Pain encompasses both sensory discrimination and affective evaluation, yet the precise behavioral and neurobiological mechanisms of this well-conserved phenomenon are still incompletely understood. Although the lateral hypothalamus area (LHA) has been implicated in nociceptive modulation, its underlying circuitry and causal mechanisms remain elusive. In this study, formalininduced pain-like behaviors in mice were associated with attenuated activity in LHAGAD2-positive neurons, a pattern also observed during acute restraint stress in adult male transgenetic mice. Chemogenetic activation of LHAGAD2 neurons significantly alleviated formalin-evoked nociceptive responses and reduced aversive behavioral phenotypes. Additionally, functional analyses revealed a GABAergic projection from the LHA to the lateral habenula that selectively mitigated affective disturbances in a neuropathic pain model. In parallel, projections from LHAGAD2 neurons to specific neuronal subsets within the ventrolateral periaqueductal gray modulated nociceptive responses under neuropathic pain conditions. These findings delineate a dual-pathway mechanism by which LHAGAD2 neurons independently regulate sensory and affective dimensions of pain-like behavior, offering a basis for targeted pain relief. Collectively, the results reveal previously uncharacterized aspects of pain processing by discrete LHA GABAergic subpopulations and potentially inform the development of subregion-or cell type-specific therapies for pain management.

Adiponectin (ADPN) is an adipocyte-derived peptide that exerts a pivotal regulatory role in lipid metabolism in mammals. However, its functional role in avian lipid metabolism needs to be further explored, particularly in the liver, the central organ governing metabolic homeostasis in poultry. In this study, the effects of exogenous recombinant adiponectin on lipid metabolism processes were examined in primary chicken hepatocytes. Regardless of palmitic acid pretreatment, adiponectin significantly attenuated intracellular lipid accumulation. Mechanistically, adiponectin was accompanied by increased adiponectin receptor 2 (ADPNR2) mRNA expression and stimulated the efflux of triglycerides (TG) and very low-density lipoproteins (VLDL) from hepatocytes. These effects were accompanied by short-term activation of the AMP-activated protein kinase (AMPK) signaling pathway. Meanwhile, adiponectin enhanced the cellular uptake of glucose and fatty acids and upregulated the expression of genes related to fatty acid synthesis. It also suppressed the expression of genes involved in fatty acid oxidation, suggesting a cell-intrinsic negative feedback mechanism. In conclusion, the results indicate that enhanced lipid efflux may be an important mechanism contributing to the adiponectin-mediated reduction of hepatic lipid accumulation. These findings provide further evidence for the involvement of adiponectin in the regulation of avian hepatic lipid metabolism and suggest that adiponectin and its receptor pathways may represent potential targets for future studies aimed at improving liver health and productivity in poultry.

Background: Postoperative neurocognitive disorders (PND) in the elderly remain a critical clinical challenge, yet the network-level mechanisms driving this vulnerability are poorly understood. While conventional models focus on neuroinflammation or synaptic attrition, emerging evidence suggests that PND is driven by the disintegration of large-scale cortical networks. Hypocretin/orexin (LHHcrt) neurons are critical for network reintegration during anaesthesia recovery, and recent findings indicate that aging induces a KCNQ2/3-mediated channelopathy, leading to LHHcrt hyperexcitability. However, whether this hypothalamic channelopathy directly causes cortical network failure and cognitive deficits remains untested. Methods: We investigated whether anaesthetic-induced network disintegration is driven by an age-dependent KCNQ2/3 deficit in LHHcrt neurons. Findings: We demonstrate that sevoflurane and aging synergistically downregulate KCNQ2/3 in LHHcrt neurons, causing a repolarizing brake failure that transforms tonic firing into hyperexcitable, unstable burst activity. This aberrant drive propagates via a projection-defined cluster 4 (C4) LHHcrt axonal axis to the frontal-parietal-occipital cortex, forcing global cortical decoupling and pathological delta-gamma dysrhythmia. These electrophysiological signatures precisely mirror the behavioural syntax fragmentation and contextual fear memory impairment observed in aged mice. Pharmacological KCNQ2/3 activation rescued these multiscale deficits, while targeted Kcnq2/3 knockdown in young adult LHHcrt neurons fully recapitulated the aged phenotypes. Interpretation: Our findings establish a continuous causal cascade from hypothalamic KCNQ2/3 channelopathy to systems-level cognitive disintegration, redefining PND as an acute channelopathy and identifying KCNQ2/3 as a precision therapeutic target for preserving cognitive resilience in the aging surgical population.

