BACKGROUND:Perioperative neurocognitive disorders (PNDs) encompass delayed neurocognitive recovery (dNCR; ≤30 days) and postoperative neurocognitive disorder (NCD; >30 days). While the HMGB1-TLR4/NF-κB axis drives acute neuroinflammation, temporal dynamics beyond the acute phase and distinct contributions of HMGB1 versus TLR4 to dNCR-to-NCD transition remain elusive. This study investigated whether glycyrrhizin attenuates sevoflurane-surgery-induced recognition memory deficit via HMGB1-TLR4 modulation. METHODS:Eight-month-old male C57BL/6J mice underwent right common carotid artery dissection under prolonged sevoflurane anesthesia (3%, 2 h) with or without glycyrrhizin pretreatment (30 mg/kg, i.p.; n = 15/group for batch 1, n = 7/group for batch 2). Cognitive function was assessed via open field, novel object recognition, Y-maze, and Morris water maze. Hippocampal neuroinflammation , HMGB1-TLR4-NF-κB signaling, synaptic proteins , and Nissl staining were evaluated at postoperative days 7 and 20. RESULTS:Prolonged sevoflurane exposure combined with surgery induced recognition memory impairment and reduced platform crossings, both attenuated by glycyrrhizin. While peripheral IL-6 normalized by day 7, hippocampal cytokines (IL-6, IL-1β, TNF-α) and glial activation persisted through day 20. HMGB1 was elevated at day 7 but normalized by day 20, whereas TLR4/NF-κB remained elevated at both time points; glycyrrhizin suppressed this cascade. Synaptic proteins were reduced and CA3/dentate gyrus exhibited Nissl staining reductions at days 7 and 20, protected by glycyrrhizin, whereas CA1 showed no significant alterations. CONCLUSIONS:These findings demonstrate temporal dissociation between HMGB1 normalization and sustained TLR4/NF-κB activation following sevoflurane-surgery in middle-aged mice. Prophylactic glycyrrhizin attenuates recognition memory deficits and suppresses hippocampal neuroinflammation, though mechanistic inferences remain speculative and require rigorous validation.

Cognitive impairment is the primary manifestation of neuroinflammation-related central nervous system diseases. Intranasal administration is an effective method, bypassing the blood-brain barrier and delivering drugs to the brain. Herein, we designed a biomimetic self-propelled nanomotor with an inflammation-targeting capacity. This nanomotor comprised a hollow mesoporous manganese dioxide (HMnO2) core and a polydopamine (PDA) shell. HMnO2 effectively catalyzed the conversion of endogenous H2O2 into H2O and O2, enabling the movement of the nanomotor into a wider area to reduce neuroinflammation. The nanomotor was loaded with the natural compound urolithin A (UA), which significantly improved the bioavailability of the compound and enhanced mitophagy. Furthermore, PDA modification imparted the nanomotor with strong adhesive properties, enabling them to anchor effectively to the olfactory nerve and enhancing delivery to the brain. In vitro, PDA@HMnO2@UA alleviated mitochondrial dysfunction, oxidative stress, and inflammation levels by enhancing mitophagy in lipopolysaccharide (LPS)-induced BV2 cells. Following intranasal administration, PDA@HMnO2@UA exerted neuroprotective effects by alleviating microglial activation, neuroinflammation, and neuronal loss, ultimately rescuing the neurocognitive function in the LPS-induced neuroinflammation model. In summary, this study presents an ideal nanomotor platform based on the 3-N strategy, which means “Nanomotor loaded with a Natural product to traverse a Natural anatomical pathway,” that can alleviate cognitive impairments caused by neuroinflammation, offering a promising delivery approach for treating neuroinflammatory diseases.

