BLA-involved circuits in neuropsychiatric disorders.

The basolateral amygdala (BLA) is the subregion of the amygdala located in the medial of the temporal lobe, which is connected with a wide range of brain regions to achieve diverse functions. Recently, an increasing number of studies have focused on the participation of the BLA in many neuropsychiatric disorders from the neural circuit perspective, aided by the rapid development of viral tracing methods and increasingly specific neural modulation technologies. However, how to translate this circuit-level preclinical intervention into clinical treatment using noninvasive or minor invasive manipulations to benefit patients struggling with neuropsychiatric disorders is still an inevitable question to be considered. In this review, we summarized the role of BLA-involved circuits in neuropsychiatric disorders including Alzheimer's disease, perioperative neurocognitive disorders, schizophrenia, anxiety disorders, depressive disorders, posttraumatic stress disorders, autism spectrum disorders, and pain-associative affective states and cognitive dysfunctions. Additionally, we provide insights into future directions and challenges for clinical translation.

Impaired synaptic plasticity and decreased glutamatergic neuron excitability induced by SIRT1/BDNF downregulation in the hippocampal CA1 region are involved in postoperative cognitive dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after anesthesia/surgery, especially among elderly patients, and poses a significant threat to their postoperative quality of life and overall well-being. While it is widely accepted that elderly patients may experience POCD following anesthesia/surgery, the exact mechanism behind this phenomenon remains unclear. Several studies have indicated that the interaction between silent mating type information regulation 2 homologue 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) is crucial in controlling cognitive function and is strongly linked to neurodegenerative disorders. Hence, this research aims to explore how SIRT1/BDNF impacts cognitive decline caused by anesthesia/surgery in aged mice. METHODS: Open field test (OFT) was used to determine whether anesthesia/surgery affected the motor ability of mice, while the postoperative cognitive function of 18 months old mice was evaluated with Novel object recognition test (NORT), Object location test (OLT) and Fear condition test (FC). The expressions of SIRT1 and other molecules were analyzed by western blot and immunofluorescence staining. The hippocampal synaptic plasticity was detected by Golgi staining and Long-term potentiation (LTP). The effects of SIRT1 and BDNF overexpression as well as chemogenetic activation of glutamatergic neurons in hippocampal CA1 region of 18 months old vesicular glutamate transporter 1 (VGLUT1) mice on POCD were further investigated. RESULTS: The research results revealed that older mice exhibited cognitive impairment following intramedullary fixation of tibial fracture. Additionally, a notable decrease in the expression of SIRT1/BDNF and neuronal excitability in hippocampal CA1 glutamatergic neurons was observed. By increasing levels of SIRT1/BDNF or enhancing glutamatergic neuron excitability in the CA1 region, it was possible to effectively mitigate synaptic plasticity impairment and ameliorate postoperative cognitive dysfunction. CONCLUSIONS: The decline in SIRT1/BDNF levels leading to changes in synaptic plasticity and neuronal excitability in older mice could be a significant factor contributing to cognitive impairment after anesthesia/surgery.

Preparation of Low-Molecular-Weight Polyacrylamide as the Delayed Crosslinking Plugging Agent for Drilling Fluid.

Deep wells and ultra-deep wells often encounter cracks, karst caves, and other developed strata, which can lead to leakage during drilling. Conventional bridge slurry plugging technology is prone to leaking due to the poor plugging effect of the plugging agent. The gel plugging agent possesses characteristics of flexible plugging and adaptive matching of formation leakage channels. It can fill cracks or caves and enhance the pressure-bearing capacity of the formation. A controllable crosslinking plugging agent based on low-molecular-weight polyacrylamide was studied. Polyacrylamide with different molecular weights is synthesized from acrylamide and an initiator. A crosslinking time-controllable polymer is synthesized from low-molecular-weight polyacrylamide by adding crosslinking agent and retarder. The low-molecular-weight polyacrylamide plugging agent has low viscosity before gelation and good fluidity in the wellbore. After being configured on the ground, it is transported by pipeline and sent underground to reach the thickening condition. The gel solution rapidly solidifies, and its strength improves after high-temperature crosslinking. The synthesis conditions of the polymer were as follows: a monomer concentration of 9%, initiator 3.5%, synthesis temperature of 65 °C, and hydrogen peroxide initiator. The optimal formula of the gel plugging agent is as follows: a polymer concentration of 6%, a crosslinking agent concentration of 1%, and a retarder concentration of 8%. The generated polymer molecular structure contains amide groups. This crosslinking time-controllable plugging agent based on low-molecular-weight polyacrylamide has stable rheology, and its temperature resistance can reach 150 °C. At 150 °C, the gelation time can be controlled by adjusting the concentration of retarder, and the longest can reach 4 h. The plugging efficiency of the gel plugging agent is more than 95%. With the increase in seam width, the pressure of the gel plugging agent gradually decreases.

