Biology subjects

Zhao, Y.

Publications and source records attributed to Zhao, Y..

At least 217 records · Page 12Linked to original sources

bioRxiv2025

Differential controls of forelimb versus whole-body movements by striatum

Spikes in the dorsolateral striatum (DLS) of the basal ganglia correlate with forelimb and whole-body movements, but the extent to which they contribute to movement remains unclear. Using behavior-timed optogenetic inhibition in rats performing a lever-release task, we found that DLS inhibition delayed the initiation of forelimb reaching and conditioned lever release and, when delivered during reaching, interrupted execution. Inhibition during reward retrieval impaired locomotion, especially turning, reducing movement speed and resulting in less efficient trajectories. By contrast, inhibition before the nose poke that triggered reward delivery had little effect, despite substantial DLS activity at the nose poke. These effects were accompanied by bidirectional changes in firing rates in the substantia nigra pars reticulata, a basal ganglia output nucleus, and were much weaker when the dorsomedial striatum was perturbed. Together, these findings suggest that expression of many, but not all, learned movement patterns depends continuously on DLS activity. TeaserBriefly silencing striatal neurons during behavior reveals that the dorsolateral striatum helps initiate and control the execution of forelimb and whole-body movements in rats.

neuroscience↗

bioRxiv2025

A Study on the Pharmacokinetic/Pharmacodynamic Profiles of the Novel PPAR Pan Agonist Chiglitazar Sodium in Rats with Hypoalbuminemia

ObjectiveTo compare the changes in the pharmacokinetic/pharmacodynamic (PK/PD) profiles of Chiglitazar Sodium between healthy rats and those with hypoalbuminemia, and to evaluate the medication safety of Chiglitazar in rats with hypoalbuminemia. MethodsLiquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) method was employed to determine the plasma concentration ofChiglitazar Sodium in both healthy rats and rats with hypoalbuminemia after administration. Pharmacokinetics were calculated based on the measured data. Blood glucose levels were monitored and recorded in both groups to observe pharmacodynamic changes. ResultsPharmacokinetic analysis revealed that, compared to the healthy group, only the Tmax in the hypoalbuminemia group was significantly earlier by 34.3% (P<0.001), while other pharmacokinetic parameters showed no significant differences. Pharmacodynamic studies indicated that blood glucose levels remained stable in both healthy rats and rats with hypoalbuminemia during the 0.25-10 hour monitoring period. ConclusionExcept for Tmax, there were no significant differences in PK/PD parameters between rats with hypoalbuminemia and healthy rats. Blood glucose levels remained stable in both groups after oral administration of Chiglitazar Sodium. The animal experimental results suggest that, under normal conditions, hypoalbuminemia does not affect the pharmacokinetic and pharmacodynamic profiles of Chiglitazar Sodium.

pharmacology and toxicology↗

bioRxiv2025

Language may be all omics needs: Harmonizing multimodal data for omics understanding with CellHermes

Decoding cellular systems requires integrating diverse omics data, yet most models are trained from scratch on a single modality, restricting generalization. Here we present CellHermes, a biological language model that leverages pretrained large language models (LLMs) to integrate multimodal forms of omics data, such as transcriptomic profile and PPI network, through natural language for better omics understanding. By reformulating these datasets into question-answer pairs, CellHermes emulates multiple self-supervised learning paradigms within a single, universal, language-based framework with LORA fine-tuning on existing natural language-LLM, achieving comparable or even better performance compared to current single-cell foundation models. Within this framework, CellHermes functions as an encoder, a predictor and an explainer for supporting a range of downstream tasks. For encoder, CellHermes encodes biological entities with embeddings that enable accurate network discovery and cross-dataset generalization; For predictor, CellHermes unifies heterogeneous downstream tasks by translating them into natural language question-answers pairs, allowing a single model to perform multi-task prediction by instruction fine-tuning; For explainer, CellHermes explains molecular mechanisms by combining attention analysis with text-based reasoning, leveraging the interpretability and reasoning capabilities of LLMs. We evaluated the ability of CellHermes as an encoder on representing genes and cells using 5 gene-level downstream tasks and 5 diverse single-cell datasets across different tissues compared with other single cell foundation models. We also evaluated CellHermes as a predictor on BioUniBench, a new benchmark of 10 tasks across 7 databases for LLMs, including perturbation response, cell fitness estimation, gene-disease association, and cell type identification. All benchmarks suggest CellHermes can unify multiple biological tasks within one model without compromising performance. By applying CellHermes as an explainer for a melanoma patients dataset, it can uncover potential key genes on tumor-reactive T cells. Together, CellHermes establishes natural language as a unifying medium for omics, offering a foundation that, in the future, potentially enables a more integrated and interpretable research loop of biological representation, prediction, and interpretability.