Perioperative neurocognitive disorders (PND) contribute substantially to morbidity and mortality; however, no therapeutic target has yet been identified. We hypothesized that the neural circuit underlying this surgical complication involves corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN). Using optogenetics, chemogenetics, electrophysiology, and behavioral tests, we demonstrate that surgery activates PVN CRH neurons. These neurons, via CRH receptor 1 (CRHR1), innervate glutamatergic (Glu) neurons in the hippocampal subiculum (Sub), ultimately leading to memory impairments. The PVN CRH receive projections from Glu neurons in the parabrachial nucleus (PBN), a brain region involved in processing peripheral sensory stimuli. Postoperative memory deficit is associated with activation of the PBN Glu-PVN CRH-Sub Glu circuit; chemogenetic inhibition of this circuitry rescues the memory deficit. Additionally, surgery-induced upregulation of circulating interleukin-1β (IL-1β) mediates activation of the PBN Glu-PVN CRH-Sub Glu circuit. This provides direct evidence linking peripheral inflammation to central cognitive dysfunction via a defined neural pathway. These findings advance our understanding of brain-body interactions in neurocognitive disorders and identify an anatomical target for potential intervention in PND.

Neuropathic pain (NP) is a complex chronic pain syndrome often secondary to conditions such as diabetic peripheral neuropathy and postherpetic neuralgia. It not only severely compromises patients’ quality of life but also imposes a heavy burden on healthcare systems. Recent studies indicate that plasma lipoproteins play a significant role in its pathophysiology, with functions extending beyond lipid transport to include extensive involvement in inflammatory regulation, oxidative stress, and maintenance of neural function. This review aims to systematically elucidate the intricate relationship between NP and lipoproteins, analyze its pathophysiological mechanisms, and transcend conventional perspectives by conducting in-depth analyses of the specific mechanisms of action of high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) in pain. Consequently, it explores potential therapeutic strategies based on lipoprotein metabolism. This review demonstrates that distinct lipoprotein types exert critical roles in the initiation and maintenance of NP through differentiated mechanisms involving regulation of neuroinflammation, oxidative stress, and ion channel function. These findings not only expand our understanding of pain mechanisms but also provide theoretical foundations for developing novel therapeutic strategies targeting lipoprotein metabolism. Future clinical research is essential to advance these insights into safe and effective personalized analgesic approaches.

Neuropathic pain (NP), characterized by its complex pathophysiological mechanisms, has long posed a formidable therapeutic challenge. The burden of NP is further exacerbated by the increasing prevalence of chronic diseases. Emerging evidence highlights the pivotal role of gut microbiota in modulating immune responses, offering novel insights into NP pathogenesis. This review explores recent advancements in understanding how gut microbiota-derived metabolites - including short-chain fatty acids (SCFAs), bile acids, and tryptophan derivatives - regulate immune processes that influence neuroinflammation and nociceptive signaling. We focus on key immune mediators, including macrophages, microglia, T cells, and astrocytes, elucidating their involvement in microbiota-driven immune regulation via pathways such as TLR4/NF-κB signaling, histone deacetylase (HDAC) inhibition, and aryl hydrocarbon receptor (AhR) activation. Additionally, we examine emerging evidence of sex-specific immune mechanisms in NP. Despite promising preclinical findings on microbiota-targeted therapies, such as probiotics and fecal microbiota transplantation, translational challenges, such as microbiota heterogeneity and sex-specific responses, necessitate further investigation. This review aims to bridge microbiology, neuroimmunology, and pain research, offering a multidimensional perspective and actionable insights for the future management of NP.

