Biology subjects

Gao, C.

Publications and source records attributed to Gao, C..

At least 145 records · Page 8Linked to original sources

bioRxiv2021

MicroRNA-202 safeguards meiotic progression by preventing premature degradation of REC8 mediated by separase

MicroRNAs (miRNAs) are believed to play important roles in mammalian spermatogenesis but the in vivo functions of single miRNAs in this highly complex developmental process remain unclear. Here, we reported that miR-202, a member of the let-7 family, played an important role in mouse spermatogenesis by phenotypic evaluation of miR-202 knockout (KO) mice. In miR-202 KO mice, germ cells underwent apoptosis. Multiple processes in meiosis I including synapsis and crossover formation were disrupted, and inter-sister chromatid synapses were detected. More importantly, we found that upon miR-202 KO, meiotic-specific cohesin protein REC8 was prematurely cleaved by precociously activated separase, whose mRNA was a direct target of miR-202-3p. Our findings identify miR-202 as a novel regulator of meiosis and contribute to the list of miRNAs that play specific and important roles in developmental processes.

developmental biology↗

bioRxiv2021

Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

BackgroundCardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. Methods and ResultsMice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) (Egln1Tie2Cre) exhibited left ventricular (LV) hypertrophy evident by increased thickness of anterior and posterior wall and LV mass, as well as cardiac fibrosis. Tamoxifen-induced endothelial Egln1 deletion in adult mice also induced LV hypertrophy and fibrosis. Additionally, we observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Moreover, genetic ablation of Hif2a but not Hif1a in Egln1Tie2Cre mice normalized cardiac size and function. RNA sequencing analysis also demonstrated HIF-2 as a critical mediator of signaling related to cardiac hypertrophy and fibrosis. Pharmacological inhibition of HIF-2 attenuated cardiac hypertrophy and fibrosis in Egln1Tie2Cre mice. ConclusionsThe present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2 dependent manner. PHD2 was markedly decreased in cardiovascular endothelial cells in patients with cardiomyopathy. Thus, targeting PHD2/HIF-2 signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

physiology↗

bioRxiv2021

A D-2-hydroxyglutarate biosensor based on specific transcriptional regulator DhdR

D-2-Hydroxyglutarate (D-2-HG) is a metabolite in many physiological metabolic processes. When D-2-HG is aberrantly accumulated due to mutations in isocitrate dehydrogenases or D-2-HG dehydrogenase, it functions in a pro-oncogenic manner and is thus considered a therapeutic target and biomarker in many cancers. In this study, DhdR from Achromobacter denitrificans NBRC 15125 was identified as an allosteric transcription factor that negatively regulates D-2-HG dehydrogenase expression and responds to presence of D-2-HG. It is the first known transcription regulator specifically responding to D-2-HG across all domains of life. Based on the allosteric effect of DhdR, a D-2-HG biosensor was developed by combining DhdR with amplified luminescent proximity homogeneous assay technology. The biosensor was able to detect D-2-HG in serum, urine, and cell culture with high specificity and sensitivity. Additionally, this biosensor was also successfully used to identify the role of D-2-HG metabolism in lipopolysaccharide biosynthesis of Pseudomonas aeruginosa, demonstrating its broad usages.

microbiology↗

bioRxiv2020

Spike Protein of SARS-CoV-2 Activates Macrophages and Contributes to Induction of Acute Lung Inflammations in Mice

