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In the field, necrosis area induced by pathogens is usually surrounded by a red circle in apple fruits. However, the underlying molecular mechanism of this phenomenon remains unclear. In this study, we demonstrated that accumulated salicylic acid (SA) induced by fungal infection promoted anthocyanin biosynthesis through MdNPR1-MdTGA2.2 module in apple (Malus domestica). Inoculating apple fruits with Valsa mali or Botryosphaeria dothidea induced a red circle surrounding the necrosis area, which mimicked the phenotype observed in the field. The red circle accumulated a high level of anthocyanins, which was positively correlated with SA accumulation stimulated by fungal invasion. Further analysis showed that SA promoted anthocyanin biosynthesis in a dose-dependent manner in both apple calli and fruits. We next demonstrated that MdNPR1, a master regulator of SA signaling, positively regulated anthocyanin biosynthesis in both apple and Arabidopsis. Moreover, MdNPR1 functioned as a co-activator to interact with and enhance the transactivation activity of MdTGA2.2, which could directly bind to the promoters of anthocyanin biosynthetic and regulatory genes to promote their transcription. Suppressing expression of either MdNPR1 or MdTGA2.2 inhibited coloration of apple fruits, while overexpressing either of them significantly promoted fruit coloration. Finally, we revealed that silencing either MdNPR1 or MdTGA2.2 in apple fruits repressed SA-induced fruit coloration. Therefore, our data determined that fungal-induced SA promoted anthocyanin biosynthesis through MdNPR1-MdTGA2.2 module, resulting in a red circle surrounding the necrosis area in apple fruits.
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Antocianinas , Ascomicetos , Frutas , Regulação da Expressão Gênica de Plantas , Malus , Doenças das Plantas , Proteínas de Plantas , Ácido Salicílico , Malus/microbiologia , Malus/genética , Malus/metabolismo , Ácido Salicílico/metabolismo , Antocianinas/biossíntese , Antocianinas/metabolismo , Ascomicetos/fisiologia , Doenças das Plantas/microbiologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Frutas/microbiologia , Frutas/metabolismo , Frutas/genética , Arabidopsis/microbiologia , Arabidopsis/genética , Arabidopsis/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genéticaRESUMO
Cancer is associated with the highest mortality rate globally. While life-saving screening and treatments exist, better awareness is needed. RNF187, an E3 ligase regulating biological processes, belongs to the RING domain-containing E3 ligase family. RNF187 may serve as an oncogene due to abnormal expression in tumors. However, its association with immune infiltration and prognosis across various cancers remains unclear. We searched several databases including TCGA, GTE x, CCLE, TIMER, and GSEA. R software was used to evaluate RNF187 differential expression, survival, pathology stage, DNA methylation, tumor mutational burden (TMB), microsatellite instability (MSI), gene co-expression analysis, mismatch repairs (MMRs), tumor microenvironment (TME), and immune cell infiltration. Clinicopathological data were collected, and immunohistochemistry was used to verify RNF187 expression in tumor tissues. RNF187 expression was up-regulated in various cancers compared to that in normal tissues and associated with poor patient outcomes. Dysregulation of RNF187 expression in multiple cancer types was strongly correlated with DNA methylation, MMR, MSI, and TMB. RNF187 could interact with different immune cells in cancers. Biomarkers associated with RNF187 may be helpful for prognosis and immunology in treating pan-cancer patients.