Sepsis‑induced abnormalities in brain function or sepsis‑associated encephalopathy (SAE) can manifest as cognitive dysfunction and other neuropsychiatric symptoms; however, the underlying mechanisms remain unclear. The aim of the present study was to elucidate the possible effects and mechanism of capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, on the pathological features of SAE. A model of SAE in C57BL/6 mice was generated using cecal ligation and puncture (CLP). Capsaicin (1 mg/kg) was injected subcutaneously before surgery. Cognitive function in mice was evaluated using the novel object recognition test (NORT) and Morris water maze (MWM). Immunofluorescence staining, ELISA, western blotting and transmission electron microscopy were performed to detect the degree of microglial activation (ionized calcium‑binding adapter molecule 1), proinflammatory cytokine levels (TNF‑α), autophagy and apoptosis‑related protein expression, and autophagosomes. Autophagic flux was monitored using the LC3‑GFP‑mCherry fluorescent reporter. Compared with that in the sham group mice, the expression levels of TRPV1 were significantly reduced in the hippocampal tissue of mice with sepsis. Mice with sepsis also exhibited cognitive dysfunction. Notably, a single administration of capsaicin reduced the mortality rate, but did not improve cognitive function in mice with sepsis. Furthermore, repeated administration of capsaicin was revealed to enhance the recognition index of novel objects among mice with sepsis, to reduce the latency to locate the platform and to augment the duration of mouse platform quadrant movements, according to the NORT and MWM tasks. Increased microglial activation, release of proinflammatory cytokines and expression levels of apoptosis‑related proteins were all observed in mice with CLP‑induced sepsis, as was brain tissue destruction in the hippocampal regions. By contrast, capsaicin treatment ameliorated CLP‑induced microglial activation, inflammation, neuronal apoptosis (cleaved caspase 3 expression increased) and brain tissue destruction. Furthermore, application of capsaicin increased the expression levels of LC3, reduced the expression of p62 and elevated autophagic flux compared with those in the CLP group. Finally, treatment with capsaicin effectively enhanced the levels of Bcl‑2‑interacting protein 3 (BNIP3) and BNIP3‑like (NIX) expression. These findings suggested that capsaicin may be considered a potential drug for the treatment of SAE, and BNIP3/NIX‑mediated mitophagy may be involved in this process.

General anesthesia combined with peripheral nerve blocks has become a common anesthesia regimen for knee replacement surgery. Its association with high-risk isolated distal deep venous thrombosis (IDDVT) remains uncertain. In this cohort study, we obtained consecutive data from the electronic inpatient records of Shenzhen Second People’s Hospital, including adults who underwent knee arthroplasty from 1 September 2019 to 31 August 2021. The primary outcome was the incidence of high-risk IDDVT. We compared the outcomes in patients who received general anesthesia combined with nerve blocks with those in patients who received neuraxial anesthesia without nerve blocks, using a multivariable regression model with inverse probability weighting according to the propensity score. Of the 848 patients who underwent knee arthroplasty, 330 were excluded because they lacked thrombus testing or had received other types of anesthesia. Of the remaining 518 patients, 267/518 (52 ChiCTR2200057006 ), first submitted 25 February 2022.

Chronic pain is a major cause of suffering. This interferes with daily functioning and is often accompanied by distress. However, current therapeutic strategies for chronic pain are unsatisfactory because of poor understanding of its mechanisms. Therefore, more comprehensive therapeutic targets must be identified to improve the quality of life of these patients. Myeloid differentiation primary response protein 88 (MyD88) is an adaptor protein of the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families. Recently, overexpression of MyD88 in the spinal and dorsal root ganglia was observed in multiple pain models, which also revealed that MyD88 plays an important role in the development and maintenance of chronic pain. In this review, we summarized the roles and mechanisms of MyD88 in the progression of different pain models, including chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathic pain (DNP), spinal nerve ligation (SNL), chronic constriction injury (CCI), spinal cord injury (SCI) and inflammatory pain.

Perioperative neurocognitive disorder (PND) and anxiety are major perioperative complications that are typically managed independently, despite their frequent co-occurrence and mutual exacerbation. However, treatments for each condition have drawbacks, and no effective dual therapy exists. Here, a brain-targeted liposomal formulation (D@ACLipo) was developed for the co-delivery of the perioperative sedative dexmedetomidine (DEX) and the microglia-modulating peptide COG1410, incorporating Angiopep-2 to enhance brain penetration. In the PND mouse model, D@ACLipo pretreatment provided dual benefits, significantly alleviating surgery-induced cognitive impairment and anxiety-like behaviors with superior efficacy. As neuroinflammation is a pivotal driver of PND, mechanistic studies revealed that DEX modestly attenuated it via toll-like receptor 4 (TLR4) inhibition, whereas COG1410 further amplified anti-inflammatory responses by upregulating triggering receptor expressed on myeloid cells-2 (TREM2). Additionally, in vivo fiber photometry revealed that DEX significantly suppressed corticotropin-releasing hormone (CRH) neuron activity in the paraventricular nucleus (PVN), contributing to its anxiolytic effect. These findings highlight a promising translational nanotherapeutic strategy for the dual prevention of PND and anxiety by targeting molecular signaling pathways and neural circuits.

