Biology subjects

Tang, Y.

Publications and source records attributed to Tang, Y..

At least 163 records · Page 9Linked to original sources

bioRxiv2024

Single molecule fingerprinting reveals different growth mechanisms in seed amplification assays for different polymorphs of alpha Synuclein fibrils.

Alpha-synuclein (Syn) aggregates, detected in the biofluids of patients with Parkinsons disease, have the ability to catalyze their own aggregation, leading to an increase in the number and size of aggregates. This self-templated amplification is used by newly developed assays to diagnose Parkinsons disease and turned the presence of Syn aggregates into a biomarker of the disease. It has become evident that Syn can form fibrils with slightly different structures, called "strains" or polymorphs, but little is known about their differential reactivity in diagnostic assays. Here we compared the properties of two well-described Syn polymorphs. Using single molecule techniques, we observed that one of the polymorphs had an increased tendency to undergo secondary nucleation and we showed that this could explain the differences of reactivity observed in in vitro seed amplification assay and cellular assays. Simulations and high-resolution microscopy suggest that a 100-fold difference in apparent rate of growth can be generated by a surprisingly low number of secondary nucleation "points" (1 every 2,000 monomers added by elongation). When both strains are present in the same seeded reaction, secondary nucleation displaces proportions dramatically and causes a single strain to dominate the reaction as the major end-product.

neuroscience↗

bioRxiv2024

Single-cell multiomics reveals a gene regulatory circuit promoting leukemia cell differentiation

Cancer differentiation therapy aims to induce maturation of neoplastic cells, yet how cell fate is determined in oncogenic cellular contexts is poorly understood. Here we integrate chromatin accessibility and transcriptome analysis at single-cell levels to investigate the mechanism driving the differentiation trajectory of the PML/RAR+ acute promyeloid leukemia (APL) cell line model, NB4, under the induction of all-trans-retinoid acid (ATRA). We show that differentiating NB4 cells navigate through an intermediate cell fate decision point that leads to either terminal granulopoiesis or a transient immature-lymphocyte-like state. Functional perturbation studies indicate that ATRA signaling activates discrete PML/RAR-target enhancers to induce a positive feedforward gene regulatory circuit involving two myeloid-lineage transcription factors, SPI1 and CEBPE, which is both necessary and sufficient to activate a myelocytic gene expression program in NB4. Further, ectopic expression of SPI1 and CEBPE also promotes myelocytic differentiation in non-APL leukemia cell lines HL60 and K562. Together, these results shed light on the differentiation trajectory of therapy-induced cell decisions of APL and suggest a gene regulatory circuit that may be broadly exploited to promote terminal differentiation of leukemia.

cancer biology↗

bioRxiv2024

Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension

Vascular inflammation critically regulates endothelial cell (EC) pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulation of lysosomal activity and cholesterol metabolism have known inflammatory roles in disease, but their relevance to PAH is unclear. In human pulmonary arterial ECs and in PAH, we found that inflammatory cytokine induction of the nuclear receptor coactivator 7 (NCOA7) both preserved lysosomal acidification and served as a homeostatic brake to constrain EC immunoactivation. Conversely, NCOA7 deficiency promoted lysosomal dysfunction and proinflammatory oxysterol/bile acid generation that, in turn, contributed to EC pathophenotypes. In vivo, mice deficient for Ncoa7 or exposed to the inflammatory bile acid 7-hydroxy-3-oxo-4-cholestenoic acid (7HOCA) displayed worsened PAH. Emphasizing this mechanism in human PAH, an unbiased, metabolome-wide association study (N=2,756) identified a plasma signature of the same NCOA7-dependent oxysterols/bile acids associated with PAH mortality (P<1.1x10-6). Supporting a genetic predisposition to NCOA7 deficiency, in genome-edited, stem cell-derived ECs, the common variant intronic SNP rs11154337 in NCOA7 regulated NCOA7 expression, lysosomal activity, oxysterol/bile acid production, and EC immunoactivation. Correspondingly, SNP rs11154337 was associated with PAH severity via six-minute walk distance and mortality in discovery (N=93, P=0.0250; HR=0.44, 95% CI [0.21-0.90]) and validation (N=630, P=2x10-4; HR=0.49, 95% CI [0.34-0.71]) cohorts. Finally, utilizing computational modeling of small molecule binding to NCOA7, we predicted and synthesized a novel activator of NCOA7 that prevented EC immunoactivation and reversed indices of rodent PAH. In summary, we have established a genetic and metabolic paradigm and a novel therapeutic agent that links lysosomal biology as well as oxysterol and bile acid processes to EC inflammation and PAH pathobiology. This paradigm carries broad implications for diagnostic and therapeutic development in PAH and in other conditions dependent upon acquired and innate immune regulation of vascular disease. One Sentence SummaryPulmonary arterial hypertension pathophenotypes arise from allele-specific NCOA7 regulation of lysosome function and inflammatory oxysterol generation, as demonstrated by genomic and metabolomic association studies coupled with genetic and pharmacologic mechanistic evidence. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/582142v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@896f6forg.highwire.dtl.DTLVardef@f31c2eorg.highwire.dtl.DTLVardef@bf46dcorg.highwire.dtl.DTLVardef@1c55686_HPS_FORMAT_FIGEXP M_FIG Graphical abstract. C_FIG