bioinformatics↗

bioRxiv2025

A comprehensive view of somatic mosaicism by single-cell DNA analysis

Single-cell DNA sequencing offers a powerful means of studying somatic mosaicism but requires careful analysis to mitigate DNA amplification-related artifacts. We performed primary template-directed amplification (PTA) and sequencing of 102 nuclei from postmortem lung and colon tissues of a 74-year-old male. Single-cell mutation burdens and spectra were validated by duplex sequencing and revealed heterogeneity across organs and cells, including signatures of APOBEC activity and tobacco exposure. Cells from both tissues exhibited chromosomal aneuploidies, loss of chromosome Y, and chromosomal rearrangements including rearrangements of the T-cell receptor loci indicative of T-cells. Shared embryonic mutations between cells enabled reconstruction of cellular ancestries from the zygote, which were validated by bulk sequencing. Collectively, we demonstrate a comprehensive approach for single-cell genomics that yields an expansive view of diverse somatic mutation types from development through aging across diverse tissues--insights that are obscured in bulk sequencing and only partially captured by other single-cell methods.

genomics↗

bioRxiv2025

Sensory receptor expansion and neural accommodation in butterfly color vision

The evolution of complex brains required existing neurons and neural circuits to accommodate new inputs. The genetic and developmental mechanisms that enable such integration are largely unknown. Butterflies evolved more complex retinal mosaics through the addition of a second R7 color photoreceptor per ommatidium (unit eye). In Drosophila, the unique R7 makes a stochastic choice to express one of two opsin genes. In butterflies, the two R7s make independent stochastic cell fate choices in each ommatidium, producing three ommatidial types instead of two. Here, we investigate the developmental basis of this change and how the butterfly brain accommodates expanded sensory receptor input. We first identified the changes in gene expression that cause a second R7 cell to be specified. We then modified Drosophila retinas to have butterfly-like transcription factor expression, causing recruitment of an additional R7. The two R7s make independent stochastic choices, like butterflies, leading to three stochastically distributed ommatidial types. In Drosophila, the two R7 subtypes connect to their target neurons, either yDm8 or pDm8. Dm8 neurons of both types are born in excess and Dm8s that do not find connections with their cognate y or pR7s undergo apoptosis. In the presence of extra R7s in butterfly-like fly retinas, additional Dm8s are retained, leading to two Dm8s per medulla column that make appropriate connections with the matching R7 subtypes, facilitating the expansion of color vision. We propose that the presence of cells that would otherwise die provide developmental flexibility that can allow brains to accommodate newly evolved inputs.

developmental biology↗

bioRxiv2025

Structural and Functional Insights into Alkaline-pH Sensing by the Alka Channel

The ability to detect environmental pH is essential for survival. In Drosophila melanogaster, the taste receptor Alka mediates alkaline food sensing, but the structural and functional mechanisms of Alka-mediated high-pH sensation have remained unclear. Here, we report the cryo-electron microscopy structure of Alka at near-atomic resolution. Alka assembles into a homopentamer and undergoes conformational changes between neutral and alkaline pH conditions. At nearly neutral conditions, a lysine residue (K229) in the channel activation domain forms a stabilizing salt bridge, maintaining the channel in a closed state. Under alkaline conditions, deprotonation of the K229 side chain disrupts this interaction, resulting in channel opening. Functional studies in heterologous cells and intact flies show that mutation of K229 significantly impairs alkaline pH-dependent Alka activation, demonstrating its essential role in pH sensing. Our findings uncover a previously unrecognized structural mechanism underlying alkaline pH detection and identify a lysine residue as a molecular switch for alkaline pH-mediated channel gating. Moreover, our work establishes hydroxide ions as a distinct class of ion channel ligands and reveals a molecular innovation of chemosensory receptors by which animals broaden their range of chemical senses to detect and avoid strongly alkaline environments.