BackgroundCoronavirus disease 2019 (COVID-19) patients exhibit multiple organ malfunctions with a primary manifestation of acute and diffuse lung injuries. The Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to mediate viral entry into host cells; however, whether it can be cellularly pathogenic and contribute to pulmonary hyper-inflammations in COVID-19 is not well known. Methods and FindingsIn this study, we developed a Spike protein-pseudotyped (Spp) lentivirus with the proper tropism of SARS-CoV-2 Spike protein on the surface and tracked down the fate of Spp in wild type C57BL/6J mice receiving intravenous injection of the virus. A lentivirus with vesicular stomatitis virus glycoprotein (VSV-G) was used as the control. Two hours post-infection (hpi), Spp showed more than 27-75 times more viral burden in the lungs than other organs; it also exhibited about 3-5 times more viral burden than VSV-G lentivirus in the lungs, liver, kidney and spleen. Acute pneumonia was evident in animals 24 hpi. Spp lentivirus was mainly found in LDLR+ macrophages and pneumocytes in the lungs, but not in MARC1+ macrophages. IL6, IL10, CD80 and PPAR-{gamma} were quickly upregulated in response to infection of Spp lentivirus in the lungs in vivo as well as in macrophage-like RAW264.7 cells in vitro. We further confirmed that forced expression of the Spike protein in RAW264.7 cells could significantly increase the mRNA levels of the same panel of inflammatory factors. ConclusionsOur results demonstrate that the Spike protein of SARS-CoV-2 alone can induce cellular pathology, e.g. activating macrophages and contributing to induction of acute inflammatory responses.

pathology↗

bioRxiv2020

Recombinant Fc-fusion vaccine of RBD induced protection against SARS-CoV-2 in non-human primate and mice

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to infect people globally. The increased COVID-19 cases and no licensed vaccines highlight the need to develop safe and effective vaccines against SARS-CoV-2 infection. Multiple vaccines candidates are under pre-clinical or clinical trails with different strengths and weaknesses. Here we developed a pilot scale production of a recombinant subunit vaccine (RBD-Fc Vacc) with the Receptor Binding Domain of SARS-CoV-2 S protein fused with the Fc domain of human IgG1. RBD-Fc Vacc induced SARS-CoV-2 specific neutralizing antibodies in non-human primates and human ACE2 transgenic mice. The antibodies induced in macaca fascicularis neutralized three divergent SARS-CoV2 strains, suggesting a broader neutralizing ability. Three times immunizations protected Macaca fascicularis (20ug or 40ug per dose) and mice (10ug or 20ug per dose) from SARS-CoV-2 infection respectively. These data support clinical development of SARS-CoV-2 vaccines for humans. RBD-Fc Vacc is currently being assessed in randomized controlled phase 1/II human clinical trails. SummaryThis study confirms protective efficacy of a SARS-CoV-2 RBD-Fc subunit vaccine.

immunology↗

bioRxiv2020

Developing a broadly applicable pyrF-based genetic manipulation system in Acinetobacter baumannii

Acinetobacter baumannii is an emergency pathogenic bacterium for its multidrug-resistance and high mortality rates after infection. In-depth genetic analysis of A. baumannii virulence and drug-resistant genes is highly desirable. Existing methods for genetic manipulation of A. baumannii mainly rely on the use of antibiotic as the selectable marker, and the sacB/sucrose as the counter-selectable marker, which is inconvenient and inappropriate for all research of A. baumannii. Based on the highly conserved pyrF gene and its conserved 500bp-flanking sequence, we quickly and easily generated the pyrF-deleted mutants as the uracil auxotrophic host strain in three model strains and 11 clinical strains. The pyrF-carried vectors constructed for gene editing with pyrF/5-FOA as the counter-selection were conveniently and time-saving in these pyrF-deleted mutants. Utilizing the pyrF-based genetic manipulation system, we easily and efficiently modified the cas gene and CRISPR sequence of I-F CRISPR-Cas system in A. baumannii AYE, and detected the CRISPR interference and adaptation in these mutants. In summary, the pyrF-based genetic manipulation system could be broadly applicable used for efficiently maker-less gene editing in most A. baumannii strains.

microbiology↗

bioRxiv2020

Novel enzyme for dimethyl sulfide-releasing in bacteria reveals a missing route in the marine sulfur cycle

