Biology subjects

Mueller, M.

Publications and source records attributed to Mueller, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

A Multimodal Adaptive Optical Microscope For In Vivo Imaging from Molecules to Organisms

Understanding biological systems requires observing features and processes across vast spatial and temporal scales, spanning nanometers to centimeters and milliseconds to days, often using multiple imaging modalities within complex native microenvironments. Yet, achieving this comprehensive view is challenging because microscopes optimized for specific tasks typically lack versatility due to inherent optical and sample handling trade-offs, and frequently suffer performance degradation from sample-induced optical aberrations in multicellular contexts. Here, we present MOSAIC, a reconfigurable microscope that integrates multiple advanced imaging techniques including light-sheet, label-free, super-resolution, and multi-photon, all equipped with adaptive optics. MOSAIC enables non-invasive imaging of subcellular dynamics in both cultured cells and live multicellular organisms, nanoscale mapping of molecular architectures across millimeter-scale expanded tissues, and structural/functional neural imaging within live mice. MOSAIC facilitates correlative studies across biological scales within the same specimen, providing an integrated platform for broad biological investigation.

cell biology↗

bioRxiv2025

Assessing the adaptative potential to temperature and precipitation along a steep environmental gradient in populations of European beech

Climate change poses a significant threat to European beech. These concerns highlight the need to assess the adaptive potential of European beech populations to climate change. Landscape genomics, also known as environmental association analysis, is a powerful tool for identifying gene loci that contribute to local adaptation to environmental pressures. Genotypic data was collected from [~]100 adult beech trees per stand in five locations in the South-Eastern Romanian Carpathians along an altitudinal gradient associated with precipitation and temperature. In total, 53 environmental variables, comprising frost frequency change, temperature and precipitation, were extracted from the climatology data base CHELSA. Based on these variables the Ellenberg-Quotient (EQ) was calculated. We performed environmental association analysis using LFMM (latent factor mixed models) to identify Single Nucleotide Polymorphism (SNP) markers associated with environmental variables and with the principal components calculated based on these. We identified 446 SNP markers significantly associated with the first principal component (PC). These were overlapping with the SNP markers significantly associated with all environmental variables except precipitation accumulated during the growing season. The first PC was correlated with all temperature-based variables and elevation at |r| [~]0.989 to [~]0.997 and with all precipitation-based and Ellenberg-Quotient variables at |r| [~]0.945 to 0.950, except precipitation accumulated during the growing season. A high peak region on chromosome 2 from [~]4.56 to [~]16.27 Mb appeared in all results. This region was [~]3.47 Mb downstream from a region for local adaptation identified by Lazic et al. (2024). In this peak, 273 markers located in the coding region of 22 genes were found. Ten out these 22 were described based on a literature review. Among these ten genes, two may be involved in local adaptation based on our literature review. These two genes are polygalacturonase QRT3-like and NRT1/PTR_FAMILY 5.4-like. The gene polygalacturonase QRT3-like plays a role in pollen development in Arabidopsis thaliana L. and Brassica rapa L. We observed at the corresponding SNP markers, a correlation of the minor allele frequency and temperature-based environmental variables.

genetics↗

bioRxiv2025

Landscape heterogeneity, forest structure and mammalian host diversity shape Ixodes ricinus density and Borrelia prevalence in German forests

Ticks, particularly Ixodes ricinus, and the associated Lyme borreliosis risk, represent key concerns within the One Health framework, prompting extensive research in this field. However, comprehensive studies that jointly consider landscape characteristics, local forest structure and management, climate, and host community composition - alongside direct measures of tick density and Borrelia spp. infection status - are scarce. In this study, we test the hypothesis that habitat diversity exerts a dilution effect, primarily by supporting greater diversity of mammal hosts. Therefore, we examined I. ricinus tick density and Borrelia spp. prevalence in relation to a comprehensive set of habitat and host-related variables. Ticks were collected using the flagging method and mammal hosts were monitored using an innovative camera-trapping approach across 25 forest plots along a land-use gradient within the Schwabische Alb exploratory in Germany. Our findings indicate that both tick density and Borrelia spp. prevalence are influenced by a complex interplay of habitat factors across different spatial scales, as well as the mammal host community composition. Overall, our results provide novel support to the dilution effect hypothesis, suggesting that greater habitat and host diversity contribute to a reduced Lyme borreliosis risk in this region.

