A quick method to customize pictorial blood assessment tools towards better measurement: Method development and validation.

OBJECTIVE: Identification of heavy menstrual bleeding (HMB) cases in primary care settings is often done by using pictorial blood assessment charts (PBAC). The study aims to highlight the challenge of assessing blood loss, to develop a standardized method to efficiently customize a patient-reported pictorial chart, to validate the tool produced with our proposed method, and to demonstrate the feasibility of using PBACs in settings where resources are scarce. MATERIALS AND METHODS: Using blood samples and feedback from 21 women aged 30-51 years, we followed guidelines suggested in the literature, developed a method to produce PBACs for regular, long and night sizes, and had 9 participants testuse them. Linear regression analysis was performed to determine the correlation between participants' scores and menstrual blood weight. RESULTS: The study demonstrated the feasibility of customizing product-sensitive and size-specific pictorial charts by adopting essential steps including collecting menstrual blood with menstrual cups, employing fluid application techniques, and using sanitary pads as icons for easy identification. Linear regression analyses of score versus blood weight showed that the recorded blood weight was around 95% of the scored values (R2 = 0.9428, 0.947, and 0.9508, respectively; p < 0.001). CONCLUSION: Valid patient-reported PBACs created by the proposed method provides an innovative women's healthcare solution to assist HMB identification and reduce health expenditure by preventing risks for HMB related complications in varying economic and technological contexts. Women's participation in tracking menstrual abnormalities may improve health literacy.

NextPolish2: A Repeat-aware Polishing Tool for Genomes Assembled Using HiFi Long Reads.

The high-fidelity (HiFi) long-read sequencing technology developed by PacBio has greatly improved the base-level accuracy of genome assemblies. However, these assemblies still contain base-level errors, particularly within the error-prone regions of HiFi long reads. Existing genome polishing tools usually introduce overcorrections and haplotype switch errors when correcting errors in genomes assembled from HiFi long reads. Here, we describe an upgraded genome polishing tool - NextPolish2, which can fix base errors remaining in those "highly accurate" genomes assembled from HiFi long reads without introducing excessive overcorrections and haplotype switch errors. We believe that NextPolish2 has a great significance to further improve the accuracy of telomere-to-telomere (T2T) genomes. NextPolish2 is freely available at https://github.com/Nextomics/NextPolish2.

Unveiling the mystery of nuclear RNA homeostasis.

How nuclear RNA homeostasis impacts cellular functions remains elusive. In this issue of Cell Stem Cell, Han et al.1 utilized a controllable protein degradation system targeting EXOSC2 to perturb RNA homeostasis in mouse pluripotent embryonic stem cells, revealing its vital role in orchestrating crucial nuclear events for cellular fitness.

Efficacy of radiofrequency ablation combined with sorafenib for treating liver cancer complicated with portal hypertension and prognostic factors.

BACKGROUND: Patients with liver cancer complicated by portal hypertension present complex challenges in treatment. AIM: To evaluate the efficacy of radiofrequency ablation in combination with sorafenib for improving liver function and its impact on the prognosis of patients with this condition. METHODS: Data from 100 patients with liver cancer complicated with portal hypertension from May 2014 to March 2019 were analyzed and divided into a study group (n = 50) and a control group (n = 50) according to the treatment regimen. The research group received radiofrequency ablation (RFA) in combination with sorafenib, and the control group only received RFA. The short-term efficacy of both the research and control groups was observed. Liver function and portal hypertension were compared before and after treatment. Alpha-fetoprotein (AFP), glypican-3 (GPC-3), and AFP-L3 levels were compared between the two groups prior to and after treatment. The occurrence of adverse reactions in both groups was observed. The 3-year survival rate was compared between the two groups. Basic data were compared between the survival and non-surviving groups. To identify the independent risk factors for poor prognosis in patients with liver cancer complicated by portal hypertension, multivariate logistic regression analysis was employed. RESULTS: When comparing the two groups, the research group's total effective rate (82.00%) was significantly greater than that of the control group (56.00%; P < 0.05). Following treatment, alanine aminotransferase and aspartate aminotransferase levels increased, and portal vein pressure decreased in both groups. The degree of improvement for every index was substantially greater in the research group than in the control group (P < 0.05). Following treatment, the AFP, GPC-3, and AFP-L3 levels in both groups decreased, with the research group having significantly lower levels than the control group (P < 0.05). The incidence of diarrhea, rash, nausea and vomiting, and fatigue in the research group was significantly greater than that in the control group (P < 0.05). The 1-, 2-, and 3-year survival rates of the research group (94.00%, 84.00%, and 72.00%, respectively) were significantly greater than those of the control group (80.00%, 64.00%, and 40.00%, respectively; P < 0.05). Significant differences were observed between the survival group and the non-surviving group in terms of Child-Pugh grade, history of hepatitis, number of tumors, tumor size, use of sorafenib, stage of liver cancer, histological differentiation, history of splenectomy and other basic data (P < 0.05). Logistic regression analysis demonstrated that high Child-Pugh grade, tumor size (6-10 cm), history of hepatitis, no use of sorafenib, liver cancer stage IIIC, and previous splenectomy were independent risk factors for poor prognosis in patients with liver cancer complicated with portal hypertension (P < 0.05). CONCLUSION: Patients suffering from liver cancer complicated by portal hypertension benefit from the combination of RFA and sorafenib therapy because it effectively restores liver function and increases survival rates. The prognosis of patients suffering from liver cancer complicated by portal hypertension is strongly associated with factors such as high Child-Pugh grade, tumor size (6-10 cm), history of hepatitis, lack of sorafenib use, liver cancer at stage IIIC, and prior splenectomy.