Hepatocellular carcinoma (HCC), constituting 75-85% of primary liver cancer cases, ranks as the third leading cause of global cancer-related mortality. The early diagnosis of HCC is critical for determining optimal clinical therapeutic strategies. Radiofrequency ablation (RFA) has emerged as a preferred for managing early-stage HCC cases, primarily due to its less invasive nature, simplicity and safety. Advanced imaging for pre-operative evaluation of HCC has been increasingly used. Contrast-enhanced ultrasound (CEUS) has improved the clinical application of ultrasound (US) in HCC. It also provide more accurate informations for guiding RFA procedures. In the future, CEUS, through its convergence with emerging artificial intelligence (AI)-driven technologies, will play an even greater role in HCC management. This systematic review evaluates the utility of Sonazoid-enhanced contrast ultrasound (Sonazoid-CEUS), particularly its unique Kupffer phase imaging, in improving HCC diagnostic and optimizing RFA precision via real-time monitoring capabilities and prolonged imaging windows (up to 60 minutes).

Chronic stress disrupts sleep maintenance, yet its neural basis remains unclear. Here, we demonstrated that mice subjected to chronic social defeat stress exhibit fragmented non-rapid eye movement sleep (NREMs), accompanied by reduced density and quality of sleep spindles. Chronic stress enhances the firing and burst activity of ventral tegmental area dopaminergic (VTADA) neurons, leading to excessive dopamine release in the medial prefrontal cortex (mPFC). This dopaminergic surge disrupts the continuity of electroencephalogram (EEG) spindles, thereby disturbing the stability of NREMs. Blocking dopamine signaling along the VTA-mPFC pathway during stress exposure or pharmacologically inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated Ih currents of VTA neurons after chronic stress attenuated sleep fragmentation and restored normal spindle metrics. Our study identifies aberrant VTADA burst firing as a critical circuit-level contributor to stress-induced sleep disturbance and proposes a potential mechanistic entry point for dissecting dopamine-dependent regulation of NREMs stability.

Methamphetamine (METH) is highly addictive and causes severe public health burdens and social harm. Secretin (SCT), secreted by S cells of the duodenum and jejunum, exerts multiple biological functions in the central nervous system. Nevertheless, the role and neural mechanism of the secretin/secretin receptor (SCT/SCTR) axis in METH addiction remain largely unclear. Here, we investigated the effects of the SCT/SCTR pathway on METH-induced conditioned place preference (CPP), neuronal activity and associated molecular alterations. Our results demonstrated that SCT expression in plasma and colon was significantly decreased in METH-addicted mice. Both intraperitoneal SCT injection and colon-specific SCT overexpression effectively alleviated METH-evoked CPP. SCTR was abundantly expressed in glutamatergic neurons of the hippocampal dentate gyrus (DG) and markedly downregulated upon METH exposure. DG-specific SCTR knockdown exacerbated addiction-like behaviors, while SCTR overexpression mitigated these deficits. METH activated DG glutamatergic neurons, and SCT/SCTR modulation substantially reversed such neuronal hyperactivity. SCTR overexpression suppressed DG neuronal excitability and glutamate levels, and SCTR knockdown abolished the protective effect of SCT. Moreover, activation of DG glutamatergic neurons abrogated the inhibitory action of SCTR overexpression on METH-induced CPP. RNA-seq further identified differentially expressed molecules associated with immune response and cytokine production following SCTR overexpression. Collectively, the SCT/SCTR pathway represents a promising novel therapeutic target for METH addiction.