Repeated Ketamine Anesthesia during the Neonatal Period Impairs Hippocampal Neurogenesis and Long-Term Neurocognitive Function by Inhibiting Mfn2-Mediated Mitochondrial Fusion in Neural Stem Cells.

The mechanism of ketamine-induced neurotoxicity development remains elusive. Mitochondrial fusion/fission dynamics play a critical role in regulating neurogenesis. Therefore, this study was aimed to evaluate whether mitochondrial dynamics were involved in ketamine-induced impairment of neurogenesis in neonatal rats and long-term synaptic plasticity dysfunction. In the in vivo study, postnatal day 7 (PND-7) rats received intraperitoneal (i.p.) injection of 40 mg/kg ketamine for four consecutive times at 1 h intervals. The present findings revealed that ketamine induced mitochondrial fusion dysfunction in hippocampal neural stem cells (NSCs) by downregulating Mitofusin 2 (Mfn2) expression. In the in vitro study, ketamine treatment at 100 µM for 6 h significantly decreased the Mfn2 expression, and increased ROS generation, decreased mitochondrial membrane potential and ATP levels in cultured hippocampal NSCs. For the interventional study, lentivirus (LV) overexpressing Mfn2 (LV-Mfn2) or control LV vehicle was microinjected into the hippocampal dentate gyrus (DG) 4 days before ketamine administration. Targeted Mfn2 overexpression in the DG region could restore mitochondrial fusion in NSCs and reverse the inhibitory effect of ketamine on NSC proliferation and its faciliatory effect on neuronal differentiation. In addition, synaptic plasticity was evaluated by transmission electron microscopy, Golgi-Cox staining and long-term potentiation (LTP) recordings at 24 h after the end of the behavioral test. Preconditioning with LV-Mfn2 improved long-term cognitive dysfunction after repeated neonatal ketamine exposure by reversing the inhibitory effect of ketamine on synaptic plasticity in the hippocampal DG. The present findings demonstrated that Mfn2-mediated mitochondrial fusion dysfunction plays a critical role in the impairment of long-term neurocognitive function and synaptic plasticity caused by repeated neonatal ketamine exposure by interfering with hippocampal neurogenesis. Thus, Mfn2 might be a novel therapeutic target for the prevention of the developmental neurotoxicity of ketamine.

Development and Application of the Anti-High-Temperature Delayed Crosslinking Polymer as a Gel Plugging Additive for Drilling Fluid.

With the gradual deepening of the exploration and development of deep and ultra-deep oil and gas resources, the problem of lost circulation in drilling operations is becoming more and more complex. From field experience, conventional plugging materials cannot fully meet the technical requirements of plugging operations in drilling engineering. In this study, a high-temperature- and salt-resistant polymer HDZ-A was synthesized. A high-temperature and delayed crosslinking polymer gel plugging agent can be prepared by adding a certain concentration of a crosslinking agent and a retarder. In this paper, the optimum synthesis conditions of the HDZ-A were determined with orthogonal experiments using viscoelasticity and viscosity as evaluation criteria for newly developed polymers. The molecular structure, temperature resistance, and relative molecular mass of HDZ-A were determined using infrared spectroscopy, nuclear magnetic resonance spectroscopy, and gel permeation chromatography. In addition, the optimal formula of the gel plugging agent was determined using gel strength as the evaluation standard. The results show that the newly developed gel plugging agent has stable performance after high-temperature crosslinking, and can resist high temperatures of 160 °C during formation. Under conditions of 160 °C, the gelation time can reach 4.5 h, and the plugging efficiency can reach more than 97%. Finally, the field test of the newly developed high-temperature-resistant delayed crosslinking polymer gel plugging agent was carried out in the direct exploration well KT-14X in the Ordos Basin. The field test showed that the plugging effect of the HDZ-A gel plugging agent was remarkable.