Risk factors for anxiety and its impacts on acute exacerbation in older patients with chronic obstructive pulmonary disease.

Background: Anxiety is common in patients with chronic obstructive pulmonary disease (COPD), especially in older patients with the definition of age over 60 years old. Few studies have focused on anxiety in older COPD patients. This study aimed to analyze the risk factors of anxiety in older COPD patients and the impacts of anxiety on future acute exacerbation. Methods: The general information, questionnaire data, previous acute exacerbation and pulmonary function were collected. Hamilton Anxiety Rating Scale (HAMA) was used to evaluate the anxiety of older COPD patients. The patients were followed up for one year, the number and the degrees of acute exacerbations of COPD were recorded. Results: A total of 424 older COPD patients were included in the analysis. 19.81% (N = 84) had anxiety symptoms, and 80.19% (N = 340) had no anxiety symptoms. There were increased pack-years, more comorbidities, and more previous acute exacerbations in older COPD patients with anxiety compared to those without anxiety (P < 0.05). Meanwhile, a higher modified Medical Research Council (mMRC), a higher COPD assessment test (CAT) score and a shorter six-minute walking distance (6MWD) were found in older COPD patients with anxiety (P < 0.05). The BODE index, mMRC, CAT score, comorbidities and acute exacerbations were associated with anxiety. Eventually, anxiety will increase the risk of future acute exacerbation in older COPD patients (OR = 4.250, 95% CI: 2.369-7.626). Conclusion: Older COPD patients with anxiety had worsening symptoms, more comorbidities and frequent acute exacerbation. Meanwhile, anxiety may increase the risk of acute exacerbation in the future. Therefore, interventions should be provided to reduce the risk of anxiety in older COPD patients at an early stage.

Pseudotetrahedral Organotin-Capped Chalcogenidometalate Supermolecules with Optical Limiting Performance.

The rational design of crystalline clusters with adjustable compositions and dimensions is highly sought after but quite challenging as it is important to understand their structural evolution processes and to systematically establish structure-property relationships. Herein, a family of organotin-based sulfidometalate supertetrahedral clusters has been prepared via mixed metal and organotin strategies at low temperatures (60-120 °C). By engineering the metal composition, we can effectively control the size of the clusters, which ranges from 8 to 35, accompanied by variable configurations: P1-[(RSn)4M4S13], T3-[(RSn)4In4M2S16] (R = nbutyl-Bu and phenyl-Ph; M = Cd, Zn, and Mn), T4-[(BuSn)4In13Cu3S31], truncated P2, viz. TP2-[(BuSn)6In10Cu6S31], and even T5-[(BuSn)4In22Zn6Cu3S52], all of which are the largest organometallic supertetrahedral clusters known to date. Of note, the arylstannane approach plays a critical role in regulating the peripheral ligands and further enriching geometric structures of the supertetrahedral clusters. This is demonstrated by the formation of tin-oxysulfide clusters, such as T3-[(RSn)4Sn6O4S16] (R = Bu, Ph, and benzyl = Be) and its variants, truncated T3, viz., TT3-[(BuSn)6Sn3O4S13] and augmented T3, viz., T3-[(Bu3SnS)4Sn6O4S16]. Especially, two extraordinary truncated clusters break the tetrahedral symmetry observed in typical supertetrahedral clusters, further substantiating the advantages offered by the arylstannane approach in expanding cluster chemistry. These organometallic supertetrahedral clusters are highly soluble and stable in common solvents. Additionally, they have tunable third-order nonlinear optical behaviors by controlling the size, heterometallic combination, organic modification, and intercluster interaction.