Chronic psychological stress is a major predisposing factor that worsens sepsis outcomes, yet the central neural mechanisms linking stress exposure to immune dysregulation remain poorly defined. Here, using a mouse model of chronic restraint stress followed by endotoxemia, we show that prior stress markedly worsens survival outcomes, amplifies systemic inflammation, and disrupts immune homeostasis during sepsis. We identify a stress-sensitive cortical–brainstem circuit in which dysfunction of the medial prefrontal cortex (mPFC) alters autonomic signaling through the dorsal motor nucleus of the vagus (DMV). In vivo splenic neuroelectrophysiological recordings and neurotransmitter profiling reveal pronounced dysregulation of splenic nerve activity and norepinephrine/acetylcholine balance in stress-primed sepsis. Notably, chemogenetic activation of the mPFC-to-DMV circuit normalizes splenic autonomic output and neurotransmitter dynamics, accompanied by attenuation of inflammatory responses and associated with improved survival. Stress exposure is further associated with altered splenic T cell polarization, including impaired regulatory T cell responses, which are partially restored following mPFC–DMV circuit activation. Together, these findings identify a functional cortical–autonomic gate linking stress exposure to neuroimmune dysregulation in sepsis and highlight cortical neuromodulation as a potential strategy to improve outcomes in stress-primed sepsis.

Dexmedetomidine (DEX) induces a distinct state of “arousable sedation,” yet the neural circuits that sustain arousal capacity remain unclear. Here, we identified that 40 μg/kg DEX produced sedation from which animals could be transiently aroused by tactile stimulation of the back, whereas 100 μg/kg induced deeper, unresponsive sedation. Functional mapping revealed selective activation of the central medial thalamus (CMT). Fiber photometry further confirmed that DEX dose-dependently and selectively activated glutamatergic neurons in the CMT while simultaneously suppressing activity in other thalamic regions. Chemogenetic inhibition of CMT glutamatergic neurons deepened DEX sedation and impaired tactile‑stimulation-induced arousal following administration of 40 μg/kg DEX, whereas activation of CMT glutamatergic neurons under a high-dose DEX (100 μg/kg) attenuated sedation and restored tactile responsiveness. Together, these results establish the CMT as a critical thalamic node for maintaining arousal capacity during DEX sedation.

Major depressive disorder is a leading cause of disability that significantly exacerbates the disease burden worldwide. FAM26F is a calcium homeostasis regulatory protein, and no studies have reported on its expression and function in brain regions involved in emotional regulation. However, the molecular mechanism by which FAM26F is involved in the pathogenesis of depression is unclear. Here, we observed that the FAM26F expression in the hippocampal dentate gyrus (DG) region was significantly downregulated and predominantly localized in glutamatergic neurons. Specific knockdown of FAM26F in glutamatergic neurons within the DG region induced depression-like behaviors in mice, whereas targeted overexpression ameliorated chronic unpredictable stress (CUS)-induced depression-like behaviors. Then, fiber optic recordings indicated that following FAM26F knockout, the neuronal activity of glutamatergic neurons as well as glutamate levels within the DG were decreased. Furthermore, FAM26F modulated glutamate homeostasis by regulating the function of glutamate synthesis, transport and the expression of glutamate receptors. Finally, high-throughput RNA-seq analysis showed that knockdown of FAM26F altered the expression of genes governing synaptic vesicle cycling and transporter complex. Our findings emphasize that FAM26F can regulate depression-related behaviors in mice by influencing the activity of glutamatergic neurons in the DG.

AIMS:Conventional antidepressants exhibit limited efficacy and delayed onset. This study aimed to elucidate the antidepressant effects of urolithin B (UB) and its regulatory role in microglia-mediated hippocampal neuronal dysfunction. METHODS:The mouse model of depression was established using both chronic unpredicted stress (CUS) and lipopolysaccharide (LPS) injection. The therapeutic efficacy of UB was assessed through behavioral paradigms. The microglia activation, cellular cytotoxicity and apoptosis levels, and underlying molecular mechanisms were delineated utilizing proteomics analysis, immunofluorescence staining, real-time PCR and Western blotting. RESULTS:UB efficiently alleviated depression-related behaviors, accompanied by suppressed microglia activation, neuroinflammation, changes of classic activation (M1)/alternative activation (M2) polarization and recovered sirtuin-1 (SIRT1) and forkhead box protein O1 (FOXO1) expression in the hippocampus. Additionally, UB reduced the cytotoxicity and apoptosis of HT22 cells and depression-related phenotypes treated by the cellular supernatant from LPS-incubated BV2 cells, which was mediated by the SIRT1-FOXO1 pathway. The proteomics analysis of the cellular supernatant content revealed abundant secreting proteins among the LPS/UB application. CONCLUSION:This study confirmed that microglial SIRT1 mediates UB's antidepressant effects, positioning UB as a promising therapeutic candidate for depression by targeting neuroinflammatory pathways.