Background: The analgesic effects between fentanyl, sufentanil, and butorphanol combined with flurbiprofen axetil on postoperative patient-controlled intravenous analgesia (PCIA) after cesarean delivery has never been evaluated. Objectives: To evaluate the postoperative analgesic efficacy of selected PCIA formulae. Study Design: This is a retrospective study. Setting: Department of Anesthesiology, Shenzhen Second People's Hospital, a medical center in Shenzhen City, Guangdong Province, People's Republic of China. Methods: From January 2022 through October 2023, the records of 463 patients who underwent a cesarean delivery were reviewed at Shenzhen Second People's hospital. All used a postoperative PCIA formula combined with flurbiprofen axetil and an antiemetic (ondansetron or tropisetron). The patients were placed into one of 3 groups: the Fentanyl Group (fentanyl plus flurbiprofen axetil plus ondansetron or tropisetron, 178 patients); the Sufentanil Group (sufentanil plus flurbiprofen axetil plus ondansetron or tropisetron, 159 patients); or the Butorphanol Group (butorphanol plus flurbiprofen axetil plus ondansetron or tropisetron, 126 patients). The primary data collected were the perioperative use of analgesics, postoperative Visual Analog Scale score, and no differences in adverse reactions were observed, except for the incidence of nausea and vomiting. Results: A significant difference was found between using epidural analgesics (such as morphine) and intravenous analgesics (such as butorphanol, flurbiprofen axetil, tramadol, parecoxib, and dexmedetomidine). There was no difference among the groups in postoperative Visual Analog Scale scores at 24 hours and 48 hours post cesarean delivery. There also was no difference in adverse reactions. Limitations: Our study was limited by a small sample size and did not differentiate the Visual Analog Scale scores between states of rest and movement. Conclusion: The analgesic effect in patients who underwent cesarean delivery is similar when using different postoperative PCIA formulae. Although butorphanol displayed no analgesic advantage over fentanyl and sufentanil postoperatively, it caused fewer postoperative nausea and vomiting incidences than fentanyl and sufentanil.

BACKGROUND:Acute kidney injury (AKI) remains a common complication of coronary revascularization and increases poor outcomes in critically ill surgical patients. Compared to the plasma volume status (PVS), estimated plasma volume status (ePVS) has the advantages of being noninvasive and simple and has been shown to be associated with worse prognosis in patients undergoing coronary revascularization. This study was to evaluate the association of ePVS with the risk of AKI in patients who underwent coronary revascularization. METHODS:In this retrospective cohort study, data of patients who underwent coronary revascularization were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database (2008-2019). The outcome was the occurrence of AKI after ICU admission. The covariates were screened via the LASSO regression method. Univariate and multivariate Logistic regression models were performed to assess the association of ePVS and PVS and the odds of AKI in patients who underwent coronary revascularization, with results shown as odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses of age, surgery, and anticoagulation agents and sequential organ failure assessment (SOFA) score were performed to further explore the association of ePVS with AKI. RESULTS:A total of 3,961 patients who underwent coronary revascularization were included in this study, of whom 2,863 (72.28%) had AKI. The high ePVS was associated with the higher odds of AKI in patients who received coronary revascularization (OR = 1.06, 95%CI: 1.02-1.10), after adjusting for the covariates such as age, race, SAPS-II score, SOFA score, CCI, weight, heart rate, WBC, RDW-CV, PT, BUN, glucose, calcium, PH, PaO2, mechanical ventilation, vasopressors, and diuretic. Similar results were found in patients who underwent the CABG (OR = 1.07, 95%CI: 1.02-1.11), without anticoagulation agents use (OR = 1.07, 95%CI: 1.03-1.12) and with high SOFA score (OR = 1.10, 95%CI: 1.04-1.17). No relationship was found between PVS and the odds of AKI in patients who underwent the coronary revascularization. CONCLUSION:The ePVS may be a promising parameter to evaluate the risk of AKI in patients undergoing coronary revascularization, which provides a certain reference for the risk stratification management of ICU patients who underwent coronary revascularization.