Dimethylsulfoniopropionate (DMSP) is an abundant and ubiquitous organosulfur molecule and plays important roles in the global sulfur cycle. Cleavage of DMSP produces volatile dimethyl sulfide (DMS), which has impacts on the global climate. Multiple pathways for DMSP catabolism have been identified. Here we identified yet another novel pathway, the ATP DMSP lysis pathway. The key enzyme, AcoD, is an ATP-dependent DMSP lyase. AcoD belongs to the acyl-CoA synthetase superfamily, which is totally different from other DMSP lyases, showing a new evolution route. AcoD catalyses the conversion of DMSP to DMS by a two-step reaction: the ligation of DMSP with CoA to form the intermediate DMSP-CoA, which is then cleaved to DMS and acryloyl-CoA. The novel catalytic mechanism was elucidated by structural and biochemical analyses. AcoD is widely distributed in many bacterial lineages including Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria and Firmicutes, revealing this new pathway plays important roles in global DMSP/DMS cycles.

ecology↗

bioRxiv2020

Higher Variability in Fungi Compared to Bacteria in the Foraging Honey Bee

Microbial communities in the honey bee gut have emerged as a model system to understand the effects of host-associated microbes on animals and plants. The specific distribution patterns of bacterial associates among honey bee gut regions remains a key finding within the field. The mid- and hindgut of foraging bees house a deterministic set of core species that affect host health. In contrast, the crop, or honey stomach, contains a more diverse set of bacteria that is highly variable in composition among individual bees. Whether this contrast between the two gut regions also applies to fungi, another major group of gut-associated microbes, remains unclear despite their potential influence on host health. In honey bees caught foraging at four sites across the San Francisco Peninsula, we found that fungi were much less distinct in species composition between the crop and the mid- and hindgut than bacteria. Unlike bacteria, fungi were highly variable in composition throughout the gut, and much of this variation was attributable to bee collection site. These patterns suggest that the fungi may be passengers rather than functionally significant gut symbionts. However, many of the fungi we found in the bees have been recognized as plant pathogens. Assuming that some fungi remain viable after passage through the gut, the distribution patterns we report here point to the potential importance of honey bees as vectors of fungal pathogens and suggest a more prominent role of honey bees in plant pathogen transmission than generally thought. Importance (Nontechnical explanation of why the work was undertaken)Along with bacteria, fungi make up a significant portion of animal- and plant-associated microbial communities. However, we have only begun to describe these fungi, much less examine their effects on most animals and plants. The honey bee, Apis mellifera, has emerged as a model system for studying host-associated microbes. Honey bees contain well-characterized bacteria specialized to inhabit different regions of the gut. Fungi also exist in the honey bee gut, but their composition and function remain largely undescribed. Here we show that, unlike bacteria, fungi vary substantially in species composition throughout the honey bee gut, contingent on where the bees are sampled. This observation suggests that fungi may be transient passengers and therefore unimportant as gut symbionts. However, our findings also indicate that honey bees could be major vectors of infectious plant diseases as many of the fungi we found in the honey bee gut are recognized as plant pathogens.

ecology↗

bioRxiv2020

Genome assembly and transcriptome analysis provide insights into the anti-schistosome mechanism of Microtus fortis

Microtus fortis (M. fortis) so far is the only mammal host that exhibits intrinsic resistance against Schistosoma japonicum infection. However, the underlying molecular mechanisms of this intrinsic resistance are not yet known. Here we performed the first de novo genome assembly of M. fortis, comprehensive gene annotation and evolution analysis. Furthermore, we compared the recovery rate of schistosome, pathological change and liver transcriptome between non-permissive host M. fortis and susceptible host mouse at different time points after Schistosome infection. We reveal that Immune response of M. fortis and mouse is different in time and type. M. fortis activates immune and inflammatory responses on the 10th days post infection, involving in multiple pathways, such as leukocyte extravasation, antibody activation (especially IgG3), Fc-gamma receptor mediated phagocytosis, and interferon signaling cascade. The strong immune responses of M. fortis in early stages of infection play important roles in preventing the development of schistosome. On the contrary, intense immune response occurred in mouse in late stages of infection (28~42 days post infection), and cannot eliminate schistosome. Infected mouse suffers severe pathological injury and continuous decrease of important functions such as cell cycle and lipid metabolism. Our findings offer new insights to the intrinsic resistance mechanism of M. fortis against schistosome infection. The genome sequence also provides bases for future studies of other important traits in M. fortis.

bioinformatics↗

bioRxiv2020

The wheat cytosolic glutamine synthetase GS1.1 modulates N assimilation and spike development by characterizing CRISPR-edited mutants