Meta-analysis and systematic review of the relationship between sex and the risk or incidence of poststroke aphasia and its types.

OBJECTIVE: To analyse and discuss the association of gender differences with the risk and incidence of poststroke aphasia (PSA) and its types, and to provide evidence-based guidance for the prevention and treatment of poststroke aphasia in clinical practice. DATA SOURCES: Embase, PubMed, Cochrane Library and Web of Science were searched from January 1, 2002, to December 1, 2023. STUDY SELECTION: Including the total number of strokes, aphasia, the number of different sexes or the number of PSA corresponding to different sex. DATA EXTRACTION: Studies with missing data, aphasia caused by nonstroke and noncompliance with the requirements of literature types were excluded. DATA SYNTHESIS: 36 papers were included, from 19 countries. The analysis of 168,259 patients with stroke and 31,058 patients with PSA showed that the risk of PSA was 1.23 times higher in female than in male (OR = 1.23, 95% CI = 1.19-1.29, P < 0.001), with a prevalence of PSA of 31% in men and 36% in women, and an overall prevalence of 34% (P < 0.001). Analysis of the risk of the different types of aphasia in 1,048 patients with PSA showed a high risk in females for global, broca and Wenicke aphasia, and a high risk in males for anomic, conductive and transcortical aphasia, which was not statistically significant by meta-analysis. The incidence of global aphasia (males vs. females, 29% vs. 32%) and broca aphasia (17% vs 19%) were higher in females, and anomic aphasia (19% vs 14%) was higher in males, which was statistically significant (P < 0.05). CONCLUSIONS: There are gender differences in the incidence and types of PSA. The risk of PSA in female is higher than that in male.

Bone regeneration with hydroxyapatite particles loaded in photo-cross-linkable hydrogel: An experimental study.

This study explores the use of in situ cross-linked hyaluronic acid methacryloyl (HAMA) and hydroxyapatite particles (HAP) for bone defect repair. Human periodontal ligament stem cells (PDLSCs) were isolated and co-cultured with the HAMA-HAP composite. Osteogenic differentiation was evaluated using Alizarin Red staining, alkaline phosphatase activity quantification, and polymerase chain reaction (PCR). A cranial defect was induced in Sprague-Dawley rats. This defect was then filled with the HAMA-HAP composite and cross-linked using UV light exposure. Bone formation was assessed through radiographic and histological analyses. The HAMA-HAP composite was found to promote cell viability similarly to pure HAP. It also enhanced gene expression of ALP, OPN, and Runx2, and increased ALP activity and mineralized nodule formation in vitro. Micro-CT scans showed defect restoration in the HAMA-HAP and HAP groups compared to the control group. The HAMA-HAP group exhibited higher Tb.N, Tb.Sp, Tb.Th, and BV/TV. Masson staining showed the HAMA-HAP composite restored the defect site, with new bone formation thicker than in the HAP group. The HAMA-HAP composite showed excellent biocompatibility and promoted osteogenic differentiation of PDLSCs. It effectively repaired cranial defects, indicating its potential for clinical use in bone defect repair.

FOXK1 promotes hormonally responsive breast carcinogenesis by suppressing apoptosis.

BACKGROUND: Globally, breast cancer constitutes the predominant malignancy in women. Abnormal regulation of epigenetic factors plays a key role in the development of tumors. Anti-apoptosis is a characteristic of tumor cells. Therefore, exploring and identifying relevant epigenetic factors that regulate the apoptosis of tumor cells is the foundation for clarifying the pathogenesis of tumors and achieving precision antitumor therapy. METHOD: This study focused on exploring the epigenetic mechanism of FOXK1 in the development of estrogen receptor-positive (ER+ ) breast cancer. We used overexpressing FLAG-FOXK1 MCF-7 cells to perform silver staining mass spectrometry analysis and conducted Co-IP experiments to verify the interactions. ChIP-seq was conducted on MCF-7 cells to examine FOXK1's binding across the genome and its transcriptional target sites. To validate the ChIP-seq results, qChIP, western blotting, and quantitative polymerase chain reaction (qPCR) were performed. Through TUNEL assay, cell counting assay, colony formation assay, and the mouse xenograft models, the effect of FOXK1 on breast cancer progression was detected. Finally, by analyzing online databases, the correlation between FOXK1 and the survival of breast cancer patients was examined. RESULTS: FOXK1 interacts with the REST/CoREST transcriptional corepression complex to transcriptionally inhibit target genes representing the apoptotic pathway. Abnormally high expression of FOXK1 prevents the apoptosis of ER+ breast cancer cells in vitro and promotes ER+ breast tumor progression in vivo. Furthermore, the expression of FOXK1 is negatively correlated with the survival of ER+ breast cancer patients. CONCLUSION: FOXK1 promotes ER+ breast carcinogenesis through anti-apoptosis and acts as a potential target for ER+ breast cancer treatment.