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Biomarcadores Tumorais , Neoplasias , Humanos , Biomarcadores Tumorais/genética , Prognóstico , Neoplasias/diagnóstico , Neoplasias/genética , Software , Ubiquitina-Proteína Ligases/genética , Microambiente Tumoral/genética , TransativadoresRESUMO
MAIN CONCLUSION: Overexpression of MdLBD3 in Arabidopsis reduced sensitivity to salt and drought stresses and was instrumental in promoting early flowering. Salt and drought stresses have serious effects on plant growth. LATERAL ORGAN BOUNDARY DOMAIN (LBD) proteins are a plant-specific transcription factors (TFs) family and play important roles in plants in resisting to abiotic stress. However, about the function of LBDs in apple and other woody plants is little known. In this study, protein sequences of the LBD family TFs in apples were identified which contained conserved LOB domains. The qRT-PCR analysis showed that the MdLBD3 gene was widely expressed in various tissues and organs. The subcellular localization assay showed that the MdLBD3 protein was localized in the nucleus. Ectopic expression of MdLBD3 in Arabidopsis positively regulated its salt and drought resistance, and promoted early flowering. Collectively, these results showed that MdLBD3 improved the abiotic stress resistance, plant growth and development. Overall, this study provided a new gene for breeding that can increase the abiotic stress tolerance in apple.
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Arabidopsis , Malus , Fatores de Transcrição , Secas , Melhoramento Vegetal , Estresse Salino , Clonagem MolecularRESUMO
Fruit colour is a critical determinant for the appearance quality and commercial value of apple fruits. Viroid-induced dapple symptom severely affects the fruit coloration, however, the underlying mechanism remains unknown. In this study, we identified an apple dimple fruit viroid (ADFVd)-derived small interfering RNA, named vsiR693, which targeted the mRNA coding for a bHLH transcription factor MdPIF1 (PHYTOCHROME-INTERACTING FACTOR 1) to regulate anthocyanin biosynthesis in apple. 5' RLM-RACE and artificial microRNA transient expression system proved that vsiR693 directly targeted the mRNA of MdPIF1 for cleavage. MdPIF1 positively regulated anthocyanin biosynthesis in both apple calli and fruits, and it directly bound to G-box element in the promoter of MdPAL and MdF3H, two anthocyanin biosynthetic genes, to promote their transcription. Expression of vsiR693 negatively regulated anthocyanin biosynthesis in both apple calli and fruits. Furthermore, co-expression of vsiR693 and MdPIF1 suppressed MdPIF1-promoted anthocyanin biosynthesis in apple fruits. Infiltration of ADFVd infectious clone suppressed coloration surrounding the injection sites in apple fruits, while a mutated version of ADFVd, in which the vsiR693 producing region was mutated, failed to repress fruit coloration around the injection sites. These data provide evidence that a viroid-derived small interfering RNA targets host transcription factor to regulate anthocyanin biosynthesis in apple.
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Drought stress is one of the main environmental factors limiting plant growth and development. Plants adapt to changing soil moisture by modifying root architecture, inducing stomatal closure, and inhibiting shoot growth. The AP2/ERF transcription factor DREB2A plays a key role in maintaining plant growth in response to drought stress, but the molecular mechanism underlying this process remains to be elucidated. Here, it was found that overexpression of MdDREB2A positively regulated nitrogen utilisation by interacting with DRE cis-elements of the MdNIR1 promoter. Meanwhile, MdDREB2A could also directly bind to the promoter of MdSWEET12, which may enhance root development and nitrogen assimilation, ultimately promoting plant growth. Overall, this regulatory mechanism provides an idea for plants in coordinating with drought tolerance and nitrogen assimilation to maintain optimal plant growth and development under drought stress.
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Secas , Proteínas de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Regiões Promotoras Genéticas , Sacarose/metabolismo , Regulação da Expressão Gênica de Plantas , Estresse Fisiológico/genéticaRESUMO
Alginate oligosaccharides (AOS), products of alginate degradation by endotype alginate lyases, possess favorable biological activities and have broad applications. Although many have been reported, alginate lyases with homogeneous AOS products and secretory production by an engineered host are scarce. Herein, the alginate lyase AlyC7 from Vibrio sp. C42 was characterized as a trisaccharide-producing lyase exhibiting high activity and broad substrate specificity. With PelB as the signal peptide and 500 mM glycine as the additive, the extracellular production of AlyC7 in Escherichia coli reached 1122.8 U/mL after 27 h cultivation in Luria-Bertani medium. The yield of trisaccharides from sodium alginate degradation by the produced AlyC7 reached 758.6 mg/g, with a purity of 85.1%. The prepared AOS at 20 µg/mL increased the root length of lettuce, tomato, wheat, and maize by 27.5%, 25.7%, 9.7%, and 11.1%, respectively. This study establishes a robust foundation for the industrial and agricultural applications of AlyC7.