Demography and Population Projection of Tetranychus urticae (Tetranychidae) on Phaseolus vulgaris (Fabaceae) Colonized by Entomopathogenic Fungal Endophytes.

Tetranychus urticae is a highly polyphagous and global pest. Spider mites primarily feed on the underside of leaves, resulting in decreased photosynthesis, nutritional loss, and the development of chlorotic patches. We investigated the life tables of the two-spotted spider mite T. urticae on fungal endophyte Beauveria bassiana colonized and untreated plants of the common Phaseolus vulgaris L., a bean plant. Based on the age-stage, two-sex life table theory, data were evaluated. The mites raised on untreated plants had protonymphs, deutonymphs, and total pre-adult stage durations that were considerably shorter (1.76, 2.14, and 9.77 d, respectively) than the mites raised on plants that had been colonized (2.02, 2.45, and 10.49 d, respectively). The fecundity (F) varied from 28.01 eggs per female of colonized plants to 57.67 eggs per female of endophyte-untreated plants. The net reproductive rate (R0) in the plants with and without endophytes was 19.26 and 42.53 brood, respectively. The untreated plants had an intrinsic rate of increase (rm) of 0.245 days as opposed to the colonized plants, which had an r of 0.196 days and a finite rate of increase (λ) (1.27 and 1.21, respectively). Population forecasts based on a two-sex, age-stage life table demonstrated the dynamism and variability of the stage structure. Furthermore, the colonization of B. bassiana had a negative impact on the growth and development of T. urticae. It lowered the adult mite life span, female fecundity, net reproduction rate, and intrinsic growth rate. We propose that future research should better use entomopathogenic fungal endophytes to understand host plant resistance strategies in integrated pest management.

Thymopentin plays a key role in restoring the function of macrophages to alleviate the sepsis process.

Immune dysfunction is one of the leading causes of death of sepsis. How to regulate host immune functions to improve prognoses of septic patients has always been a clinical focus. Here we elaborate on the efficacy and potential mechanism of a classical drug, thymopentin (TP5). TP5 could decrease peritoneal bacterial load, and reduce inflammatory cytokine levels both in the peritoneal lavage fluid (PLF) and serum, alleviate pathological injuries in tissue and organ, coaxed by cecal ligation and perforation (CLP) in mice, ultimately improve the prognosis of septic mice. Regarding the mechanism, using RNA-seq and flow cytometry, we found that TP5 induced peptidoglycan recognition protein 1 (PGLYRP1) expression, increased phagocytosis and restored TNF-α expression of small peritoneal macrophage (SPM) in the septic mice. This may be increased SPM's ability to clear peritoneal bacteria, thereby attenuates the inflammatory response both in the peritoneal cavity and the serum. It was shown that TP5 plays a key role in restoring the function of peritoneal macrophages to alleviate the sepsis process. We reckon that this is closely relevant to SPM phagocytosis, which might involve increased PGLYRP1 expression and restored TNF-α secretion.

Genome-wide identification and immune response analysis of mitogen-activated protein kinase cascades in tea geometrid, Ectropis grisescens Warren (Geometridae, Lepidoptera).

BACKGROUND: Tea geometrid Ectropis grisescens (Geometridae: Lepidoptera), is one of the most destructive defoliators in tea plantations in China. The MAPK cascade is known to be an evolutionarily conserved signaling module, acting as pivotal cores of host-pathogen interactions. Although the chromosome-level reference genome of E. grisescens was published, the whole MAPK cascade gene family has not been fully identified yet, especially the expression patterns of MAPK cascade gene family members upon an ecological biopesticide, Metarhizium anisopliae, remains to be understood. RESULTS: In this study, we have identified 19 MAPK cascade gene family members in E. grisescens, including 5 MAPKs, 4 MAP2Ks, 8 MAP3Ks, and 2 MAP4Ks. The molecular evolution characteristics of the whole Eg-MAPK cascade gene family, including gene structures, protein structural organization, chromosomal localization, orthologs construction and gene duplication, were systematically investigated. Our results showed that the members of Eg-MAPK cascade gene family were unevenly distributed in 13 chromosomes, and the clustered members in each group shared similar structures of the genes and proteins. Gene expression data revealed that MAPK cascade genes were expressed in all four developmental stages of E. grisescens and were fairly and evenly distributed in four different larva tissues. Importantly, most of the MAPK cascade genes were induced or constitutively expressed upon M. anisopliae infection. CONCLUSIONS: In summary, the present study was one of few studies on MAPK cascade gene in E. grisescens. The characterization and expression profiles of Eg-MAPK cascades genes might help develop new ecofriendly biological insecticides to protect tea trees.