biophysics↗

bioRxiv2025

Differentially acetylated chitosan oligosaccharides as plant defense elicitors against spider mites

The increasing challenges of pesticide resistance and environmental degradation in modern agriculture require sustainable pest management strategies. This study investigates the efficacy of a specific type of hetero-chitooligosaccharide called DACOS, as a plant defense inducer against the two-spotted spider mite, Tetranychus urticae Koch. DACOS is characterized with 85% deacetylation and an average molecular weight of 1 kDa. In planta bioassays revealed a dose-dependent suppression of mite performance on DACOS-treated leaves of kidney bean seedlings, with peak efficacy occurring at 80 ppm. This concentration reduced mite survival by 30% and fecundity by 59% after six days. In addition to the local effects, mite survival and fecundity were also reduced on untreated leaves of the same seedlings, confirming that the effect of DACOS on plant defense is systemic. Behavioral choice assays revealed that DACOS-treated leaves induced 73% mite repellency. No direct acaricidal effects were observed, which confirms the role of DACOS as a plant defense elicitor. Metabolic profiling revealed enriched pathways (e.g., monoterpenoid biosynthesis and -linolenic acid metabolism) that produce volatile organic compounds with repellent properties. These findings suggest that DACOS is an environmentally friendly biostimulant that can enhance plant defense, bypass pesticide resistance, and promote the sustainability of crop production.

physiology↗

bioRxiv2025

Is the whole more than the sum of its parts? Considering global and local features of the connectome improves prediction of individuals and phenotype

Popular methods for analyzing the brains functional connectome examine statistical associations between pairs of atlas-defined brain regions, viewing the strength of these links as independent values. However, edges within a standard connectivity matrix, i.e., correlations between individual regions or nodes, are not independent. They are part of an interconnected system. Here, we propose that consideration of both independent, linear relationships (as in standard approaches such as linear kernel ridge regression and connectome-based predictive modeling) as well as higher order statistical associations - such as tertiary interactions between matrix components and global features of the matrix space - will enhance identification of meaningful individual differences. To test this, we adopt a geometrically grounded measure of similarity that accounts for higher-order local statistical relationships and global interactions, the Wasserstein metric. Results indicate that considering connectivity matrices as representations of their associated Gaussian distributions significantly improves both identification of individuals based on their connectivity matrices (aka, fingerprinting) and prediction of individual differences in phenotypes such as fluid intelligence and openness to experience. Thus, both pairwise local and global brain connectivity properties encode for meaningful individual differences that relate to phenotypic expressions and should be considered in brain-behavior predictive models.

neuroscience↗

bioRxiv2025

Lymphatics unload VEGFR3 in response to the endothelial stress upon VEGFR2 insufficiency