Current pharmacotherapies for post-traumatic stress disorder (PTSD) are limited by delayed onset and side effects. Despite ketamine exhibiting rapid relief of the core symptoms of PTSD, its clinical efficacy varies considerably depending on the timing of drug delivery. However, the underlying mechanism remains unclear. In this study, the therapeutic effects of early (day 1) and late (day 7) administration of S-Ketamine on behavioral phenotypes in rodent's models of PTSD are compared. It is observed that early rather than late administration of S-Ketamine significantly ameliorates PTSD symptoms, especially impaired fear extinction. The firing and burst rates of VTADA neurons consecutively decrease following PTSD modeling and are restored by early S-Ketamine intervention. In particular, VTADA neurons respond to the conditioned stimuli, mediating the replacement of aversive memory encoding during fear extinction. The inhibition of VTADA-OFC interrupts the PTSD treatment induced by S-Ketamine. A non-invasive temporally interfering brain stimulation targeting the OFC is further developed, sensitizing cortical dopaminergic transmission and extending the effective time window of S-Ketamine for anti-PTSD. Overall, a neural mechanism for the heterogeneous VTADA-OFC neurocircuit-mediated time-dependent therapeutic effect of S-Ketamine is illustrated. In addition, a novel technique is developed to optimize the strategy of ketamine-assisted psychotherapy for PTSD treatment.

BACKGROUND:The central nucleus of the amygdala (CeA) is a multifunctional structure involved in the regulation of fear, pain, and feeding behaviours, and also plays a key role in modulating consciousness. CeA GABAergic neurones, activated by general anaesthetics, mediate analgesic effects that appear to be independent of sedation. However, the extent to which a circuit-based CeA GABAergic framework contributes to anaesthesia-arousal regulation remains unclear. METHODS:In vivo electrophysiology and fibre photometry were used to monitor CeAVgat neuronal activity during anaesthesia. Optogenetic and chemogenetic manipulations, combined with EEG and behavioural assessments, were used to test neurocircuit modulation of the transition between anaesthesia-arousal states. In vitro patch-clamp electrophysiology was used to explore the underlying mechanism of the CeAVgat-ventral tegmental area (VTA) circuitry under isoflurane anaesthesia. RESULTS:CeAVgat neuronal activity was associated with isoflurane anaesthesia: 63.3% of CeAVgat neurones exhibited reduced firing during anaesthetic induction, with a gradual recovery observed during emergence. Chemogenetic activation of CeAVgat neurones delayed anaesthetic induction and accelerated emergence. Optogenetic activation of CeAVgat neurones and their terminals in the VTA reduced EEG burst suppression and altered spectral power during maintenance. Patch-clamp recordings demonstrated mutual disinhibition via inhibitory CeAVgat projections to VTA dopaminergic neurones. CONCLUSIONS:These findings highlight a critical role for CeAVgat neurones in modulating wakefulness. Disinhibitory projections from CeA to VTA promote behavioural and cortical emergence from isoflurane anaesthesia, identifying a novel neural circuit underlying consciousness regulation.

BACKGROUND AND PURPOSE:Osteoarthritis (OA) is the most common form of arthritis worldwide. Here, we have sought to clarify the regulatory mechanisms by which the cellular retinoic acid-binding protein 2 (Crabp2) modulated OA occurrence and to elucidate the role of the insular cortex in regulating OA and anxiety. EXPERIMENTAL APPROACH:A model of OA was established following intra-articular injection of monosodium iodoacetate in mice, and a series of assessments and behavioural experiments were conducted to investigate the pathological features of OA and anxiety-related behaviours. KEY RESULTS:RNA-sequencing analysis revealed an increased Crabp2 expression in the articular cartilage of OA mice. Using the adeno-associated virus (AAV) strategy, Crabp2 overexpression in articular cartilage was shown to exacerbate progression of OA and anxiety-related behaviours. Neural linkages from the insular cortex to the knee joints were identified using a retrograde transneuronal viral tracing technique. Hyperexcitability of glutamatergic neurons in the insular cortex of OA mice was assessed by monitoring expression of FosB and Ca2+-sensitive fibre photometry recordings. Activation of glutamatergic neurons in the insular cortex promoted the development of OA and anxiety-related behaviours, whereas inhibiting these neurons attenuated the pathological features of OA and anxiety phenotypes. CONCLUSION AND IMPLICATIONS:Our results emphasized the role of Crabp2 in the regulation of OA and related anxiety disorders by interacting with the insular cortex. This brain area may function as a pathogenetic gene and serve as a therapeutic target in the treatment of OA and its related anxiety disorders.