In silico and in vitro analyses of a novel FoxO1 agonist reducing Aß levels via downregulation of BACE1.

AIMS: FoxO1 is an important target in the treatment of Alzheimer's disease (AD). However, FoxO1-specific agonists and their effects on AD have not yet been reported. This study aimed to identify small molecules that upregulate the activity of FoxO1 to attenuate the symptoms of AD. METHODS: FoxO1 agonists were identified by in silico screening and molecular dynamics simulation. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to assess protein and gene expression levels of P21, BIM, and PPARγ downstream of FoxO1 in SH-SY5Y cells, respectively. Western blotting and enzyme-linked immunoassays were performed to explore the effect of FoxO1 agonists on APP metabolism. RESULTS: N-(3-methylisothiazol-5-yl)-2-(2-oxobenzo[d]oxazol-3(2H)-yl) acetamide (compound D) had the highest affinity for FoxO1. Compound D activated FoxO1 and regulated the expression of its downstream target genes, P21, BIM, and PPARγ. In SH-SY5Y cells treated with compound D, BACE1 expression levels were downregulated, and the levels of Aß1-40 and Aß1-42 were also reduced. CONCLUSIONS: We present a novel small-molecule FoxO1 agonist with good anti-AD effects. This study highlights a promising strategy for new drug discovery for AD.

Emerging roles of nuclear bodies in genome spatial organization.

Nuclear bodies (NBs) are biomolecular condensates that participate in various cellular processes and respond to cellular stimuli in the nucleus. The assembly and function of these protein- and RNA-rich bodies, such as nucleoli, nuclear speckles, and promyelocytic leukemia (PML) NBs, contribute to the spatial organization of the nucleus, regulating chromatin activities locally and globally. Recent technological advancements, including spatial multiomics approaches, have revealed novel roles of nucleoli in modulating ribosomal DNA (rDNA) and adjacent non-rDNA chromatin activity, nuclear speckles in scaffolding active genome architecture, and PML NBs in maintaining genome stability during stress conditions. In this review, we summarize emerging functions of these important NBs in the spatial organization of the genome, aided by recently developed spatial multiomics approaches toward this direction.

Two Polarity-Sensitive Fluorescent Probes Based on Curcumin Analogs for Visualizing Polarity Changes in Lipid Droplets.

As a class of highly dynamic organelles, lipid droplets (LDs) are involved in numerous physiological functions, and the changes in polarity of LDs are closely related to a variety of diseases. In this work, we developed two polarity-sensitive fluorescent probes (CC-CH and CC-Cl) based on curcumin analogs. CC-CH and CC-Cl with a donor-acceptor-donor (D-A-D) structure exhibited the property of intramolecular charge transfer (ICT); thus, their fluorescence emissions were significantly attenuated with increasing ambient polarity. Cell experiments indicated that CC-CH and CC-Cl showed excellent photostability, a low cytotoxicity, and a superior targeting ability regarding LDs. After treatment with oleic acid (OA) and methyl-ß-cyclodextrin (M-ß-CD), the polarity changes of LDs in living cells could be visualized by using CC-CH and CC-Cl. In addition, CC-CH and CC-Cl could monitor polarity changes of LDs in different pathological processes, including inflammatory responses, nutrient deprivation, and H2O2-induced oxidative stress. Therefore, CC-CH and CC-Cl are promising potential fluorescent probes for tracking intracellular LD polarity changes.

Increased retinoic acid signaling decreases lung metastasis in salivary adenoid cystic carcinoma by inhibiting the noncanonical Notch1 pathway.