Modulation of electromagnetic wave absorption via porosity in Pechini-derived carbon guided by a random network model.

It is well established that porosity in carbon materials can benefit electromagnetic wave absorption by providing stronger interfacial polarization, better impedance matching, multiple reflections, and lower density, but an in-depth assessment is still lacking on this issue. The random network model describes the dielectric behavior of a conduction-loss absorber-matrix mixture with two parameters related to the volume fraction and conductivity, respectively. In this work, the porosity in carbon materials was tuned by a simple, green, and low-cost Pechini method, and the mechanism of how porosity affects EM wave absorption was investigated quantitatively based on the model. It was discovered that porosity was crucial for the formation of a random network, and a higher specific pore volume led to a larger volume fraction parameter and a lower conductivity parameter. Guided by the high throughput parameter sweeping based on the model, the Pechini-derived porous carbon could achieve an effective absorption bandwidth of 6.2 GHz at 2.2 mm. This study further verifies the random network model, unveiling the implication and influencing factors of the parameters, and opens a new path to optimize the electromagnetic wave absorption performance of conduction-loss materials.

Single-cell transcriptomic analysis of tumor heterogeneity and intercellular networks in human urothelial carcinoma.

BACKGROUND: Heterogeneity of tumor cells and the tumor microenvironment (TME) is significantly associated with clinical outcomes and treatment responses in patients with urothelial carcinoma (UC). Comprehensive profiling of the cellular diversity and interactions between malignant cells and TME may clarify the mechanisms underlying UC progression and guide the development of novel therapies. This study aimed to extend our understanding of intra-tumoral heterogeneity and the immunosuppressive TME in UC and provide basic support for the development of novel UC therapies. METHODS: Seven patients with UC were included who underwent curative surgery at our hospital between July 2020 and October 2020. We performed single-cell RNA sequencing (scRNA-seq) analysis in seven tumors with six matched adjacent normal tissues and integrated the results with two public scRNA-seq datasets. The functional properties and intercellular interactions between single cells were characterized, and the results were validated using multiplex immunofluorescence staining, flow cytometry, and bulk transcriptomic datasets. All statistical analyses were performed using the R package with two-sided tests. Wilcoxon-rank test, log-rank test, one-way analysis of variance test, and Pearson correlation analysis were used properly. RESULTS: Unsupervised t-distributed stochastic neighbor embedding clustering analysis identified ten main cellular subclusters in urothelial tissues. Of them, seven urothelial subtypes were noted, and malignant urothelial cells were characterized with enhanced cellular proliferation and reduced immunogenicity. CD8 + T cell subclusters exhibited enhanced cellular cytotoxicity activities along with increased exhaustion signature in UC tissues, and the recruitment of CD4 + T regulatory cells was also increased in tumor tissues. Regarding myeloid cells, coordinated reprogramming of infiltrated neutrophils, M2-type polarized macrophages, and LAMP3 + dendritic cells contribute to immunosuppressive TME in UC tissues. Tumor tissues demonstrated enhanced angiogenesis mediated by KDR + endothelial cells and RGS5 + /ACTA2 + pericytes. Through deconvolution analysis, we identified multiple cellular subtypes may influence the programmed death-ligand 1 (PD-L1) immunotherapy response in patients with UC. CONCLUSION: Our scRNA-seq analysis clarified intra-tumoral heterogeneity and delineated the pro-tumoral and immunosuppressive microenvironment in UC tissues, which may provide novel therapeutic targets.

DNMT1 Mediates Chronic Pain-Related Depression by Inhibiting GABAergic Neuronal Activation in the Central Amygdala.