Major depressive disorder (MDD) is a primary driver of disability and greatly escalates the worldwide disease burden. Sirtuin 1 (Sirt1), a key regulator of cellular metabolism, is associated with genetic variations in MDD. We investigated how Sirt1 in serotonin (5-HT) neurons within the dorsal raphe nucleus (DRN) in mice affected behaviors associated with depression and susceptibility to stress. Our findings revealed that Sirt1 expression in the DRN was decreased when chronic unpredictable stress was induced in depressed female mice. Additionally, Sirt1 was co-localized with 5-HT neurons within the DRN, and its selective ablation in these neurons have induced depressive phenotypes in female mice but not in males. Adeno-associated virus-mediated knockdown of Sirt1 in adult female mice induced depressive behaviors, whereas Sirt1 overexpression eliminated these behaviors. Moreover, fiber-optic recordings showed a decrease in the neural excitability of 5-HT neurons and 5-HT levels in the DRN after Sirt1 knockdown. Furthermore, we observed that Sirt1 knockdown reduced the expression of tryptophan hydroxylase-2 (Tph2) and phosphorylation levels of extracellular signal-regulated kinase (ERK) and CAMP response element binding protein (CREB). Finally, variable molecular targets regarding immune responses and cytokine productions after Sirt1 knockdown were analyzed via high-throughput RNA-seq analysis of specimens from the DRN. The findings of this study emphasize the importance of Sirt1 for regulating depression-related behaviors in female mice by influencing the activity of 5-HT neurons in the DRN.

Feeding behavior changes induced by opioid addiction significantly contribute to the worsening opioid crisis. Activation of the reward system has shown to provoke binge eating disorder in individuals with opioid use disorder, whereas prolonged opioid exposure leads to weight loss. Understanding the mechanisms underlying these phenomena is essential for addressing this pressing societal issue. This study demonstrates that weight loss resulting from feeding behavior changes during morphine addiction requires the activation of the ventral tegmental area dopamine (DA) system, which suppresses the orexin feeding center. Specifically, DA exerts an inhibitory effect on orexin neurons in the lateral hypothalamus area (LHA) through a feedforward inhibition mediated by GABA neurons in the LHA, involving D1 receptors (D1R) and T-type Ca2+ channels. Moreover, the morphine addiction-induced reduction in body weight and food intake can be reversed by the D1R antagonist SCH23390 and chemogenetic silencing of GABA neurons in the LHA. These findings delineate a neuromodulatory mechanism underlying morphine addiction-associated feeding behavior changes and weight loss.

BACKGROUND:Orexin can induce arousal from general anaesthesia; however, the underlying mechanisms are not fully understood. Nucleus accumbens (NAc), a downstream target of orexinergic neurones, plays a role in regulating consciousness. We aimed to clarify whether and how the NAc mediates the arousal effects of orexin. METHODS:Fibre photometry was used to track changes of orexinergic afferent activity during isoflurane anaesthesia and arousal from anaesthesia. Optogenetics was used to study the effects of orexinergic afferents to the NAc. Neuropharmacology approaches were used to assess receptor mechanisms. Optogenetics and in vivo electrophysiology were used to assess the influence of orexin on NAc neuronal firing and communication between the NAc and the frontal cortex. RESULTS:Orexinergic afferents in the NAc were wake-active during isoflurane anaesthesia and the arousal process. Optogenetic activation of orexinergic terminals in the NAc prolonged the time to induction, shortened time to emergence, and reduced the burst suppression ratio (from 67.4% [2.5%] to 14.5% [1.0%]; n=6, P<0.001) during 1.4 vol% isoflurane anaesthesia. Microinjection of orexin-A into the NAc promoted arousal from isoflurane anaesthesia. Orexin-1 receptors were primarily expressed in NAc D1 receptor-positive (D1R+) neurones. Optogenetic activation of orexinergic terminals increased D1R+ neuronal firing (from 0.77 [0.54] spikes s-1 to 2.53 [0.46] spikes s-1; n=24, P=0.0194) and restored NAc-to-frontal cortex coherence during isoflurane anaesthesia. CONCLUSIONS:Orexin restores communication between the NAc and frontal cortex by upregulating the activity of D1R+ neurones, thereby promoting arousal from isoflurane anaesthesia.