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Escherichia coli , Polissacarídeo-Liases , Trissacarídeos , Vibrio , Polissacarídeo-Liases/metabolismo , Trissacarídeos/biossíntese , Vibrio/enzimologia , Especificidade por Substrato , Alginatos , Zea mays , OligossacarídeosRESUMO
Plants possess the remarkable ability to sense detrimental environmental stimuli and launch sophisticated signal cascades that culminate in tailored responses to facilitate their survival, and transcription factors (TFs) are closely involved in these processes. Phytochrome interacting factors (PIFs) are among these TFs and belong to the basic helix-loop-helix family. PIFs are initially identified and have now been well established as core regulators of phytochrome-associated pathways in response to the light signal in plants. However, a growing body of evidence has unraveled that PIFs also play a crucial role in adapting plants to various biological and environmental pressures. In this review, we summarize and highlight that PIFs function as a signal hub that integrates multiple environmental cues, including abiotic (i.e., drought, temperature, and salinity) and biotic stresses to optimize plant growth and development. PIFs not only function as transcription factors to reprogram the expression of related genes, but also interact with various factors to adapt plants to harsh environments. This review will contribute to understanding the multifaceted functions of PIFs in response to different stress conditions, which will shed light on efforts to further dissect the novel functions of PIFs, especially in adaption to detrimental environments for a better survival of plants.
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Proteínas de Arabidopsis , Fitocromo , Fitocromo/genética , Fitocromo/metabolismo , Proteínas de Arabidopsis/genética , Transdução de Sinais/genética , Regulação da Expressão Gênica de Plantas , Plantas/genética , Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Estresse Fisiológico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismoRESUMO
BACKGROUND: This study aimed to identify prognostic factors for pregnancy outcomes and construct a prognostic model for pregnancy outcomes in women with Recurrent Spontaneous Abortions (RSA) treated with cyclosporin A. METHODS: A total of 154 RSA patients treated with cyclosporin A between October 2016 and October 2018 were retrospectively recruited. Multivariate logistic regression was applied to identify the prognostic factors for pregnancy success in RSA women treated with cyclosporin A. The Receiver Operating Characteristic (ROC) curve was applied to construct prognostic value, and the prognostic performance was assessed using area under the ROC. RESULTS: After adjusting potential confounding factors, the authors noted increased age (OR = 0.771; 95 % CI 0.693â0.858; p < 0.001) and positive antinuclear antibodies (OR = 0.204; 95 % CI 0.079â0.526; p = 0.001) were associated with a reduced incidence of pregnancy success, while positive anti-ß2 glycoprotein-I-antibody (OR = 21.941; 95 % CI 1.176â409.281; p = 0.039) was associated with an increased incidence of pregnancy success after treated with cyclosporin A. The AUC of combining these variables for predicting pregnancy failure was 0.809 (95 % CI 0.735â0.880). CONCLUSIONS: This study systematically identified the prognostic factors for pregnancy success in women treated with cyclosporin A, and the constructed prognostic model based on these factors with relatively higher prognostic value. Further large-scale prospective studies should be performed to validate the prognostic value of the constructed model.