ecology↗

bioRxiv2025

The proteasome maturation factor POMP moonlights as a stress-induced transcriptional regulator

Proteostasis - the maintenance of proteins at proper concentrations, conformations, and subcellular locations - is essential for cellular function and is governed by tightly regulated protein synthesis and degradation pathways. The Proteasome Maturation Protein (POMP) is a key chaperone involved in assembling the proteasome, the primary complex responsible for protein degradation. Despite the conserved role of POMP, its loss produces contrasting proteostatic effects in yeast and mammalian cells, pointing to additional, unexplored functions. In this study, we investigated the possibility that POMP plays a moonlighting role in proteostasis regulation. We discovered that upon proteasome disruption, POMP rapidly accumulates in the nucleolus in a manner dependent on HSF1 and reactive oxygen species (ROS). Proteomic analysis of POMP interactors revealed RNA processing factors and transcriptomic profiling showed that nucleolar POMP orchestrates a protective transcriptional program. Our findings indicate POMP is a built-in sensor and effector within the proteasome assembly pathway, capable of buffering disturbances in proteasome function through a novel, non-canonical role. Notably, this mechanism is developmentally controlled and active in neurodegenerative disease contexts. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/650603v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@196cd2borg.highwire.dtl.DTLVardef@177d240org.highwire.dtl.DTLVardef@18c9bcborg.highwire.dtl.DTLVardef@483b94_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Genome-wide association study in European beech (Fagus sylvatica L.) for drought stress traits

Forest tree breeding is an extremely long and tedious process. To study the genetic architecture of polygenic traits in long-lived species such as forest trees, costly field experiments are implemented. Phenotypic data on traits, that are measured at maturity, are only available after a long time and juvenile-mature correlations are often unknown. Genome-wide association studies (GWAS) aim to identify loci associated with drought stress, tree physiology, growth or wood quality traits, which could be prioritized in breeding programs. Genotypic and phenotypic data were collected from approximately 100 adult beech trees per stand in five locations in the South-Eastern Romanian Carpathians along an altitudinal gradient associated with precipitation and temperature. We performed GWAS using PLINK to identify SNP markers associated with traits related to drought stress. A total of 121 markers on eight chromosomes were identified as being associated with stomatal density. Sixty-four markers are located on chromosome 10 in a region spreading from [~]4.89 to 13.67 Mb. There are five genes in this region that are thought to play a role in controlling stomatal density. All markers within this region exhibit similar allele frequencies, which are correlated with stomatal density and the altitudinal gradient of the stands. We assume this entire region is jointly involved in local adaptation to drought stress. We identified one interesting candidate SNP associated with leaf nitrogen content. Two SNP markers were identified as being significantly associated with {delta}13C as measure of intrinsic water use efficiency. Additionally, signals of significant polygenic selection for {delta}13C were observed.

genetics↗

bioRxiv2025

Endogenous RALF peptide function is required for powdery mildew host colonization

The receptor kinase FERONIA (FER) is a susceptibility factor for biotrophic powdery mildew fungal pathogens in Arabidopsis thaliana, but the underlying molecular mechanisms remain largely unknown. FER is required for the perception of endogenous RAPID ALKALINIZATION FACTOR (RALF) peptides to control various aspects of plant growth, development and immunity. RALFs are perceived by FER-LORELEI-LIKE GPI-ANCHORED PROTEIN (LLG) heterocomplexes to induce cellular responses and bind to LEUCINE-RICH REPEAT EXTENSIN (LRX) proteins as structural components of the cell wall. Combining genetics, cell biology and biochemistry, we found that FERs endogenous RALF ligands are necessary for full colonization success of the powdery mildew species Erysiphe cruciferarum. We reveal that LLGs and LRXs are also powdery mildew susceptibility factors. We show that cell wall remodeling and apoplastic pH homeostasis, hallmark features of RALF function, support powdery mildew reproductive success. Moreover, we provide data that RALF-dependent powdery mildew pathogenesis is partially independent of FER. Powdery mildew fungi likely do not produce RALF peptide mimics, suggesting their reliance on endogenous RALFs for successful host colonization. We propose that powdery mildew fungi require RALF-mediated modulation of apoplastic pH and pectin re-modelling for successful host colonization, highlighting a new susceptibility mechanism by obligate biotrophic fungi.