Vascular endothelial growth factor receptor 2 (VEGFR2) is a key target for regulating the endothelial cell lineage and angiogenesis. It is also expressed by lymphatic endothelial cells (LEC) while its participation in the process of lymphangiogenesis remains inadequately characterized. We show in this study that VEGFR2 is highly expressed in dermal initial lymphatic vessels and valves. The induced deletion of pan-endothelial Vegfr2 at the neonatal stage produced a potent suppression of dermal lymphatic growth, including the thinner lymphatic diameter, the decrease of LEC number and lymphatic valves. Mechanistically, the VEGFR2 insufficiency led to a dramatic decrease of lymphatic VEGFR3, a key regulator mediating signals for lymphatic growth and remodeling. The RNA sequencing analysis revealed that GO terms enriched for the downregulated genes included biological processes related to the EC development while pathways related to the hematopoiesis and immune responses were upregulated in the skin of Vegfr2 mutants compared with the littermate controls. This was further confirmed by the RNA-seq analysis of dermal tissues 48 hours after the endothelial Vegfr2 deletion. Consistently, an inhibitory effect on the dermal lymphatic growth was also observed by targeting Vegfr2 in PROX1+ cells, manifesting a similarly altered transcriptome signature. The alteration of lymphatic gene expression was further validated by the siRNA mediated knockdown of Vegfr2 in primary lymphatic endothelial cells, showing a transcriptional trend of LEC to hematopoietic transition. Findings from this study imply that VEGFR2 is required for the maintenance of endothelial identity and its insufficiency may trigger the alteration of lymphatic transcriptional programs to diminish the VEGFR3-mediated lymphangiogenesis.

developmental biology↗

bioRxiv2025

Single-cell RNA sequencing and large-scale bulk combination with machine learning reveal gastric cancer-related macrophage heterogeneity

BackgroundThe tumor microenvironment (TME) significantly impacts cancer progression and overall patient survival. However, the complexity of tumor cell-TME interactions in gastric cancer (GC) and their underlying molecular basis remain to be systematically elucidated. MethodsWe performed single-cell RNA sequencing (scRNA-seq) on paired tumor and adjacent tissues from 3 treatment-naive GC patients. We conducted an in-depth characterization of the cellular composition and molecular features of the GC TME, with a particular focus on tumor-associated macrophages (TAMs) subsets and their mediated intercellular communication. Investigating the effect of C1q on the polarisation of THP-1 induced macrophages through migration and invasion experiments ResultsTranscriptomic analysis of 56,151 single cells identified a key TAM subset - C1QA{square} TAMs. This subset is characterized by high expression of genes including C1QA, C1QB, C1QC and FN1, exhibiting a distinct M2-like macrophage phenotype. We developed a LASSO-based predictive model, C1Q-LASSO, to accurately stratify patients based on survival outcomes and chemotherapy responses, independently of established prognostic parameters. In vitro functional experiments further confirmed that C1q directly promotes malignant phenotypes in GC cells. Additionally, C1q significantly enhances the malignant progression of gastric cancer induced by M2 macrophages. ConclusionsUtilizing scRNA-seq technology, this study systematically delineated the heterogeneous landscape of the GC immune microenvironment and its complex cellular interaction network at single-cell resolution. We first identified and functionally validated the C1QA{square} TAM subset, demonstrating its association with poor prognosis and pro-tumorigenic functions.

cancer biology↗

bioRxiv2025

Cancer cell-selective ecotopic expression of CD20 as an antigen enables rituximab repurposing for solid tumor immunotherapy

Despite the clinical success of cancer immunotherapies, their efficacy is often compromised by antigen-related problems, including heterogeneity, downregulation, loss, and off-tumor toxicity. To overcome these limitations that challenge the current immunotherapies dependent on native antigens, we here describe a new cancer immunotherapy strategy, which artificially and specifically expresses a clinical validated antigen on variant tumors and thus repurposes clinical antibody drugs to treat cancers not belonging to their indications. To authenticate the strategy, we delivered a CD20 gene under a control of NF-{kappa}B-specific promoter to tumors by adeno-associated virus and then treated them with a CD20 antibody, rituximab. We found that CD20 was selectively expressed in tumors and the followed rituximab treatment activated natural killer (NK) cell to kill cancer cells by antibody-dependent cellular cytotoxicity. We demonstrated that this strategy is effective not only in variant cultivated cancer cells, HCT116 spheroids, and patient-derived organoids of human colorectal cancer, but also in humanized mouse with HCT116 xenograft and immunocompetent mouse with CT26 transplant. The strategy showed high cancer cell specificity in both in vitro and in vivo treatments, leading to high security in animal treatments. This strategy thus creates a new modality of cancer immune-redirection therapy by repurposing the clinical validated both antigen and antibody.