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Aborto Habitual , Ciclosporina , Imunossupressores , Resultado da Gravidez , Humanos , Feminino , Gravidez , Ciclosporina/uso terapêutico , Adulto , Estudos Retrospectivos , Prognóstico , Aborto Habitual/tratamento farmacológico , Imunossupressores/uso terapêutico , Curva ROC , Adulto JovemRESUMO
BACKGROUND: Gastric ulcers (GUs) have a high risk of clinical morbidity and recurrence, and further exploration is needed for the prevention, diagnosis, and treatment of the disease. AIM: To investigated the effects of a diet plan on pepsinogen (PG) I, PG II, gastrin-17 (G-17) levels and nutritional status in patients with GUs. METHODS: A total of 100 patients with GUs treated between May 2022 and May 2023 were enrolled, with 47 patients in the control group receiving routine nursing and 53 patients in the experimental group receiving dietary nursing intervention based on a diet plan. The study compared the two groups in terms of nursing efficacy, adverse events (vomiting, acid reflux, and celialgia), time to symptom improvement (burning sensation, acid reflux, and celialgia), gastric function (PG I, PG II, and G-17 levels), and nutritional status [prealbumin (PA) and albumin (ALB) levels]. RESULTS: The experimental group showed a markedly higher total effective rate of nursing, a significantly lower incidence of adverse events, and a shorter time to symptom improvement than the control group. Additionally, the experimental group's post-intervention PG I, PG II, and G-17 levels were significantly lower than pre-intervention or control group levels, whereas PA and ALB levels were significantly higher. CONCLUSION: The diet plan significantly reduced PG I, PG II, and G-17 levels in patients with GUs and significantly improved their nutritional status.
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BACKGROUND: The precise role of mitochondrial carrier homolog 2 (MTCH2) in promoting malignancy in gastric mucosal cells and its involvement in gastric cancer cell metastasis have not been fully elucidated. AIM: To determine the role of MTCH2 in gastric cancer. METHODS: We collected 65 samples of poorly differentiated gastric cancer tissue and adjacent tissues, constructed MTCH2-overexpressing and MTCH2-knockdown cell models, and evaluated the proliferation, migration, and invasion of human gastric epithelial cells (GES-1) and human gastric cancer cells (AGS) cells. The mitochondrial membrane potential (MMP), mitochondrial permeability transformation pore (mPTP) and ATP fluorescence probe were used to detect mitochondrial function. Mitochondrial function and ATP synthase protein levels were detected via Western blotting. RESULTS: The expression of MTCH2 and ATP2A2 in gastric cancer tissues was significantly greater than that in adjacent tissues. Overexpression of MTCH2 promoted colony formation, invasion, migration, MMP expression and ATP production in GES-1 and AGS cells while upregulating ATP2A2 expression and inhibiting cell apoptosis; knockdown of MTCH2 had the opposite effect, promoting overactivation of the mPTP and promoting apoptosis. CONCLUSION: MTCH2 can increase the malignant phenotype of GES-1 cells and promote the proliferation, invasion, and migration of gastric cancer cells by regulating mitochondrial function, providing a basis for targeted therapy for gastric cancer cells.
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PURPOSE: PAFAH1B1, also known as LIS1, is associated with type I lissencephaly in humans, which is a severe developmental brain disorder believed to result from abnormal neuronal migration. Our objective was to characterize the genotypes and phenotypes of PAFAH1B1-related epilepsy. METHODS: We conducted a comprehensive analysis of the medical histories, magnetic resonance imaging findings, and video-electroencephalogram recordings of 11 patients with PAFAH1B1 variants at the Neurology Department of Beijing Children's Hospital from June 2017 to November 2022. RESULTS: The age of onset of epilepsy ranged from 2 months to 4 years, with a median onset age of 5 months. Among these 11 patients (comprising 6 boys and 5 girls), all were diagnosed with lissencephaly type 1. Predominantly, generalized tonic-clonic and spasm seizures characterized PAFAH1B1-related epilepsy. Additionally, 10 out of the 11 patients exhibited severe developmental disorders. All patients exhibited de novo variants, with three individuals displaying 17p13.3 deletions linked to haploinsufficiency of PAFAH1B1. Four variants were previously unreported. Notably, three patients with 17p13.3 deletions displayed developmental delay and drug resistant epilepsy, whereas the single patient with mild developmental delay, Intelligence Quotient (IQ) 57 and well-controlled seizures had a splicing-site variant. CONCLUSION: The severity of the phenotype in patients with PAFAH1B1 variants ranged from drug-responsive seizures to severe epileptic encephalopathy. These observations underscore the clinical heterogeneity of PAFAH1B1-related disorders, with most patients exhibiting developmental disorders. Moreover, the severity of epilepsy appears to be linked to genetic variations.