BACKGROUND: Chronic pain can induce depressive emotion. DNA methyltransferases (DNMTs) have been shown to be involved in the development of chronic pain and depression. However, the role and mechanism of DNMTs in chronic pain-induced depression are not well understood. METHODS: In well-established spared nerve injury (SNI)-induced chronic pain-related depression models, the expression of DNMTs and the functional roles and underlying mechanisms of DNMT1 in central amygdala (CeA) GABAergic (gamma-aminobutyric acidergic) neurons were investigated using molecular, pharmacological, electrophysiological, optogenetic, and chemogenetic techniques and behavioral tests. RESULTS: DNMT1, but not DNMT3a or DNMT3b, was upregulated in the CeA of rats with SNI-induced chronic pain-depression. Inhibition of DNMT1 by 5-Aza or viral knockdown of DNMT1 in GABAergic neurons in the CeA effectively ameliorated the depression-like behaviors induced by chronic pain. The DNMT1 action was associated with methylation at the CpG-rich Gad1 promoter and GAD67 downregulation, leading to a decrease of GABAergic neuronal activity. Optogenetic activation of GABAergic neurons in the CeA improved SNI-induced depression-like behaviors. Moreover, optogenetic or chemogenetic inhibition of GABAergic neurons in the CeA reversed DNMT1 knockdown-induced improvement of depression-like behaviors in SNI mice. CONCLUSIONS: Our findings suggest that DNMT1 is involved in the development of chronic pain-related depression by epigenetic repression of GAD67, leading to the inhibition of GABAergic neuronal activation. This study indicates that DNMT1 could be a potential target for the treatment of chronic pain-related depression.

LncRNA XR_351665 Contributes to Chronic Pain-Induced Depression by Upregulating DNMT1 via Sponging miR-152-3p.

Chronic pain is frequently comorbid with depression. However, the mechanisms underlying chronic pain-induced depression remain unclear. Here, we found that DNA methyltransferase 1 (DNMT1) was upregulated in the central amygdala (CeA) of spared nerve injury (SNI)-induced chronic pain-depression rats, and knockdown of DNMT1 could improve the depression-like behaviors in SNI rats. Additionally, a panel of differentially expressed lncRNAs, including 38 upregulated and 12 downregulated lncRNAs, were identified by microarray analysis. Bioinformatics analysis suggested that the upregulated lncRNA XR_351665 was the upstream molecule to regulate DNMT1 expression. The knockdown of XR_351665 significantly alleviated the depression-like behaviors in SNI rats, whereas overexpression of XR_351665 induced the depression-like behaviors in naïve rats. Further mechanism-related researches uncovered that XR_351665 functioned as a competing endogenous RNA (ceRNA) to upregulate DNMT1 by competitively sponging miR-152-3p, and subsequently promoted the development of chronic pain-induced depression. Our findings suggest that lncRNA XR_351665 is involved in the development of chronic pain-induced depression by upregulating DNMT1 via sponging miR-152-3p. These data provide novel insight into understanding the pathogenesis of chronic pain-induced depression and identify a potential therapeutic target. PERSPECTIVE: LncRNA XR_351665 in CeA functions as a ceRNA to block the inhibitory effect of miR-152-3p on DNMT1 and contributes to the development of chronic pain-induced depression. These data suggest that manipulation of XR_351665/miR-152-3p/DNMT1 axis may be a potential method to attenuate chronic pain-induced depression.

SIRT3-Mediated CypD-K166 Deacetylation Alleviates Neuropathic Pain by Improving Mitochondrial Dysfunction and Inhibiting Oxidative Stress.

Numerous studies have shown that mitochondrial dysfunction manifested by increased mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) level, and decreased mitochondrial membrane potential (MMP) plays an important role in the development of neuropathic pain. Sirtuin3 (SIRT3), a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, has been shown to inhibit mitochondrial oxidative stress. However, the role of SIRT3 in neuropathic pain is unclear. In this study, we found that the protein and mRNA levels of SIRT3 were significantly downregulated in the spinal cords of spared nerve injury- (SNI-) induced neuropathic pain mice, while overexpression of spinal SIRT3 reversed SNI-induced pain hypersensitivity. Further study showed that SIRT3 overexpression reduced the acetylation level of lysine 166 (K166) on cyclophilin D (CypD), the regulatory component of the mPTP, inhibited the mPTP opening, decreased ROS and malondialdehyde (MDA) levels, and increased MMP and manganese superoxide dismutase (MnSOD) in SNI mice. Point mutation of K166 to arginine on CypD (CypD-K166R) abrogated SNI-induced mitochondrial dysfunction and neuropathic pain in mice. Moreover, inhibiting mPTP opening by cyclosporin A (CsA) improved mitochondrial function and neuropathic pain in SNI mice. Together, these data show that SIRT3 is necessary to prevent neuropathic pain by deacetylating CypD-K166 and further improving mitochondrial dysfunction. This study may shed light on a potential drug target for the treatment of neuropathic pain.