Diabetic kidney disease (DKD) is the primary cause of end-stage renal disease. This study examines the diagnostic efficacy of multi-modal ultrasound imaging technology for the early detection of DKD, offering a valuable reference for the prompt diagnosis of affected patients. The clinical data of 88 patients with early-stage type 2 diabetic kidney disease (E-T2DKD group), 82 patients with uncomplicated type 2 diabetes (T2DM group), and 82 healthy individuals (control group) who underwent physical examinations at the outpatient clinic of the Affiliated Jiangning Hospital with Nanjing Medical University, were analyzed. Multimodal ultrasound imaging technology (MUIT) was employed to detect various parameter indicators, and a prediction model was developed using the receiver operating characteristic (ROC) curve. The results indicated no significant differences in age, gender, and BMI among the three patient groups. In comparison to the patients in the T2DM group, those in the E-T2DKD group exhibited significantly higher durations of diabetes and HbA1C levels. Significant differences were observed in the renal function-related indicators assessed across the three groups, including Cystatin C, β2-microglobulin (β2-MG), serum retinol-binding protein (S-RBP), serum creatinine (Scr), plasma urea nitrogen (PUN), estimated glomerular filtration rate (eGFR), urine neutrophil gelatinase-associated lipocalin (U-NGAL), urine retinol-binding protein (U-RBP), urine N-acetyl-β-D-glucosaminidase (U-NAG) and urinary albumin excretion rates (UAER) (p < 0.05), whereas no significant differences were found in eGFR, Scr and PUN levels between the control group and the T2DM group. Notable statistical differences among the three groups were also identified in the MUIT detection parameters, including renal cortex shear wave elastography (SWE), kidney volume index (KVI), interlobar artery (IA) Vsmax, IA Vdmin, IA resistance index (RI), and IA pulsatility index (PI) (p < 0.05). The early SWE, KVI, IA RI, and IA PI in the E-T2DKD group were significantly higher than those in both the T2DM and control groups, while RCT/RMT, IA Vsmax, and IA Vdmin were significantly lower in comparison to the T2DM and control groups (p < 0.05). These indicators were incorporated into a binary logistic regression model, and the joint predictive value was fitted based on the regression coefficients. Further ROC analysis revealed that the prediction area under the curve (AUC) for MUIT and clinical characteristics reached 0.993, indicating a high predictive value for E-T2DKD.

BACKGROUND:Perioperative cognitive disorder (PND) affects up to 31% of surgical patients. Although clinical studies have identified a variety of risk factors, no effective prevention has been developed. From our previous cohort of PND patients, several single-nucleotide polymorphism (SNP) sites on ctnna2 were identified. The current study aims to decipher the role and regulatory mechanism of ctnna2 in the PND model and to develop decoy oligodeoxynucleotides (decoy) for the possible prevention of PND. METHODS:Both mice model (exploratory laparotomy+isoflurane) and the neuronal model (TNFα+isoflurane, T + I) for PND were used. Bioinformatic research was utilized to identify transcriptive active areas on ctnna2, foxo3 sequence, and to predict possible transcriptional factors for regulation. Molecular biological techniques were used to decipher the regulatory mechanism and specific sites of the Sirt1-foxo3-ctnna2 axis in the development of PND. Finally, an decoy targeting the Foxo3-ctnna2 interaction was designed and tested for effectiveness in PND. RESULTS:Our results showed that the SNP rs12472215 is located at a newly defined enhancer region within the ctnna2 intron that can be regulated by Foxo3 in the human genome. The rs12472215 A>T mutation potentiates Foxo3's transcriptive inhibitory effect on ctnna2. Experimental laparotomy in mice revealed that hippocampal Foxo3 upregulation and α-N-catenin reduction are involved in PND development. ChIP-PCR deciphered two regulatory sites (R1 and R2) of Foxo3 on ctnna2 in the mice that are strengthened by T + I. siAscl1 abolished the rescue effect of carbenoxolone (CBX, Foxo3-specific inhibitor) on α-N-catenin expression in the T + I model, indicating that Foxo3 inhibits ctnna2 transcription indirectly through Ascl1. Reduction of Sirt1 increased acetyl-Foxo3, which enhanced its stability in PND. Sirt1 activation reduced Foxo3 expression, acetyl-Foxo3 level, and rescued α-N-catenin expression in T + I stimulated neurons. More importantly, the new decoy disturbing Foxo3-ctnna2 interaction effectively prevents α-N-catenin reduction, CA1 pyramidal neuron morphological change, electrophysiological dysfunction, and improves cognitive deficit in PND mice. CONCLUSIONS:These results provided a new revenue for identifying targets and developing interventions for PND. The decoy, due to its specificity and short acting time, merits further exploration for possible clinical use.