One of the functions of organism cells is to maintain energy homeostasis to promote metabolism and adapt to the environment. The 3 major pathways of cellular energy metabolism are glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS). Neurons, astrocytes, and microglia are crucial in allodynia, hyperalgesia, and sensitization in nociceptive pathways. This review focused on these 3 major cellular energy metabolism pathways, aiming to elucidate the relationship between neurocyte and pain sensation and present the reprogramming of energy metabolism on pain, as well as the cellular and molecular mechanism underlying various forms of pain. The clinical and preclinical drugs involved in pain treatment and molecular mechanisms via cellular energy metabolism were also discussed.

S-Nitrosylation is a reversible covalent post -translational modification. Under physiological conditions, S-nitrosylation plays a dynamic role in a wide range of biological processes by regulating the function of substrate proteins. Like other post -translational modifications, S-nitrosylation can affect protein conformation, activity, localization, aggregation, and protein interactions. Aberrant S-nitrosylation can lead to protein misfolding, mitochondrial fragmentation, synaptic damage, and autophagy. Mitochondria are essential organelles in energy production, metabolite biosynthesis, cell death, and immune responses, among other processes. Mitochondrial dysfunction can result in cell death and has been implicated in the development of many human diseases. Recent evidence suggests that S-nitrosylation and mitochondrial dysfunction are important modulators of the progression of several diseases. In this review, we highlight recent findings regarding the aberrant Snitrosylation of mitochondrial proteins that regulate mitochondrial biosynthesis, fission and fusion, and autophagy. Specifically, we discuss the mechanisms by which S-nitrosylated mitochondrial proteins exercise mitochondrial quality control under pathological conditions, thereby influencing disease. A better understanding of these pathological events may provide novel therapeutic targets to mitigate the development of neurological diseases.

Neuropathic pain (NP) is characterized by its complex and multifactorial nature and limited responses to opioid therapy; NP is associated with risks of drug resistance, addiction, difficulty in treatment cessation, and psychological disorders. Emerging research on gut microbiota and their metabolites has demonstrated their effectiveness in alleviating NP and augmenting opioid-based pain management, concurrently mitigating the adverse effects of opioids. This review addresses the following key points: (1) the current advances in gut microbiota research and the challenges in using opioids to treat NP, (2) the reciprocal effects and benefits of gut microbiota on NP, and (3) the interaction between opioids with gut microbiota, as well as the benefits of gut microbiota in opioid-based treatment of NP. Through various intricate mechanisms, gut microbiota influences the onset and progression of NP, ultimately enhancing the efficacy of opioids in the management of NP. These insights pave the way for further pragmatic clinical research, ultimately enhancing the efficacy of opioid-based pain management.

Studies have suggested that microglial IL-6 modulates inflammatory pain; however, the exact mechanism of action remains unclear. We therefore hypothesized that PKCε and MEG2 competitively bind to STAT3 and contribute to IL-6-mediated microglial hyperalgesia during inflammatory pain. Freund's complete adjuvant (FCA) and lipopolysaccharide (LPS) were used to induce hyperalgesia model mice and microglial inflammation. Mechanical allodynia was evaluated using von Frey tests in vivo. The interaction among PKCε, MEG2, and STAT3 was determined using ELISA and immunoprecipitation assay in vitro. The PKCε, MEG2, t-STAT3, pSTAT3Tyr705, pSTAT3Ser727, IL-6, GLUT3, and TREM2 were assessed by Western blot. IL-6 promoter activity and IL-6 concentration were examined using dual luciferase assays and ELISA. Overexpression of PKCε and MEG2 promoted and attenuated inflammatory pain, accompanied by an increase and decrease in IL-6 expression, respectively. PKCε displayed a stronger binding ability to STAT3 when competing with MEG2. STAT3Ser727 phosphorylation increased STAT3 interaction with both PKCε and MEG2. Moreover, LPS increased PKCε, MEG2, pSTAT3Tyr705, pSTAT3Ser727, IL-6, and GLUT3 levels and decreased TREM2 during microglia inflammation. IL-6 promoter activity was enhanced or inhibited by PKCε or MEG2 in the presence of STAT3 and LPS stimulation, respectively. In microglia, overexpression of PKCε and/or MEG2 resulted in the elevation of tSTAT3, pSTAT3Tyr705, pSTAT3Ser727, IL-6, and TREM2, and the reduction of GLUT3. PKCε is more potent than MEG2 when competitively binding to STAT3, displaying dual modulatory effects of IL-6 production, thus regulating the GLUT3 and TREM2 in microglia during inflammatory pain sensation.