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1-Alquil-2-acetilglicerofosfocolina Esterase , Epilepsia , Proteínas Associadas aos Microtúbulos , Humanos , Masculino , Feminino , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Pré-Escolar , Lactente , Epilepsia/genética , Epilepsia/fisiopatologia , Eletroencefalografia , Fenótipo , Imageamento por Ressonância Magnética , Deficiências do Desenvolvimento/genética , CriançaRESUMO
BTB and TAZ domain proteins (BTs) function as specialized adaptors facilitating substrate recognition of the CUL3-RING ubiquitin ligase (CRL3) complex that targets proteins for ubiquitination in reaction to diverse pressures. Nonetheless, knowledge of the molecular mechanisms by which the apple scaffold protein MdBT2 responds to external and internal signals is limited. Here we demonstrate that a putative Ca 2+ sensor, calmodulin-like 15 (MdCML15), acts as an upstream regulator of MdBT2 to negatively modulate its functions in plasma membrane H+-ATPase regulation and iron deficiency tolerance. MdCML15 was identified to be substantially linked to MdBT2, and to result in the ubiquitination and degradation of the MdBT2 target protein MdbHLH104. Consequently, MdCML15 repressed the MdbHLH104 target, MdAHA8's expression, reducing levels of a specific membrane H+-ATPase. Finally, the phenotype of transgenic apple plantlets and calli demonstrated that MdCML15 modulates membrane H+-ATPase-produced rhizosphere pH lowering alongside iron homeostasis through an MdCML15-MdBT2-MdbHLH104-MdAHA8 pathway. Our results provide new insights into the relationship between Ca2+ signaling and iron homeostasis.
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The Tetratricopeptide repeat (TPR)-like superfamily with TPR conserved domains is widely involved in the growth and abiotic stress in many plants. In this report, the gene MdTPR16 belongs to the TPR family in apple (Malus domestica). Promoter analysis reveal that MdTPR16 incorporated various stress response elements, including the drought stress response elements. And different abiotic stress treatments, drought especially, significantly induce the response of MdTPR16. Overexpression of MdTPR16 result in better drought tolerance in apple and Arabidopsis by up-regulating the expression levels of drought stress-related genes, achieving a higher chlorophyll content level, more material accumulation, and overall better growth compared to WT in the drought. Under drought stress, the overexpressed MdTPR16 also mitigate the oxidative damage in cells by reducing the electrolyte leakage, malondialdehyde content, and the H2O2 and O2- accumulation in apples and Arabidopsis. In conclusion, MdTPR16 act as a beneficial regulator of drought stress response by regulating the expression of related genes and the cumulation of reactive oxygen species (ROS).