cancer biology↗

bioRxiv2025

ARHGEF17 Deficiency Induces Endothelial Dysfunction and Intracranial Aneurysm Formation via RhoA/ROCK2/MLC Signaling Pathway

BACKGROUNDGenetic susceptibility is a major determinant in intracranial aneurysm (IA) formation and rupture, yet the underlying mechanisms linking genetic variation to vascular dysfunction remain largely unknown. We have identified mutations in ARHGEF17, a guanine nucleotide exchange factor that regulates RhoA activation and cytoskeletal organization, as potential risk variants for IA. Given ARHGEF17s regulatory role in endothelial barrier integrity and actin remodeling, we hypothesized that ARHGEF17 deficiency promotes IA pathogenesis through dysregulation of the RhoA/ROCK2/MLC signaling axis, leading to endothelial dysfunction and vascular wall instability. METHODSCRISPR-Cas9-mediated ARHGEF17 knockout (ARHGEF17-/-) mice and morpholino-based ARHGEF17-deficient zebrafish were established to assess the in vivo vascular effects of ARHGEF17 loss. An intracranial aneurysm model combining elastase injection and deoxycorticosterone acetate (DOCA)-induced hypertension was used to evaluate aneurysm incidence, rupture rate, and survival. Structural remodeling of the Circle of Willis (CoW) was assessed by Victoria Blue, EVG, and Picrosirius Red staining, as well as immunofluorescence for -SMA, OPN, CD31, and inflammatory markers. Complementary in vitro studies were performed in HUVECs using lentiviral ARHGEF17 silencing (three shRNAs of varying efficiency) to examine endothelial proliferation, migration, tube formation, and barrier function (TEER). Activation of RhoA/ROCK2/MLC signaling was quantified by G-LISA and Western blotting. The ROCK inhibitor Y-27632 (10 M) was applied to determine pathway dependence. RESULTSARHGEF17-/- mice exhibited a significantly higher incidence and rupture rate of intracranial aneurysms, accompanied by fragmentation of elastic fibers, loss of collagen organization, vascular smooth muscle cell dedifferentiation, and robust inflammatory activation in the CoW. Zebrafish lacking ARHGEF17 showed frequent intracranial hemorrhage and compromised vascular wall integrity, further confirming ARHGEF17s role in cerebrovascular stability. In ECs, ARHGEF17 knockdown impaired proliferation, migration, tube formation, and barrier integrity in a silencing-efficiency-dependent manner. Mechanistically, ARHGEF17 deficiency activated the RhoA/ROCK2/MLC pathway, leading to increased phosphorylation of MLC and MYPT1 and disorganization of F-actin and junctional proteins. Pharmacological inhibition with Y-27632 restored endothelial function, normalized cytoskeletal structure, and re-established junctional continuity, indicating a ROCK2-dependent mechanism. CONCLUSIONSOur findings establish ARHGEF17 as a critical regulator of cerebrovascular integrity and identify RhoA/ROCK2/MLC mediated cytoskeletal remodeling as the mechanistic link between ARHGEF17 deficiency and aneurysm pathogenesis. Loss of ARHGEF17 compromises endothelial barrier function, triggers vascular inflammation, and promotes aneurysm formation and rupture. Importantly, ROCK inhibition rescues endothelial dysfunction, highlighting the RhoA/ROCK2/MLC axis as a promising therapeutic target for ARHGEF17 mutation-associated intracranial aneurysms.

neuroscience↗

bioRxiv2025

Visuospatial attention exerts opposite modulatory effects on explicit and implicit audiovisual subjective synchrony via the frontoparietal network