plant biology↗

bioRxiv2025

The MYCN/Aurora-A complex is a cyclin activating kinase for CDK12

Deregulated MYCN is a driver of aggressive pediatric and adult neuroendocrine tumors, but critical oncogenic processes downstream of MYCN remain poorly defined. In neuroblastoma, MYCN interacts with and activates the Aurora-A kinase. Here we show that Aurora-A is a CDK-activating kinase for CDK12 by phosphorylating T893 in the T-loop, thereby enhancing its kinase activity. Aurora-A-dependent activation of CDK12 controls phosphorylation of T4 of RNA polymerase and recruits transcription termination complexes, thereby preventing transcription-replication conflicts. Enhanced crosslinking and immunoprecipitation sequencing reveals that Aurora-A associates with splice sites on nascent RNA. RNA-bound Aurora-A is catalytically inactive. MYCN competes with RNA for binding to Aurora-A and displaces Aurora-A from RNA in cells, promoting its CDK12 kinase activity. Combining Aurora-A and CDK12 inhibition potently suppresses the growth of MYCN-amplified neuroblastoma cells and patient-derived xenografts. Our data demonstrate that an Aurora-A/CDK12-dependent transcription termination pathway is a critical and targetable dependency of MYCN-driven tumors.

cancer biology↗

bioRxiv2025

Corticotropin-releasing hormone in melanoma and non-melanoma skin cancer.

BackgroundCorticotropin-releasing hormone (CRH) is involved in the regulation of immunological and cellular processes. Recently, CRH has been found to be expressed in skin cancers, where its expression appears to correlate with the degree of malignancy. ObjectiveThis study correlates CRH expression in melanoma metastases with patient survival and compares the intensity of CRH expression in melanoma to that in less aggressive skin cancer entities. MethodsTissue microarrays with cores from 94 melanomas and 40 melanocytic nevi and 51 slides from 41 basal cell carcinomas (BCC) and 10 squamous cell carcinomas (SCC) were immunohistochemically stained for CRH. The intensity of CRH expression in melanoma metastases was stratified by sex and correlated with patient survival. Furthermore, proliferation and apoptosis were assessed in CRH-stimulated A431 cells using enzyme-linked immunosorbent assays and an apoptosis detection kit. ResultsThe intensity of CRH expression was higher in primary melanomas than in melanocytic nevi. Higher CRH expression was also found in melanoma metastases from women compared to men. However, higher CRH expression was correlated with reduced overall survival only in men. Compared to melanoma, BCCs and SCCs showed weaker CRH expression, which was in line with the finding that in vitro, CRH stimulation of the A431 cells reduced their proliferative activity. ConclusionCRH does not necessarily correlate with the degree of malignancy, as semi-malignant cancers such as BCC show higher levels of CRH expression than SCCs. In melanoma, CRH expression in metastases may be an important prognostic factor for overall survival in men, which needs further evaluation. Statement of contributionMarcel Mueller and Susanne Melchers performed all experiments and wrote the first draft of the manuscript. Iris Mueller helped with the experiments and reviewed the manuscript, Jochen Utikal assembled the tissue microarrays and reviewed the manuscript, Julia Krug helped with the figures and reviewed the manuscript, and Astrid Schmieder designed and supervised the project and corrected the manuscript.

cancer biology↗

bioRxiv2024

Yeast elongation factor homolog New1 protects a subset of mRNAs from degradation by no-go decay