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Regulação da Expressão Gênica de Plantas , Malus , Proteínas de Plantas , Malus/genética , Malus/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Secas , Arabidopsis/genética , Arabidopsis/metabolismo , Estresse Fisiológico/genética , Plantas Geneticamente Modificadas/genética , Repetições de Tetratricopeptídeos/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
Plants have evolved a complex and elaborate signaling network to respond appropriately to the pathogen invasion by regulating expression of defensive genes through certain transcription factors. The APETALA2/ethylene response factor (AP2/ERF) family members have been determined as key regulators in growth, development, and stress responses in plants. Moreover, a growing body of evidence has demonstrated the critical roles of AP2/ERFs in plant disease resistance. In this review, we describe recent advances for the function of AP2/ERFs in defense responses against microbial pathogens. We summarize that AP2/ERFs are involved in plant disease resistance by acting downstream of mitogen activated protein kinase (MAPK) cascades, and regulating expression of genes associated with hormonal signaling pathways, biosynthesis of secondary metabolites, and formation of physical barriers in an MAPK-dependent or -independent manner. The present review provides a multidimensional perspective on the functions of AP2/ERFs in plant disease resistance, which will facilitate the understanding and future investigation on the roles of AP2/ERFs in plant immunity.
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Abscisic acid (ABA), as a plant hormone, plays a positive role in leaf chlorosis; however, the underlying molecular mechanism is less known. Our findings provide ABA treatment reduced the chlorophyll accumulation in apple, and Malus × domestica Sucrose Non-fermenting 1-Related Protein Kinase 1.1 (MdSnRK1.1) participates in the process. MdSnRK1.1 interacts with MdGLK1, a GOLDEN2-like transcription factor that orchestrates development of the chloroplast. Furthermore, MdSnRK1.1 affects MdGLK1 protein stability through phosphorylation. We found that Ser468 of MdGLK1 is target site of MdSnRK1.1 phosphorylation. MdSnRK1.1-mediated phosphorylation was critical for MdGLK1 binding to the target gene MdHEMA1 promoters. Collectively, our results demonstrate that ABA activates MdSnRK1.1 to degrade MdGLK1 and inhibit the accumulation of chlorophyll. These findings extend our understanding on how MdSnRK1.1 balances normal growth and hormone response.
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Artificially enhancing photosynthesis is critical for improving crop yields and fruit qualities. Nanomaterials have demonstrated great potential to enhance photosynthetic efficiency; however, the mechanisms underlying their effects are poorly understood. This study revealed that the electron transfer pathway participated in nitrogen-doped carbon dots (N-CDs)-induced photosynthetic efficiency enhancement (24.29%), resulting in the improvements of apple fruit qualities (soluble sugar content: 11.43%) in the orchard. We also found that N-CDs alleviated mterf5 mutant-modulated photosystem II (PSII) defects, but not psa3 mutant-modulated photosystem I (PSI) defects, suggesting that the N-CDs-targeting sites were located between PSII and PSI. Measurements of chlorophyll fluorescence parameters suggested that plastoquinone (PQ), the mobile electron carrier in the photosynthesis electron transfer chain (PETC), was the photosynthesis component that N-CDs targeted. In vitro experiments demonstrated that plastoquinone-9 (PQ-9) could accept electrons from light-excited N-CDs to produce the reduced plastoquinone 9 (PQH2-9). These findings suggested that N-CDs, as electron donors, offer a PQ-9-involved complement of PETC to improve photosynthesis and thereby fruit quality. Our study uncovered a mechanism by which nanomaterials enhanced plant photosynthesis and provided some insights that will be useful in the design of efficient nanomaterials for agricultural/horticultural applications.
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Cuticular waxes play important roles in plant development and the interaction between plants and their environment. Researches on wax biosynthetic pathways have been reported in several plant species. Also, wax formation is closely related to environmental condition. However, the regulatory mechanism between wax and environmental factors, especially essential mineral elements, is less studied. Here we found that nitrogen (N) played a negative role in the regulation of wax synthesis in apple. We therefore analysed wax content, composition and crystals in BTB-TAZ domain protein 2 (MdBT2) overexpressing and antisense transgenic apple seedlings and found that MdBT2 could downregulate wax biosynthesis. Furthermore, R2R3-MYB transcription factor 16-like protein (MdMYB106) interacted with MdBT2, and MdBT2 mediated its ubiquitination and degradation through the 26S proteasome pathway. Finally, HXXXD-type acyl-transferase ECERIFERUM 2-like1 (MdCER2L1) was confirmed as a downstream target gene of MdMYB106. Our findings reveal an N-mediated apple wax biosynthesis pathway and lay a foundation for further study of the environmental factors associated with wax regulatory networks in apple.