Synchronization and integration constitute two essential subprocesses of audiovisual binding, commonly indexed by explicit subjective synchrony (ESS) and implicit subjective synchrony (ISS), respectively. Previous studies have shown that spontaneous fluctuations in visual attention are associated with ESS, and that ESS and ISS are negatively correlated, consistent with the temporal renormalization theory. However, it remains unknown whether controlled manipulations of visuospatial attention can causally modulate ESS and ISS in opposite directions via distinct neural mechanisms. To address this question, we conducted two complementary EEG experiments. In Experiment 1, ESS was assessed using a spatially cued beep-flash synchrony judgment task and the point of subjective simultaneity (PSS). In Experiment 2, ISS was measured using fusion and fission variants of the sound- induced flash illusion, with the peak illusion rate (PIR) as the behavioral index. This dual-paradigm design enabled direct comparison between explicit and implicit synchrony under matched attentional manipulations. Behaviorally, asymmetric allocation of visuospatial attention between auditory- and visual-leading conditions induced opposite shifts in PSS and PIR, specifically in the fusion variant. At the neural level, prestimulus frontal theta oscillations were associated with variations in PSS, whereas bilateral frontotemporal and left posterior beta oscillations were associated with variations in PIR. These results demonstrate that visuospatial attention exerts opposite modulatory effects on ESS and ISS through distinct oscillatory dynamics, providing causal evidence for the temporal renormalization theory and advancing understanding of how attentional control shapes multisensory temporal binding.

animal behavior and cognition↗

bioRxiv2025

Bioinformatic analysis and experimental validation of ursolic acid's effects on Staphylococcus aureus-induced osteomyelitis

Osteomyelitis (OM), particularly methicillin-resistant Staphylococcus aureus (MRSA)-induced OM, remains a serious clinical challenge due to complex pathogenesis and rising antibiotic resistance. This study aimed to elucidate the therapeutic mechanism of ursolic acid (UA) against MRSA- induced OM using integrated network pharmacology, bioinformatics, and experimental validation. Through target prediction and multi-database mining, we identified 57 common targets of UA and OM. ML algorithms, including Least Absolute Shrinkage and Selection Operator (LASSO) and random forest, pinpointed three core genes: Neutrophil Elastase (ELANE), Lactoferrin (LTF), and S100A12. Enrichment analyses revealed significant involvement in neutrophil extracellular trap (NET) formation, inflammatory response, and immune regulation. Molecular docking and dynamics simulations confirmed stable binding between UA and ELANE. In vitro, UA exhibited antibacterial activity against clinical MRSA isolates (MIC = 16-64 g/mL) and showed synergistic effects with Penicillin (FICI = 0.125-0.5). These results demonstrate that UA combats OM through immunomodulation, anti-inflammatory actions, and direct antibacterial activity, providing a foundation for its use as an adjuvant therapy against MRSA-related OM.

microbiology↗

bioRxiv2025

Prolactin links psychological stress to psoriasis via a fibroblast-chemokine pathway

Psoriasis is a chronic inflammatory skin disease that forms a vicious cycle with psychological stress. Whether and how the hypothalamic-pituitary (HP) axis-mediated neuroendocrine system regulates psoriasis remains obscure. Here, we report elevated levels of the pituitary hormone prolactin (PRL) in both psoriasis patients and imiquimod (IMQ)-induced psoriasis mice. Mechanistically, PRL acts on dermal PRLR-expressing fibroblasts to promote the production of the chemokines CCL2 and CCL7, which then recruit monocytes/macrophages into psoriatic lesional skin, thereby activating local IL-17A-producing T cells. Accordingly, pharmacological targeting of PRL signaling inhibits the recruitment of monocytes/macrophages, decreases the frequency of IL-17A-producing T cells, and alleviates IMQ-induced psoriasis in mice. In summary, our results delineate a mechanism by which the neuroendocrine hormone PRL aggravates psoriasis and highlight a potential therapeutic strategy of inhibiting PRL-PRLR signaling, particularly in psoriasis patients experiencing psychological stress.

immunology↗

bioRxiv2025

Single-cell lineage tracing identifies hemogenic endothelial cells in the adult mouse bone marrow