Glutamine synthetase (GS) mediates the first step in the assimilation of inorganic nitrogen (N) into amino acids, however the function of GS encoding genes is not well understood in wheat (Triticum aestivum). We found that the cytosolic TaGS1.1 was the major transcripted GS1 gene and was up-regulated by low-N availability. CRISPR/Cas9 mediated genome editing was employed to develop two gs1.1 mutants with mutated TaGS1.1-6A, -6B, and -6D. Both mutants had lower grains per spike and grain yield per plant than the wild type under both low-N and high-N conditions in field experiments. In a hydroponic culture treated with different N resources, the two mutants was more sensitive to low-N stress than the wild type, but showed similar sensitivity to high ammonium stress with the wild type. The growth deficiency and impaired spike development were associated with the imbalance of N metabolites in the mutant plants. During grain filling, TaGS1.1 mutation reduced N translocation efficiency and delayed leaf N loss and grain N filling. Our results suggested that TaGS1.1 is important for N assimilation and remobilization, and required for wheat adaptation to N-limited conditions and spike development. HighlightThe wheat cytosolic glutamine synthetase TaGS1.1 is important for N assimilation and remobilization, and is required for wheat adaptation to low-N stress and spike development.

plant biology↗

bioRxiv2020

SARS-CoV-2 ORF9b Antagonizes Type I and III Interferons by Targeting Multiple Components of RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING Signaling Pathways

Severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2), the etiologic agent of the coronavirus disease 2019 (COVID-19), has a catastrophic effect on human health and society. Clinical findings indicated that the suppression of innate antiviral immunity, especially the type I and III interferon (IFN) production, contributes to the pathogenesis of COVID-19. However, how SARS-CoV-2 evades antiviral immunity still needs further investigations. Here, we reported that the open reading frame 9b (ORF9b) protein encoded by the SARS-CoV-2 genome inhibits the activation of type I and III IFN response by targeting multiple molecules of innate antiviral signaling pathways. SARS-CoV-2 ORF9b impaired the induction of type I and III IFNs by Sendai virus or the dsRNA mimic poly (I:C). SARS-CoV-2 ORF9b inhibits the activation of type I and III IFNs induced by the components of cytosolic dsRNA-sensing pathways of RIG-I/MDA5-MAVS signaling, including RIG-I, MDA-5, MAVS, TBK1, and IKK{varepsilon} rather than IRF3-5D, the active form of IRF3. SARS-CoV-2 ORF9b also suppressed the induction of type I and III IFNs by TRIF and STING, the adaptor protein of endosome RNA-sensing pathway of TLR3-TRIF signaling and the adaptor protein of cytosolic DNA-sensing pathway of cGAS-STING signaling, respectively. Mechanistically, SARS-CoV-2 ORF9b protein interacts with RIG-I, MDA-5, MAVS, TRIF, STING, TBK1, and prevents TBK1 phosphorylation, thus impeding the phosphorylation and nuclear trans-localization of IRF3 activation. Overexpression of SARS-CoV-2 ORF9b facilitates the replication of the vesicular stomatitis virus. Therefore, SARS-CoV-2 ORF9b negatively regulates antiviral immunity, thus, facilitate virus replication. This study contributes to our understanding of the molecular mechanism of how SARS-CoV-2 impaired antiviral immunity and providing an essential clue to the pathogenesis of COVID-19.

microbiology↗

bioRxiv2020

SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors

The spike (S) glycoprotein in the envelope of SARS-CoV-2 is densely glycosylated but the functions of its glycosylation are unknown. Here we demonstrate that S is recognized in a glycan-dependent manner by multiple innate immune receptors including the mannose receptor MR/CD206, DC-SIGN/CD209, L-SIGN/CD209L, and MGL/CLEC10A/CD301. Single-cell RNA sequencing analyses indicate that such receptors are highly expressed in innate immune cells in tissues susceptible to SARS-CoV-2 infection. Binding of the above receptors to S is characterized by affinities in the picomolar range and consistent with S glycosylation analysis demonstrating a variety of N- and O-glycans as receptor ligands. These results indicate multiple routes for SARS-CoV-2 to interact with human cells and suggest alternative strategies for therapeutic intervention.