MYB-NFIB fusion and NOTCH1 mutation are common hallmark genetic events in salivary gland adenoid cystic carcinoma (SACC). However, abnormal expression of MYB and NOTCH1 is also observed in patients without MYB-NFIB fusion and NOTCH1 mutation. Here, we explore in-depth the molecular mechanisms of lung metastasis through single-cell RNA sequencing (scRNA-seq) and exome target capture sequencing in two SACC patients without MYB-NFIB fusion and NOTCH1 mutation. Twenty-five types of cells in primary and metastatic tissues were identified via Seurat clustering and categorized into four main stages ranging from near-normal to cancer-based on the abundance of each cell cluster in normal tissue. In this context, we identified the Notch signaling pathway enrichment in almost all cancer cells; RNA velocity, trajectory, and sub-clustering analyses were performed to deeply investigate cancer progenitor-like cell clusters in primary tumor-associated lung metastases, and signature genes of progenitor-like cells were enriched in the "MYC_TARGETS_V2" gene set. In vitro, we detected the NICD1-MYB-MYC complex by co-immunoprecipitation (Co-IP) and incidentally identified retinoic acid (RA) as an endogenous antagonist of genes in the "MYC_TARGETS_V2" gene set. Following this, we confirmed that all-trans retinoic acid (ATRA) suppresses the lung metastasis of SACC by correcting erroneous cell differentiation mainly caused by aberrant NOTCH1 or MYB expression. Bioinformatic, RNA-seq, and immunohistochemical (IHC) analyses of primary tissues and metastatic lung tissues from patients with SACC suggested that RA system insufficiency partially promotes lung metastasis. These findings imply the value of the RA system in diagnosis and treatment.

Nucleolar URB1 ensures 3' ETS rRNA removal to prevent exosome surveillance.

The nucleolus is the most prominent membraneless condensate in the nucleus. It comprises hundreds of proteins with distinct roles in the rapid transcription of ribosomal RNA (rRNA) and efficient processing within units comprising a fibrillar centre and a dense fibrillar component and ribosome assembly in a granular component1. The precise localization of most nucleolar proteins and whether their specific localization contributes to the radial flux of pre-rRNA processing have remained unknown owing to insufficient resolution in imaging studies2-5. Therefore, how these nucleolar proteins are functionally coordinated with stepwise pre-rRNA processing requires further investigation. Here we screened 200 candidate nucleolar proteins using high-resolution live-cell microscopy and identified 12 proteins that are enriched towards the periphery of the dense fibrillar component (PDFC). Among these proteins, unhealthy ribosome biogenesis 1 (URB1) is a static, nucleolar protein that ensures 3' end pre-rRNA anchoring and folding for U8 small nucleolar RNA recognition and the subsequent removal of the 3' external transcribed spacer (ETS) at the dense fibrillar component-PDFC boundary. URB1 depletion leads to a disrupted PDFC, uncontrolled pre-rRNA movement, altered pre-rRNA conformation and retention of the 3' ETS. These aberrant 3' ETS-attached pre-rRNA intermediates activate exosome-dependent nucleolar surveillance, resulting in decreased 28S rRNA production, head malformations in zebrafish and delayed embryonic development in mice. This study provides insight into functional sub-nucleolar organization and identifies a physiologically essential step in rRNA maturation that requires the static protein URB1 in the phase-separated nucleolus.

Zinc-finger protein CXXC5 promotes breast carcinogenesis by regulating the TSC1/mTOR signaling pathway.

CXXC5, a member of the CXXC family of zinc-finger proteins, is associated with numerous pathological processes. However, the pathophysiological function of CXXC5 has not been clearly established. Herein, we found that CXXC5 interacts with the CRL4B and NuRD complexes. Screening of transcriptional targets downstream of the CXXC5-CRL4B-NuRD complex by next-generation sequencing (chromatin immunoprecipitation sequencing) revealed that the complex regulates the transcriptional repression process of a cohort of genes, including TSC1 (tuberous sclerosis complex subunit 1), which play important roles in cell growth and mammalian target of rapamycin signaling pathway regulation, and whose abnormal regulation results in the activation of programmed cell death-ligand protein 1 (PD-L1). Intriguingly, CXXC5 expression increased after stimulation with vitamin B2 but decreased after vitamin D treatment. We also found that the CXXC5-CRL4B-NuRD complex promotes the proliferation of tumor cells in vitro and accelerates the growth of breast cancer in vivo. The expression of CXXC5, CUL4B, and MTA1 increased during the occurrence and development of breast cancer, and correspondingly, TSC1 expression decreased. Meanwhile, a high expression of CXXC5 was positively correlated with the histological grade of high malignancy and poor survival of patients. In conclusion, our study revealed that CXXC5-mediated TSC1 suppression activates the mammalian target of rapamycin pathway, reduces autophagic cell death, induces PD-L1-mediated immune suppression, and results in tumor development, shedding light on the mechanism of the pathophysiological function of CXXC5.