New1 is a homologue of the essential yeast translation elongation factor eEF3. Lack of New1 has previously been shown to induce queueing of ribosomes upstream of the stop codon on mRNAs encoding specific C-terminal amino acids, primarily lysine and arginine. Here, we used UV crosslinking and analysis of cDNA, long-read nanopore sequencing and proteomics to address the open question of what consequences such queues have for the yeast cell. We show that these queues are ribosomal collisions, which are recognized by the collision sensor and E3 ubiquitin ligase Hel2, marking these collided ribosome complexes for mRNA degradation via canonical no-go decay. Decay is initiated by Cue2-mediated cleavage upstream of the stop codon. Ultimately, this leads to downregulation of encoded proteins, including highly abundant and important metabolic enzymes Pgk1 and Gpm1, as well as translation elongation factors eEF1-alpha and eEF1-beta. Collisions and resulting downstream effects are codon-, rather than amino acid dependent. E.g., for C-terminal lysine and arginine, only specific codons induce collisions upon lack of New1. Our study shows that New1 protects highly abundant and essential genes from degradation by no-go decay thatwould otherwise occur in the absence of translation inhibitors or other direct perturbations of translation.

molecular biology↗

bioRxiv2024

A cereblon (CRBN) molecular glue degrader of NIMA-related kinase 7 (NEK7) reveals a context-dependent role in NLRP3 inflammasome activation

The NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome is a cytoplasmic signaling complex that promotes inflammation in response to signals from infection and cellular damage. Increased activation of the NLRP3 inflammasome is linked to numerous diseases including gout, osteoarthritis, cardiovascular disease, neuroinflammatory diseases and cancer, which has prompted the search for therapeutics that can inhibit the NLRP3 pathway. Recent work suggested that NIMA-related kinase 7 (NEK7) may be required for proper assembly and activation of the NLRP3 inflammasome independent of its kinase activity, and that hence reduction of NEK7 protein levels may block NLRP3 activation. Since NEK7 contains a glycine beta hairpin loop structural degron found in many targets of cereblon (CRBN) molecular glue degraders, we used this strategy to degrade NEK7 and inhibit the NLRP3 inflammasome. We identified NK7-902, a CRBN glue degrader of NEK7. NK7-902 potently and selectively degraded NEK7 in human primary monocytes, peripheral blood mononuclear cells (PBMCs) and whole blood. Unexpectedly, full NEK7 degradation led to only partial blockade of NLRP3-dependent interleukin-1{beta} (IL-1{beta}) release in these cells under different stimulation conditions, with the extent of IL-1{beta} inhibition varying greatly across donors. Unlike most CRBN glue degraders, NK7-902 degraded NEK7 in mouse cells and efficiently inhibited NLRP3-dependent IL-1{beta} release in a mouse cryopyrin-associated syndrome (CAPS) model. By contrast, oral administration of NK7-902 in non-human primates led to profound and long lasting NEK7 degradation but only transiently blocked IL-1{beta} production in blood. Collectively, our data suggest that NEK7 is involved but may not be strictly required for NLRP3 activation in primates and humans. HighlightsO_LIIdentification of NK7-902, a CRBN molecular glue degrader of NEK7 C_LIO_LINK7-902 fully degrades NEK7 in human primary monocytes and whole blood but only partially inhibits NLRP3-dependent IL-1{beta} production C_LIO_LIUnlike most CRBN glue degraders, NK7-902 shows activity in murine systems C_LIO_LIIn vivo oral administration of NK7-902 in non-human primates leads to profound and long-lasting NEK7 degradation but only transiently blocks NLRP3 inflammasome activation C_LI

immunology↗

bioRxiv2024

Cortical layer 6b mediates state-dependent changes in brain activity and effects of orexin on waking and sleep

One of the most distinctive features of the mammalian cerebral cortex is its laminar structure. Of all cortical layers, layer 6b (L6b) is by far the least-studied, despite exhibiting direct sensitivity to orexin and having widespread connectivity, suggesting an important role in regulating cortical oscillations and brain state. We performed chronic electroencephalogram (EEG) recordings in mice in which a subset of L6b neurons was conditionally "silenced", during undisturbed conditions, after sleep deprivation (SD), and after intracerebroventricular (ICV) administration of orexin. While the total amount of waking and sleep or the response to SD were not altered, L6b-silenced mice showed a slowing of theta frequency (6-9 Hz) during wake and REM sleep, and a marked reduction of total EEG power, especially in NREM sleep. The infusion of orexin A increased wakefulness in both genotypes, but subsequent levels of EEG slow-wave activity during NREM sleep were lower in L6b-silenced animals in the occipital derivation. In summary, these results demonstrate a role for cortical L6b in state-dependent brain oscillations and in the response to orexinergic neurotransmission. Our findings provide new insights in functions of L6b neurons and could inform the understanding of abnormal regulation of brain states in neurodevelopmental and psychiatric disorders.