LncRNA-84277 is involved in chronic pain-related depressive behaviors through miR-128-3p/SIRT1 axis in central amygdala.

Long-term chronic pain can lead to depression. However, the mechanism underlying chronic pain-related depression remains unclear. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase (HDAC). Our previous studies have demonstrated that SIRT1 in the central nucleus of the amygdala (CeA) is involved in the development of chronic pain-related depression. In addition, increasing studies have indicated that long non-coding RNAs (lncRNAs) play a vital role in the pathogenesis of pain or depression. However, whether lncRNAs are involved in SIRT1-mediated chronic pain-related depression remains largely unknown. In this study, we identified that a novel lncRNA-84277 in CeA was the upstream molecule to regulate SIRT1 expression. Functionally, lncRNA-84277 overexpression in CeA significantly alleviated the depression-like behaviors in spared nerve injury (SNI)-induced chronic pain rats, whereas lncRNA-84277 knockdown in CeA induced the depression-like behaviors in naïve rats. Mechanically, lncRNA-84277 acted as a competing endogenous RNA (ceRNA) to upregulate SIRT1 expression by competitively sponging miR-128-3p, and therefore improved chronic pain-related depression-like behaviors. Our findings reveal the critical role of lncRNA-84277 in CeA specifically in guarding against chronic pain-related depression via a ceRNA mechanism and provide a potential therapeutic target for chronic pain-related depression.

Dynorphin promotes stress-induced depressive behaviors by inhibiting ventral pallidal neurons in rats.

AIM: Endogenous dynorphin signaling via kappa opioid receptors (KORs) plays a key role in producing the depressive and aversive consequences of stress. We investigated the behavioral effects of the dynorphin/KOR system in the ventral pallidum (VP) and studied the underlying mechanisms. METHODS: To investigate the effects of dynorphin on the VP, we conducted behavioral experiments after microinjection of drugs or shRNA and brain-slice electrophysiological recordings. Histological tracing and molecular biological experiments were used to identify the distribution of KORs and the possible sources of dynorphin projections to the VP. RESULTS: An elevated dynorphin concentration and increased KOR activity were observed in the VP after acute stress. Infusion of dynorphin-A into the VP produced depressive-like phenotypes including anhedonia and despair and anxiety behaviors, but did not alter locomotor behavior. Mechanistically, dynorphin had an inhibitory effect on VP neurons-reducing their firing rate and inhibiting excitatory transmission-through direct activation of KORs and modulation of downstream G-protein-gated inwardly rectifying potassium (GIRK) channels and high-voltage gated calcium channels (VGCCs). Tracing revealed direct innervation of VP neurons by dynorphin-positive projections; potential sources of these dynorphinergic projections include the nucleus accumbens, amygdala, and hypothalamus. Blockade of dynorphin/KOR signaling in the VP by drugs or viral knock-down of KORs significantly reduced despair behavior in rats. CONCLUSIONS: Endogenous dynorphinergic modulation of the VP plays a critical role in mediating depressive reactions to stress.

The Role of Epigenetic Modifications in Neurotoxicity Induced by Neonatal General Anesthesia.

It has been widely demonstrated by numerous preclinical studies and clinical trials that the neonates receiving repeated or long-time general anesthesia (GA) could develop prolonged cognitive dysfunction. However, the definite mechanism remains largely unknown. Epigenetics, which is defined as heritable alterations in gene expression that are not a result of alteration of DNA sequence, includes DNA methylation, histone post-translational modifications, non-coding RNAs (ncRNAs), and RNA methylation. In recent years, the role of epigenetic modifications in neonatal GA-induced neurotoxicity has been widely explored and reported. In this review, we discuss and conclude the epigenetic mechanisms involving in the process of neonatal anesthesia-induced cognitive dysfunction. Also, we analyze the wide prospects of epigenetics in this field and its possibility to work as treatment target.

The Effect of SIRT3/Ac-SOD2 Mediated Oxidative Stress and HCN1 Channel Activity on Anesthesia/Surgery Induced Anxiety-Like Behavior in Mice.