biochemistry↗

bioRxiv2020

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) Protein Inhibits Type I and III Interferon Production by Targeting RIG-I/MDA-5 Signaling

The coronavirus disease 2019 (COVID-19) caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread worldwide and has infected more than ten million individuals. One of the typical features of COVID-19 is that both type I and III interferon (IFN)-mediated antiviral immunity are suppressed. However, the molecular mechanism by which SARS-CoV-2 evades this antiviral immunity remains elusive. Here, we report that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway of RIG-I/MDA-5-MAVS signaling. The SARS-CoV2 M protein also dampens type I and III IFN induction stimulated by Sendai virus infection or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1 and prevents the formation of a multi-protein complex containing RIG-I, MAVS, TRAF3, and TBK1, thus impeding IRF3 phosphorylation, nuclear translocation, and activation. Consequently, the ectopic expression of the SARS-CoV2 M protein facilitates the replication of vesicular stomatitis virus (VSV). Taken together, the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of the SARS-CoV-2-induced antiviral immune suppression and sheds light on the pathogenic mechanism of COVID-19.

immunology↗

bioRxiv2020

G-CSF SECRETED BY EPIGENETICALLY REPROGRAMMED MUTANT IDH1 GLIOMA STEM CELLS REVERSES THE MYELOID CELLS'-MEDIATED IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT

Mutation in isocitrate dehydrogenase (mIDH) is a gain of function mutation resulting in the production of the oncometabolite, R-2-hydroxyglutarate, that inhibits DNA and histone demethylases. The resultant hypermethylation phenotype reprograms the glioma cells transcriptome and elicits profound effects on glioma immunity. We report that in mouse models and human gliomas, mIDH1 in the context of ATRX and TP53 inactivation results in global expansion of the granulocytic myeloid cells compartment. Single-cell RNA-sequencing coupled with mass cytometry analysis revealed that these granulocytes are mainly non-immunosuppressive neutrophils and pre-neutrophils; with a small fraction of polymorphonuclear myeloid-derived suppressor cells. The mechanism of mIDH1 mediated pre-neutrophils expansion involves epigenetic reprogramming which leads to enhanced expression of the granulocyte colony-stimulating factor (G-CSF). Blocking G-CSF restored the inhibitory potential of PMN-MDSCs and enhanced tumor progression. Thus, G-CSF induces remodeling of the inhibitory PMN-MDSCs in mIDH1 glioma rendering them non-immunosuppressive; and having significant therapeutic implications. SIGNIFICANCEmIDH1 is the most common mutation in gliomas associated with improved prognosis. Gliomas harboring mIDH1, together with ATRX and TP53 inactivation, exhibit higher circulating levels of G-CSF, ensuing the recruitment and expansion of non-suppressive neutrophils, pre-neutrophils and small fraction of PMN-MDSCs to the TME leading to an immune permissive phenotype.

cancer biology↗

bioRxiv2020

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

Aging is characterized by degeneration in cellular and organismal functions leading to increased disease susceptibility and death. Although our understanding of aging biology in model systems has increased dramatically, large-scale sequencing studies to understand human aging are now just beginning. We applied exome sequencing and association analyses (ExWAS) to identify age-related variants on 58,470 participants of the DiscovEHR cohort. Linear Mixed Model regression analyses of age at last encounter revealed variants in genes known to be linked with clonal hematopoiesis of indeterminate potential, which are associated with myelodysplastic syndromes, as top signals in our analysis, suggestive of age-related somatic mutation accumulation in hematopoietic cells despite patients lacking clinical diagnoses. In addition to APOE, we identified rare DISP2 rs183775254 (p = 7.40x10-10) and ZYG11A rs74227999 (p = 2.50x10-08) variants that were negatively associated with age in either both sexes combined and females, respectively, which were replicated with directional consistency in two independent cohorts. Epigenetic mapping showed these variants are located within cell-type-specific enhancers, suggestive of important transcriptional regulatory functions. To discover variants associated with extreme age, we performed exome-sequencing on persons of Ashkenazi Jewish descent ascertained for extensive lifespans. Case-Control analyses in 525 Ashkenazi Jews cases (Males [≥] 92 years, Females [≥] 95years) were compared to 482 controls. Our results showed variants in APOE (rs429358, rs6857), and TMTC2 (rs7976168) passed Bonferroni-adjusted p-value, as well as several nominally-associated population-specific variants. Collectively, our Age-ExWAS, the largest performed to date, confirmed and identified previously unreported candidate variants associated with human age.