During mouse development, hematopoietic stem and progenitor cells (HSPC) originate from hemogenic endothelial cells (ECs) through a process of endothelial-to-hematopoietic transition. These HSPC are thought to fully sustain adult hematopoiesis. However, it remains unknown whether adult ECs retain hemogenic potential. Here we used in vivo genetic lineage tracking at population and single-cell (sc) levels, scRNA sequencing, and bone marrow transplantation to detect hemogenic ECs in adult mice. We identify and characterize bone marrow-resident, adult Cdh5/VE-Cadherin+ ECs that produce hematopoietic cell-progeny in vitro and in mice. These adult hemogenic ECs and their hematopoietic cell progeny give rise to hematopoietic cells following adoptive transfer into adult mice. Furthermore, blood cells generated from adult and developmental ECs comparably home to peripheral tissues, where they similarly contribute to inflammatory responses. Thus, our results identify previously unrecognized bone marrow-derived adult hemogenic ECs that generate HSPC and functional mature blood cells.

cell biology↗

bioRxiv2025

A Quest for a Histaminergic or Orexinergic Biomarker for Sudden Infant Death Syndrome

AimsThis study aimed to investigate the role of the Hypocretin/Orexin (Ox) and Histamine (HA) systems--two key regulators of wakefulness --in sudden infant death syndrome (SIDS), a condition characterized by impaired arousal responses during sleep. MethodsCerebrospinal fluid (CSF) Ox levels were measured in 61 healthy controls, 70 Sudden Unexpected Death Infants (SUDI) (38 SIDS cases and 32 explained deaths (ED). HA and its metabolite, tele-methylhistamine (t-MeHA), were analysed in an additional 46 SUDI (34 SIDS, 12 ED) and 42 controls. Immunocytochemistry was performed on hypothalamic tissue from 11 SIDS and 13 ED cases to assess the number of Ox and HA neurons, using markers for Orexin-A and histidine decarboxylase (HDC), respectively. ResultsOverall CSF Ox levels did not differ significantly between groups. However, while an age-related decline in Ox levels was observed in controls (0-2 vs. 2-6 months), this pattern was absent in deceased infants, resulting in relatively higher Ox concentrations in the 2-6 month age group. HA and t-MeHA levels were significantly elevated in both SIDS and ED cases, likely due to postmortem release. Immunohistochemical analysis revealed an increased number of Ox-immunoreactive neurons in the rostral and caudal dorsolateral hypothalamus in SIDS cases compared to EDs. No differences were observed in the number or morphology of HA neurons. ConclusionFindings suggest increased Ox activity in SIDS cases, potentially reflecting repeated exposure to stress or hypoxia prior to death. In contrast, HA neurons do not appear to play a role in the pathophysiology of SIDS. Further research is needed to identify more specific biomarkers for assessing SIDS risk.

neuroscience↗

bioRxiv2025

Distinct contributions of anterior and posterior orbitofrontal cortex to outcome-guided behavior

The lateral orbitofrontal cortex (OFC) is critical for flexibly adjusting choices when outcome values change. Anterior and posterior parts of the human lateral OFC differ in cytoarchitecture and connectivity, but whether these subregions make differential contributions to outcome-guided (i.e., goal-directed) behavior remains unclear. Outcome-guided behavior requires (a) representations of stimulus-outcome associations and (b) inferring the current value of options when making decisions. Here, we test whether these two functions are differentially supported by the posterior (pOFC) and anterior (aOFC) parts of the lateral OFC, using transcranial magnetic stimulation (TMS) to selectively disrupt activity in functional networks centered on the pOFC and aOFC during a two-day outcome devaluation task. Participants (n = 48) received pOFC or aOFC network-targeted TMS either on day 1 before learning associations between visual stimuli and sweet or savory food odors, or on day 2 before a meal that selectively devalued one of these outcomes, followed by a choice test. TMS targeting pOFC, but not aOFC, before the meal on day 2 disrupted outcome-guided behavior, as measured by choices of stimuli predicting non-sated rewards in the post-meal choice test. In contrast, TMS targeting aOFC, but not pOFC, before learning on day 1 similarly impaired behavior in the post-meal choice test on day 2. These findings demonstrate that anterior and posterior parts of the lateral OFC make distinct contributions to outcome-guided behavior by supporting learning of stimulus-outcome associations and inferring the current value of options, respectively.

neuroscience↗