AIMS:Poly (ADP-ribose) polymerase (PARP) has been extensively investigated in human cancers. Recent studies verified that current available PARP inhibitors (Olaparib or Veliparib) provided clinical palliation of clinical patients suffering from paclitaxel-induced neuropathic pain (PINP). However, the underlying mechanism of PARP overactivation in the development of PINP remains to be investigated. METHODS AND RESULTS:We reported induction of DNA oxidative damage, PARP-1 overactivation, and subsequent nicotinamide adenine dinucleotide (NAD+) depletion as crucial events in the pathogenesis of PINP. Therefore, we developed an Olaparib PROTAC to achieve the efficient degradation of PARP. Continuous intrathecal injection of Olaparib PROTAC protected against PINP by inhibiting the activity of PARP-1 in rats. PARP-1, but not PARP-2, was shown to be a crucial enzyme in the development of PINP. Specific inhibition of PARP-1 enhanced mitochondrial redox metabolism partly by upregulating the expression and deacetylase activity of sirtuin-3 (SIRT3) in the dorsal root ganglions and spinal cord in the PINP rats. Moreover, an increase in the NAD+ level was found to be a crucial mechanism by which PARP-1 inhibition enhanced SIRT3 activity. CONCLUSION:The findings provide a novel insight into the mechanism of DNA oxidative damage in the development of PINP and implicate PARP-1 as a possible therapeutic target for clinical PINP treatment.

Adequate drug delivery across the blood-brain barrier(BBB)is a critical factor in treating central nervous system(CNS)disorders.Inspired by swimming fish and the microstructure of the nasal cavity,this study is the first to develop swimming short fibrous nasal drops that can directly target the nasal mucosa and swim in the nasal cavity,which can effectively deliver drugs to the brain.Briefly,swimming short fibrous nasal drops with charged controlled drug release were fabricated by electrospinning,homogenization,the π-π conjugation between indole group of fibers,the benzene ring of leucine-rich repeat kinase 2(LRRK2)inhibitor along with charge-dipole interaction between positively charged poly-lysine(PLL)and negatively charged surface of fibers;this enabled these fibers to stick to nasal mucosa,prolonged the residence time on mucosa,and prevented rapid mucociliary clearance.In vitro,swimming short fibrous nasal drops were biocompatible and inhibited microglial activation by releasing an LRRK2 inhibi-tor.In vivo,luciferase-labelled swimming short fibrous nasal drops delivered an LRRK2 inhibitor to the brain through the nasal mucosa,alleviating cognitive dysfunction caused by sepsis-associated encephalopathy by inhibiting microglial inflammation and improving synaptic plasticity.Thus,swim-ming short fibrous nasal drops is a promising strategy for the treatment of CNS diseases.