genetics↗

bioRxiv2020

Pseudogene-mediated DNA demethylation leads to oncogene activation

Despite being one of the leading causes of cancer-related deaths, there is an unmet clinical need for hepatocellular carcinoma (HCC) patients. The lack of effective treatment is, at least in part, due to our lack of understanding of the molecular pathogenesis of this disease. Oncofetal protein SALL4 is re-activated in patients with aggressive HCC along with other solid tumors and hematologic malignancies. This study identifies a previously unrecognized mechanism of SALL4 reactivation which is mediated by pseudogene-induced demethylation. Using a locus-specific demethylating technology, we identified the critical CpG region for SALL4 expression. We showed that SALL4 pseudogene 5 hypomethylates this region through interaction with DNMT1, resulting in SALL4 upregulation. Intriguingly, pseudogene 5 is significantly upregulated in a hepatitis B virus (HBV) model prior to SALL4 induction, and both are increased in HBV-HCC patients. Our results suggest that pseudogene-mediated demethylation represents a unique mechanism of oncogene activation in cancer. SignificanceOur study provides a mechanistic link between HBV infection, activation of the oncogene SALL4, and HCC. We reveal a previously undescribed capability of a pseudogene to epigenetically activate an oncogene by demethylation in a locus-specific manner.

cancer biology↗

bioRxiv2020

A fluorescent L-2-hydroxyglutarate biosensor

L-2-Hydroxyglutarate (L-2-HG) plays important roles in diverse physiological processes, such as carbon starvation response, tumorigenesis, and hypoxic adaptation. Despite its importance and intensively studied metabolism, regulation of L-2-HG metabolism remains poorly understood and a regulator specifically responded to L-2-HG has never been identified. Based on the genomic neighborhood analysis of the gene encoding L-2-HG oxidase (LhgO), LhgR, which represses the transcription of lhgO, was identified in Pseudomonas putida W619 in this study. LhgR was demonstrated to recognize L-2-HG as its specific effector molecule, and this allosteric transcription factor was then used as a biorecognition element for construction of L-2-HG-sensing FRET sensor. The newly developed L-2-HG sensor can conveniently monitor the concentrations of L-2-HG in various biological samples. In addition to bacterial L-2-HG generation during carbon starvation, biological functions of the L-2-HG dehydrogenase and hypoxia induced L-2-HG accumulation were also revealed by using the L-2-HG sensor in human cells.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biochemistry↗

bioRxiv2020

Parabrachial neuron types categorically encode thermoregulation variables during heat defense

Heat defense is crucial for survival and fitness, and its dysregulation may result in deaths due to poor management. Transmission of thermosensory signals into hypothalamic thermoregulation centers represent a key layer of regulation in heat defense. However, the mechanism by which these signals are transmitted into the hypothalamus remains poorly understood. Here, we reveal that glutamatergic prodynorphin and cholecystokinin neuron populations in the lateral parabrachial (LPB) are progressively recruited to defend elevated body temperature. These two nonoverlapping neuron types form circuitries with downstream preoptic hypothalamic neurons to inhibit BAT thermogenesis and activate tail vasodilation, respectively. Both circuitries are selectively activated by warm temperatures and are required for fever limiting. The prodynorphin circuitry is further required for regulation of energy expenditure and weight homeostasis. Thus, these findings establish that the genetic and functional specificity of heat defense neurons occurs as early as in the LPB and uncover categorical neuron types for encoding two heat defense variables, which may provide targets for treating thermoregulation disorders.

neuroscience↗