neuroscience↗

bioRxiv2024

Inhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4'-fluorouridine

RNA viruses present a constant threat to human health, often with limited options for vaccination or therapy. Notable examples include influenza viruses and coronaviruses, which have pandemic potential. Filo- and henipaviruses cause more limited outbreaks, but with high case fatality rates. All RNA viruses rely on the activity of a virus-encoded RNA-dependent RNA polymerase (RdRp). An antiviral nucleoside analogue, 4'-Fluorouridine (4'-FlU), targets RdRp and diminishes the replication of several RNA viruses, including influenza A virus and SARS-CoV-2, through incorporation into nascent viral RNA and delayed chain termination. However, the effective concentration of 4'-FlU varied among different viruses, raising the need to fortify its efficacy. Here we show that inhibitors of dihydroorotate dehydrogenase (DHODH), an enzyme essential for pyrimidine biosynthesis, can synergistically enhance the antiviral effect of 4'-FlU against influenza A viruses, SARS-CoV-2, henipaviruses, and Ebola virus. Even 4'-FlU-resistant mutant influenza A virus was re-sensitized towards 4'-FlU by DHODH inhibition. The addition of uridine rescued influenza A virus replication, strongly suggesting uridine depletion as a mechanism of this synergy. 4'-FlU was also highly effective against SARS-CoV-2 in a hamster model of COVID. We propose that the impairment of endogenous uridine synthesis by DHODH inhibition enhances the incorporation of 4'-FlU into viral RNAs. This strategy may be broadly applicable to enhance the efficacy of pyrimidine nucleoside analogues for antiviral therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/616778v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@398504org.highwire.dtl.DTLVardef@4befaeorg.highwire.dtl.DTLVardef@1648bbcorg.highwire.dtl.DTLVardef@12169e_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIStrong synergy of DHODH inhibitors with 4'-FlU C_LIO_LIActivity of the combination against previously resistant influenza virus C_LIO_LIBroadly active combination against a diverse set of RNA viruses C_LIO_LISuccessful targets include highly pathogenic Ebola and Nipah viruses C_LI

microbiology↗

bioRxiv2024

microRNA-138-5p suppresses excitatory synaptic strength at the cerebellar input layer

MicroRNAs are small, highly conserved non-coding RNAs that negatively regulate mRNA translation and stability. In the brain, microRNAs contribute to neuronal development, synaptogenesis, and synaptic plasticity. The microRNA 138-5p (miR-138-5p) controls inhibitory synaptic transmission in the hippocampus and is highly expressed in cerebellar excitatory neurons. However, its role in cerebellar synaptic transmission remains unkwown. Here, we investigated excitatory transmission within the cerebellum in mice expressing a sponge construct that sequesters endogenous miR-138-5p. Mossy fiber stimulation-evoked excitatory postsynaptic currents (EPSCs) in granule cells were significantly larger compared with controls. Furthermore, we observed larger miniature EPSC amplitudes, suggesting increased postsynaptic AMPA receptor numbers. High-frequency train stimulations revealed enhanced short-term depression following miR-138-5p downregulation. Together with computational modelling, this suggests a negative regulation of presynaptic release probability. Overall, our results demonstrate that miR-138-5p suppresses synaptic strength through pre- and postsynaptic mechanisms, providing a powerful mechanism for tuning excitatory synaptic input into the cerebellum.

neuroscience↗

bioRxiv2024

Three-photon in vivo imaging of neurons and glia in the medial prefrontal cortex with sub-cellular resolution

The medial prefrontal cortex (mPFC) is important for higher cognitive functions, including working memory, decision making, and emotional control. In vivo recordings of neuronal activity in the mPFC have been achieved via invasive electrical and optical approaches. Here we apply low invasive three-photon in vivo imaging in the mPFC of the mouse at unprecedented depth. Specifically, we measure neuronal and astrocytic Ca2+-transient parameters in awake head-fixed mice up to a depth of 1700 {micro}m. Furthermore, we longitudinally record dendritic spine density (0.41 {+/-}0.07 {micro}m-1) deeper than 1 mm for a week. Using 1650 nm wavelength to excite red fluorescent microglia, we quantify their processes motility (58.9 {+/-}2% turnover rate) at previously unreachable depths (1100 {micro}m). We establish three-photon imaging of the mPFC enabling neuronal and glial recordings with subcellular resolution that will pave the way for novel discoveries in this brain region.