Introduction With the growing emphasis on swift recovery, minimally invasive thoracic surgery has advanced significantly. Video-assisted thoracoscopic surgery (VATS) has seen rapid development, and the double-lumen tube (DLT) remains the most dependable method for tracheal intubation in VATS. However, hypoxaemia during DLT intubation poses a threat to the perioperative safety of thoracic surgery patients. Recently, transnasal high-flow nasal oxygen (HFNO) has shown promise in anaesthesia, particularly in handling short-duration hypoxic airway emergencies. Yet, its application in the perioperative period for patients undergoing pulmonary surgery with compromised cardiopulmonary function lacks evidence, and there are limited reliable clinical data.Methods and analysis A prospective, randomised, controlled, single-blind design will be employed in this study. 112 patients aged 18–60 years undergoing elective VATS-assisted pulmonary surgery will be enrolled and randomly divided into two groups: the nasal high-flow oxygen group (H group) and the traditional mask transnasal oxygen group (M group) in a 1:1 ratio. HFNO will be used during DLT intubation for the prevention of asphyxia in group H, while conventional intubation procedures will be followed by group M. Comparison will be made between the two groups in terms of minimum oxygen saturation during intubation, hypoxaemia incidence during intubation, perioperative complications and postoperative hospital days.Ethics and dissemination Approval for this study has been granted by the local ethics committee at Shenzhen Second People’s Hospital. The trial results will be disseminated through peer-reviewed journals and scientific conferences.Trial registration number NCT05666908.

The spinal cord is critical to the perception of peripheral information under sensory-guided motor behaviors in health and disease. However, the cellular activity underlie spinal cord function in freely behaving animals is not clear. Here, we developed a new method for imaging the spinal cord at cellular and subcellular resolution over weeks under naturalistic conditions. The method involves an improved surgery to reduce spinal movement, and the installation of a miniaturized two-photon microscope to obtain high-resolution imaging in moving mice. In vivo calcium imaging demonstrated that dorsal horn neurons show a sensorimotor program-dependent synchronization and heterogeneity under distinct cutaneous stimuli in behaving mice. The long-term imaging of sensory neurons revealed that in the spinal cord, healthy mice demonstrated stereotyped responses. However, in a neuropathic pain model, plasticity changes and neuronal sensitization were observed. We provide a practical method to study the function of spinal cord on sensory perception and disorders in freely behaving mice.

Background Sepsis-associated encephalopathy (SAE) is characterized by diffuse brain dysfunction, long-term cognitive impairment, and increased morbidity and mortality. The current treatment for SAE is mainly symptomatic; the lack of specific treatment options and a poor understanding of the underlying mechanism of disease are responsible for poor patient outcomes. Fgr is a member of the Src family of tyrosine kinases and is involved in the innate immune response, hematologic cancer, diet-induced obesity, and hemorrhage-induced thalamic pain. This study investigated the protection provided by an Fgr kinase inhibitor in SAE and the underlying mechanism(s) of action. Methods A cecal ligation and puncture (CLP)-induced mouse sepsis model was established. Mice were treated with or without an Fgr inhibitor and a PGC-1α inhibitor/activator. An open field test, a novel object recognition test, and an elevated plus maze were used to assess neurobehavioral changes in the mice. Western blotting and immunofluorescence were used to measure protein expression, and mRNA levels were measured using quantitative PCR (qPCR). An enzyme-linked immunosorbent assay was performed to quantify inflammatory cytokines. Mitochondrial membrane potential and morphology were measured by JC-1, electron microscopy, and the MitoTracker Deep Red probe. Oxidative stress and mitochondrial dysfunction were analyzed. In addition, the regulatory effect of Fgr on sirtuin 1 (SIRT1) was assessed. Results CLP-induced sepsis increased the expression of Fgr in the hippocampal neurons. Pharmacological inhibition of Fgr attenuated CLP-induced neuroinflammation, the survival rate, cognitive and emotional dysfunction, oxidative stress, and mitochondrial dysfunction. Moreover, Fgr interacted with SIRT1 and reduced its activity and expression. In addition, activation of SIRT1/PGC-1α promoted the protective effects of the Fgr inhibitor on CLP-induced brain dysfunction, while inactivation of SIRT1/PGC-1α counteracted the benefits of the Fgr inhibitor. Conclusions To our knowledge, this is the first report of Fgr kinase inhibition markedly ameliorating SAE through activation of the SIRT1/PGC-1α pathway, and this may be a promising therapeutic target for SAE. Graphical Abstract