The research on the efficiency of single-port plus-one robot-assisted pyeloplasty for children with UPJO / 中华泌尿外科杂志

Objective:To investigate the effect of Da Vinci robot-assisted single-port plus-one laparoscopic pyeloplasty (RSPY) in children with ureteropelvic junction obstruction (UPJO).Methods:The clinical data of 13 children with UPJO diagnosed by robot-assisted single-port plus-one laparoscopic pyeloplasty in Fujian Provincial Hospital from September 2021 to August 2022 were retrospectively analyzed. The mean age of the children was 60.0 (1.3, 108.0) months. The lesions of 10 patients were on the left, and 3 were on the right. The clinical manifestations were abdominal pain in 3 cases, urinary tract infection in 2 cases, and no symptoms in 10 cases. Preoperative isotope renogram showed affected renal function (28.32±1.82)%, and bilateral renal function difference > 10% in 7 cases. Mechanical obstruction existed in 5 cases. Preoperative ultrasound showed the affected side's renal cortex thickness of (1.98 ± 0.23) cm. During the operation, a single-port multi-channel trocar was placed in the umbilicus with another single port in the epigastrium, and a robotic system was placed to explore the subperitoneal dilated renal pelvis. The renal pelvis was suspended and pulled through the abdominal wall. The visual field was exposed, and the dilated renal pelvis was incised. The dilated renal pelvis was cut, a ureteral stent was placed, and the ureteropelvic duct was anastomosed.Results:The operation of 13 cases was successfully completed, without conversion to open surgery. The operation time was 180.0(165.0, 190.2)min. The intraoperative blood loss was < 5 ml. The postoperative hospital stay was 7.0(7.0, 7.0)d, and hospitalization costs were 56.3(52.1, 56.5)thousand yuan. The ureteral stent was removed 2 months after the operation, and no obvious complications such as urinary tract infection or low back pain occurred. The median postoperative follow-up was 12 months, ranged from 6 to 18 months. Urinary color ultrasound showed that the renal cortex was (4.95±0.57) cm, which was thicker than before. Isotope renogram showed that the renal function was (38.02±1.76)%, which was higher than before. Mechanical obstruction was transformed into incomplete obstruction.Conclusions:Da Vinci robot-assisted single-port plus-one laparoscopic pyeloplasty is precise and could achieve good surgical results on the basis of the effective restoration of lesion kidney function.

Progress of Research on Relationship Between Intestinal Flora, Immunity and Gallstone / 胃肠病学

Gallstone disease is a common and frequently seen disease of digestive system, and is a common cause of inflammation of gallbladder and bile duct, biliary tract tumor and obstructive jaundice, however, its pathogenesis is not yet fully understood. Recent studies have revealed that intestinal flora and immunity play important roles in the formation of gallstones. This paper reviewed the relationship between the abundance and composition of intestinal flora, immuno - globulins, mucins and immune cells, as well as the interactions between intestinal flora and biliary immunity and gallstone formation for providing new ideas and methods for gallstone prevention and treatment.

Somatostatin-Positive Neurons in the Rostral Zona Incerta Modulate Innate Fear-Induced Defensive Response in Mice / 神经科学通报·英文版

Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival. The zona incerta (ZI) has been demonstrated to play important roles in fear learning and fear memory, as well as modulating auditory-induced innate defensive behavior. However, whether the neuronal subtypes in the ZI and specific circuits can mediate the innate fear response is largely unknown. Here, we found that somatostatin (SST)-positive neurons in the rostral ZI of mice were activated by a visual innate fear stimulus. Optogenetic inhibition of SST-positive neurons in the rostral ZI resulted in reduced flight responses to an overhead looming stimulus. Optogenetic activation of SST-positive neurons in the rostral ZI induced fear-like defensive behavior including increased immobility and bradycardia. In addition, we demonstrated that manipulation of the GABAergic projections from SST-positive neurons in the rostral ZI to the downstream nucleus reuniens (Re) mediated fear-like defensive behavior. Retrograde trans-synaptic tracing also revealed looming stimulus-activated neurons in the superior colliculus (SC) that projected to the Re-projecting SST-positive neurons in the rostral ZI (SC-ZIrSST-Re pathway). Together, our study elucidates the function of SST-positive neurons in the rostral ZI and the SC-ZIrSST-Re tri-synaptic circuit in mediating the innate fear response.