Anxiety disorders are the most common psychiatric diseases, and perioperative factors often increase the incidence of anxiety. However, the mechanism and treatment for perioperative anxiety, especially anesthesia/surgery-induced postoperative anxiety, are largely unknown. Sirtuin 3 (SIRT3) which located in the mitochondria is the NAD-dependent deacetylase protein. SIRT3 mediated oxidative stress is associated with several neuropsychiatric diseases. In addition, hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channel is also reported involved in anxiety symptoms. The purpose was to assess the role of SIRT3 on postoperative anxiety like behavior in C57/BL6 mice. We found that SIRT3 level reduced and HCN1 expression level increased in mice medial prefrontal cortex (mPFC) as well as anxiety like behavior postoperatively. In interventional research, SIRT3 adeno-associated virus vector or control vector was injected into the mPFC brain region. Enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting were employed to detect oxidative stress reactions and HCN1 channel activity. SIRT3 overexpression attenuated postoperative anxiety in mice. Superoxide dismutase 2 (SOD2) acetylation levels, SOD2 oxidative stress activity, mitochondrial membrane potential levels, and HCN1 channels were also inhibited by SIRT3 overexpression. Furthermore, the HCN1 channel inhibitor ZD7288 significantly protected against anesthesia/surgery-induced anxiety, but without SIRT3/ac-SOD2 expression or oxidative stress changes. Our results suggest that SIRT3 may achieve antianxiety effects through regulation of SOD2 acetylation-mediated oxidative stress and HCN1 channels in the mPFC, further strengthening the therapeutic potential of targeting SIRT3 for anesthesia/surgery-induced anxiety-like behavior.

Hippocampal SIRT1-Mediated Synaptic Plasticity and Glutamatergic Neuronal Excitability Are Involved in Prolonged Cognitive Dysfunction of Neonatal Rats Exposed to Propofol.

Neonates who receive repeated or prolonged general anesthesia before the age of 4 are at a significantly higher risk of developing cognitive dysfunction later in life. In this study, we investigated the effects of repeated neonatal propofol exposure on hippocampal synaptic plasticity, neuronal excitability, and cognitive function. Adeno-associated SIRT1 virus with CaMKIIɑ promotor and a viral vector carrying the photosensitive gene ChR2 with the CaMKIIɑ promotor, as well as their control vectors, were stereotaxically injected into the hippocampal CA1 region of postnatal day 5 (PND-5) rats. PND-7 rats were given intraperitoneal injection of 60 mg/kg propofol or fat emulsion for three consecutive days. Western blotting, Golgi staining, and double immunofluorescence staining were used to evaluate the SIRT1 expression, synaptic plasticity, and the excitability of neurons in the hippocampal CA1 region. The Morris water maze (MWM) test was conducted on PND-30 to assess the learning and memory abilities of rats. Repeated neonatal propofol exposure reduced SIRT1 expression, suppressed synaptic plasticity, decreased glutamatergic neuron excitability in the hippocampus, and damaged learning and memory abilities. Overexpression of SIRT1 attenuated propofol-induced cognitive dysfunction, excitation-inhibition imbalance, and synaptic plasticity damage. After optogenetic stimulation of glutamatergic neurons in the hippocampal CA1 region, the learning and memory abilities of rats exposed to propofol were improved on PND-30. Our findings demonstrate that SIRT1 plays an important role in cognitive dysfunction induced by repeated neonatal propofol exposure by suppressing synaptic plasticity and neuronal excitability.

Hippocampal SIRT1 improves cognitive impairment by deacetylating tau protein in diabetic models.

Diabetes mellitus (DM) is associated with accelerated cognitive decline. However, the mechanism of diabetic cognitive impairment remains poorly understood. In this study, we found that the expression of Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, was downregulated significantly in the hippocampus of streptozotocin (STZ)-induced diabetic cognitive impairment rats. Viral overexpression of hippocampal SIRT1 ameliorated cognitive impairment in diabetic rats, but viral knockdown of hippocampal SIRT1 mimicked the diabetic effect, eliciting the cognitive decline in normal animals. Further study showed that the decreased level of SIRT1 may result in the increase of acetylated tau protein in the hippocampus, which may mediate the development of diabetic cognitive impairment. These results suggest that SIRT1 may be a key epigenetic regulator that guards against the development of diabetic cognitive impairment by deacetylating the tau protein. SIRT1 activator may serve as a new therapeutic approach for the treatment of diabetic cognitive impairment.