neuroscience↗

bioRxiv2024

A non-catalytic function of a disintegrin and metalloprotease 10 determines hepatic progenitor cell fate

During chronic liver disease, hepatocytes may undergo proliferative arrest, leading to the activation, expansion and differentiation of hepatic progenitor cells (HPCs). Here we observe that expression of A Disintegrin And Metalloprotease (ADAM) 10 is increased in human and murine chronic liver disease correlating with HPC expansion. We report that proteolytic processing of ADAM10 by ADAM9 and generation of an ADAM10 intracellular domain that translocates to the nucleus, rather than ADAM10 enzymatic activity is essential for the regulation of HPC gene expression and differentiation. Genetic loss of ADAM10 in vitro and in vivo enhances stemness gene expression, increases the accumulation of undifferentiated HPCs and promotes the formation of liver fibrosis. Taken together, we demonstrate that a non-catalytic function of ADAM10 is an essential regulator of HPC fate and HPC-driven regeneration. Our data ascribe a non-proteolytic function to ADAM proteases which may be a general concept in adult tissue stem cells.

cell biology↗

bioRxiv2024

Tracing Endometriosis: Coupling deeply phenotyped, single-cell based Endometrial Differences and AI for disease pathology and prediction

Endometriosis, affecting 1 in 9 women, presents treatment and diagnostic challenges. To address these issues, we generated the biggest single-cell atlas of endometrial tissue to date, comprising 466,371 cells from 35 endometriosis and 25 non-endometriosis patients without exogenous hormonal treatment. Detailed analysis reveals significant gene expression changes and altered receptor-ligand interactions present in the endometrium of endometriosis patients, including increased inflammation, adhesion, proliferation, cell survival, and angiogenesis in various cell types. These alterations may enhance endometriosis lesion formation and offer novel therapeutic targets. Using ScaiVision, we developed neural network models predicting endometriosis of varying disease severity (median AUC = 0.83), including an 11-gene signature-based model (median AUC = 0.83) for hypothesis-generation without external validation. In conclusion, our findings illuminate numerous pathway and ligand-receptor changes in the endometrium of endometriosis patients, offering insights into pathophysiology, targets for novel treatments, and diagnostic models for enhanced outcomes in endometriosis management.

molecular biology↗

bioRxiv2024

Pertpy: an end-to-end framework for perturbation analysis

Advances in single-cell technology have enabled the measurement of cell-resolved molecular states across a variety of cell lines and tissues under a plethora of genetic, chemical, environmental, or disease perturbations. Current methods focus on differential comparison or are specific to a particular task in a multi-condition setting with purely statistical perspectives. The quickly growing number, size, and complexity of such studies requires a scalable analysis framework that takes existing biological context into account. Here, we present pertpy, a Python-based modular framework for the analysis of large-scale perturbation single-cell experiments. Pertpy provides access to harmonized perturbation datasets and metadata databases along with numerous fast and user-friendly implementations of both established and novel methods such as automatic metadata annotation or perturbation distances to efficiently analyze perturbation data. As part of the scverse ecosystem, pertpy interoperates with existing libraries for the analysis of single-cell data and is designed to be easily extended.

bioinformatics↗

bioRxiv2024

An orexin-sensitive subpopulation of layer 6 neurons regulates cortical excitability and anxiety behaviour.

Cortical layer 6 (L6) neurons uniquely respond to orexin - a neuropeptide influencing arousal and emotion. We show that Drd1a-Cre+ neurons in the prefrontal cortex are selectively sensitive to orexin and regulate prefrontal network activation in vitro and in vivo. Chronically silencing these neurons impairs orexin-induced prefrontal activation and reduces anxiety-like behaviour, indicating that orexin-responsive L6 neurons modulate emotional states and may be a substrate for anxiety regulation.

neuroscience↗