippocampal neurogenesis and cognitive function in aged mice. Methods 18-month-old male Kunming mice were randomly divided into Control group (C group), Surgery group (S group), Surgery+ Aldosterone group (S+Aldo group), Surgery + Wortmannin group (S+Wort group), Surgery + Aldosterone + Wortmannin group (S+Aldo+Wort group). Laparotomy was used to establish an animal model of postoperative cognitive dysfunction. After surgery, mice were intraperitoneally injected with aldosterone (100 ug/kg,150 ug/kg,200 ug/kg) and / or wortmannin (1 mg/kg); One day before the sacrifice, mice were injected intraperitoneally with BrdU (100 mg / kg / time, 3 times in total). Mice were subjected to Morris water maze and field tests at 1, 3, 7, and 14 days after surgery. Immunofluorescence was used to detect the number of BrdU +, Nestin +, BrdU/Nestin + positive cells in the hippocampal dentate gyrus of mice at 1, 3, 7 and 14 days after surgery. Western-blot was used to detect PI3K/Akt/GSK-3β signaling pathway related proteins Akt, p-Akt, GSK-3β, P-GSK-3β expression. Results Stress impairs the performance of aged mice in water maze and open field tests, reduces the number of BrdU/Nestin+ cells in the hippocampal dentate gyrus, and inhibits the phosphorylation of Akt and GSK-3β proteins in the hippocampus. Aldosterone treatment promotes P-Akt, P-GSK-3β protein expression and hippocampal neural stem cell proliferation, and improves postoperative cognitive dysfunction. However, wortmannin treatment significantly reversed these effects of aldosterone. Conclusions The mineralocorticoid receptor agonist aldosterone promotes the proliferation of hippocampal neural stem cells and improves cognitive dysfunction in aged mice after surgery, and the mechanism may be related to activation of PI3K/Akt/GSK-3β signaling.

Inhibition of NLRP3 inflammasome activation and pyroptosis with the ethyl acetate fraction of Bungeanum ameliorated cognitive dysfunction in aged mice.

Zanthoxylum bungeanum Maxim (Rutaceae), a medicinal herb and foodstuff, has previously been demonstrated as useful for the potential prevention of age-related cognitive dysfunction. However, the mechanisms and material basis remain elusively understood. The prevention of cognitive impairment by four fractions of Z. bungeanum was evaluated in D-galactose-induced aging mice, including petroleum ether (PE), methylene chloride (DCM), ethyl acetate (EA), and n-butanol (N-BAI). The results showed that mice treated with EA and N-BAI had significantly alleviated D-galactose-induced memory deficit. In addition, EA could clearly protect neurons from cell death, alleviate oxidative damage and inhibit the activation of microglia in aging mice. Our data also showed that the activation of the NLRP3 inflammasome, the expression of pyroptosis-related proteins, and the release of IL-1β and IL-18 could be remarkably inhibited by the EA fraction in aging mice and LPS/ATP-induced BV-2 microglial cells. Besides, the chemical composition of an active EA fraction was qualitatively analyzed by using HPLC-MS/MS. Thirty-four compounds were tentatively identified based on their retention times, accurate mass, and MS/MS spectra. Moreover, eighteen reference compounds were analyzed by HPLC-MS/MS and their contents of EA were determined. The work demonstrated that the ethyl acetate fraction of Bungeanum ameliorated cognitive deficits, and its effects may be related to ameliorating oxidative stress and suppressing the NLRP3 inflammasome pathway and GSDMD-mediated pyroptosis in aging mice.

Enriched environment enhances histone acetylation of NMDA receptor in the hippocampus and improves cognitive dysfunction in aged mice.

The mechanisms of age-associated memory impairment may be associated with glutamate receptor function and chromatin modification. To observe the effect of an enriched environment on the cognitive function of mice with age-associated memory impairment, 3-month-old C57BL/6 male mice ("young" mice) were raised in a standard environment, while 24-month-old C57BL/6 male mice with memory impairment ("age-associated memory impairment" mice) were raised in either a standard environment or an enriched environment. The enriched environment included a variety of stimuli involving movement and sensation. A water maze test was then used to measure cognitive function in the mice. Furthermore, quantitative real-time polymerase chain reaction and western blot assays were used to detect right hippocampal GluN2B mRNA as well as protein expression of GluN2B and CREB binding protein in all mice. In addition, chromatin immunoprecipitation was used to measure the extent of histone acetylation of the hippocampal GluN2B gene promoters. Compared with the young mice, the water maze performance of age-associated memory impairment mice in the standard environment was significantly decreased. In addition, there were significantly lower levels of total histone acetylation and expression of CREB binding protein in the hippocampus of age-associated memory impairment mice in the standard environment compared with the young mice. There were also significantly lower levels of histone acetylation, protein expression, and mRNA expression of GluN2B in the hippocampus of these mice. In contrast, in the age-associated memory impairment mice with the enriched environment intervention, the water maze performance and molecular biological indexes were significantly improved. These data confirm that an enriched environment can improve cognitive dysfunction in age-associated memory impairment mice, and suggest that the mechanisms may be related to the increased expression of CREB binding protein and the increased degree of total histone acetylation in the hippocampus of age-associated memory impairment mice, which may cause the increase of histone acetylation of GluN2B gene promoter and the enhancement of GluN2B mRNA transcription and protein expression in hippocampus. The animal experiment was approved by the Animal Ethics Committee of Yangzhou University, China (approval No. 20170312001) in March 2017.