Postoperative delirium (POD), a common neurocognitive complication in the early postoperative period associated with high morbidity in elderly and high-risk surgical patients, faces fundamental research constraints due to the lack of quantitative rodent behavioral assessment tools, hindering therapeutic innovation. Herein, we employed a 3D-AI animal behavior analysis system to evaluate spontaneous behaviors in mice post laparotomy surgery with isoflurane anesthesia. Mice exhibited apathy, bradykinesia, inflexible motion, and abnormal behavioral transitions at the 3-day after surgery. Based on unsupervised clustering and manifold analysis, we then quantized the dynamic alteration of comprehensive behavioral phenotypes in fear conditioning test. The cued memory, cognitive flexibility, and cognitive robustness were also impaired after surgery. Furthermore, we developed a novel intraoperative temporal interference-noninvasive brain stimulation (TI-NIBS), inducing a stereo-focusing electric field targeting the dentate gyrus of dorsal hippocampus, which significantly mitigated POD symptoms by restoring hippocampal neural activity and neurotransmitter homeostasis. This study elucidates a comprehensive behavioral profile of POD symptoms and provides a therapeutic non-invasive neuro-modulatory strategy to prevent POD by restoring hippocampal function.

Background:Alzheimer's disease (AD) is associated with various pathological states for which there is no effective treatment. First documented in the Eastern Han Dynasty's medical classic, "Treatise on Febrile and Miscellaneous Diseases" (200-210 Anno Domini), Banxia Xiexin Decoction (BXD) stands as a quintessential approach to treating spleen ailments. Recent studies have shown BXD's effectiveness in mitigating memory impairment associated with AD. Yet, the precise mechanisms underlying BXD's action against AD require further exploration. Aim of the Study:To explore the important components of BXD in exerting anti-AD effects and the underlying molecular mechanisms using network pharmacology, metabolomics analysis, and in vitro and in vivo validation strategies. Initially, candidates for BXD's application in AD therapy were identified through extensive database searches, followed by an analysis of protein-protein interactions (PPI). To elucidate BXD's therapeutic pathways in AD, we engaged in Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) assessments. Further, we delved into BXD's primary constituents through ultra-high-pressure liquid chromatography coupled with Q Exactive mass spectrometry and molecular docking techniques. Finally, AD-associated Aβ42-SY5Y cells and APPswe/PS1dE9 (APP/PS1) transgenic mice models were utilized to further determine the activity and mechanisms of BXD through various molecular or phenotypic assays and metabolomics analysis. Results:Our findings identified the PI3K/Akt signaling pathways as central to BXD's effects. Using in vitro and in vivo models, we found the activity of BXD against AD to be mediated by the suppression of neuroinflammation and apoptosis, accompanied by activation of the PI3K/Akt pathway. Finally, we observed robust changes in metabolite levels in the plasma of BXD-treated APP/PS1 mice. Conclusion:Through systematic data analysis and experimental validation, the therapeutic advantages and fundamental molecular mechanisms of BXD in treating AD were revealed. These findings underscore the promising prospects and compelling potential of BXD, which targets the PI3K/Akt signaling pathway and inflammation, apoptosis, as a therapeutic strategy for improving AD.