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Arabidopsis , Malus , Arabidopsis/genética , Malus/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Aciltransferases/metabolismo , Ceras/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
OBJECTIVE: Alzheimer's disease (AD) has become a significant global concern, but effective drugs able to slow down AD progression is still lacked. Electroacupuncture (EA) has been demonstrated to ameliorate cognitive impairment in individuals with AD. However, the underlying mechanisms remains poorly understood. This study aimed at examining the neuroprotective properties of EA and its potential mechanism of action against AD. METHODS: APP/PS1 transgenic mice were employed to evaluate the protective effects of EA on Shenshu (BL 23) and Baihui (GV 20). Chemogenetic manipulation was used to activate or inhibit serotonergic neurons within the dorsal raphe nucleus (DRN). Learning and memory abilities were assessed by the novel object recognition and Morris water maze tests. Golgi staining, western blot, and immunostaining were utilized to determine EA-induced neuroprotection. RESULTS: EA at Shenshu (BL 23) and Baihui (GV 20) effectively ameliorated learning and memory impairments in APP/PS1 mice. EA attenuated dendritic spine loss, increased the expression levels of PSD95, synaptophysin, and brain-derived neurotrophic factor in hippocampus. Activation of serotonergic neurons within the DRN can ameliorate cognitive deficits in AD by activating glutamatergic neurons mediated by 5-HT1B. Chemogenetic inhibition of serotonergic neurons in the DRN reversed the effects of EA on synaptic plasticity and memory. CONCLUSION: EA can alleviate cognitive dysfunction in APP/PS1 mice by activating serotonergic neurons in the DRN. Further study is necessary to better understand how the serotonergic neurons-related neural circuits involves in EA-induced memory improvement in AD.
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Knowledge about the neuronal dynamics and the projectome are both essential for understanding how the neuronal network functions in concert. However, it remains challenging to obtain the neural activity and the brain-wide projectome for the same neurons, especially for neurons in subcortical brain regions. Here, by combining in vivo microscopy and high-definition fluorescence micro-optical sectioning tomography, we have developed strategies for mapping the brain-wide projectome of functionally relevant neurons in the somatosensory cortex, the dorsal hippocampus, and the substantia nigra pars compacta. More importantly, we also developed a strategy to achieve acquiring the neural dynamic and brain-wide projectome of the molecularly defined neuronal subtype. The strategies developed in this study solved the essential problem of linking brain-wide projectome to neuronal dynamics for neurons in subcortical structures and provided valuable approaches for understanding how the brain is functionally organized via intricate connectivity patterns.
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Endogenous opioid antinociception is a self-regulatory mechanism that reduces chronic pain, but its underlying circuit mechanism remains largely unknown. Here, we showed that endogenous opioid antinociception required the activation of mu-opioid receptors (MORs) in GABAergic neurons of the central amygdala nucleus (CEA) in a persistent-hyperalgesia mouse model. Pharmacogenetic suppression of these CEAMOR neurons, which mimics the effect of MOR activation, alleviated the persistent hyperalgesia. Furthermore, single-neuron projection analysis revealed multiple projectome-based subtypes of CEAMOR neurons, each innervating distinct target brain regions. We found that the suppression of axon branches projecting to the parabrachial nucleus (PB) of one subtype of CEAMOR neurons alleviated persistent hyperalgesia, indicating a subtype- and axonal-branch-specific mechanism of action. Further electrophysiological analysis revealed that suppression of a distinct CEA-PB disinhibitory circuit controlled endogenous opioid antinociception. Thus, this study identified the central neural circuit that underlies endogenous opioid antinociception, providing new insight into the endogenous pain modulatory mechanisms.