physiology↗

bioRxiv2024

How Fungi Biosynthesize 3-Nitropropanoic Acid: the Simplest yet Lethal Mycotoxin

We uncovered the biosynthetic pathway of the lethal mycotoxin 3-nitropropanoic acid (3-NPA) from koji mold Aspergillus oryzae through genome mining, genetic inactivation and biochemical characterization. The biosynthetic gene cluster (BGC) of 3-NPA, which encodes an amine oxidase and a decarboxylase, is conserved in many fungi used in food processing, although most of the strains have not been reported to produce 3-NPA. Our discovery will lead to efforts that improve the safety profiles of these indispensable microorganisms in making food, alcoholic beverages, and seasoning.

biochemistry↗

bioRxiv2024

From Sight to Insight: A Multi-task Approach with the Visual Language Decoding Model

Visual neural decoding aims to unlock the mysteries of how the human brain interprets the visual world. While early studies made some progress in decoding visual activity for singular type of information, they failed to concurrently reveal the multi-level interweaving linguistic information in the brain. Here, we developed a novel Visual Language Decoding Model (VLDM) capable of decoding categories, semantic labels, and textual descriptions from visual perceptual activities simultaneously. We selected the large-scale NSD dataset to ensure the efficiency of the decoding model in joint training and evaluation across multiple tasks. For category decoding, we achieved the effective classification of 12 categories with an accuracy of nearly 70%, significantly surpassing the chance level. For label decoding, we attained the precise prediction of 80 specific semantic labels with a 16-fold improvement over the chance level. For text decoding, the scores of the decoded text surpassed the corresponding baseline levels by remarkable margins on six evaluation metrics. This study contributes significantly to extensive applications in multi-layered brain-computer interfaces, potentially leading to more natural and efficient human-computer interaction experiences.

neuroscience↗

bioRxiv2024

UBA1-CDK16: A Sex-Specific Chimeric RNA and Its Role in Immune Sexual Dimorphism

RNA processing mechanisms, such as alternative splicing and RNA editing, have been recognized as critical means to expand the transcriptome. Chimeric RNAs formed by intergenic splicing provide another potential layer of RNA diversification. By analyzing a large set of RNA-Seq data and validating results in over 1,200 blood samples, we identified UBA1-CDK16, a female-specific chimeric transcript. Intriguingly, both parental genes, are expressed in males and females. Mechanistically, UBA1-CDK16 is produced by cis-splicing between the two adjacent X-linked genes, originating from the inactive X chromosome. A female-specific chromatin loop, formed between the junction sites, facilitates the alternative splicing of its readthrough precursor. This unique chimeric transcript exhibits evolutionary conservation, evolving to be female-specific from non-human primates to humans. Furthermore, our investigation reveals that UBA1-CDK16 is enriched in the myeloid lineage and plays a regulatory role in myeloid differentiation. Notably, female COVID-19 patients who tested negative for this chimeric transcript displayed higher counts of neutrophils, highlighting its potential role in disease pathogenesis. These findings support the notion that chimeric RNAs represent a new repertoire of transcripts that can be regulated independently from the parental genes, and a new class of RNA variance with potential implications in sexual dimorphism and immune responses.

genomics↗

bioRxiv2024

Deciphering the molecular mechanism of DNA-protein interactive co-condensates

Nucleic acid and protein co-condensates exhibit diverse morphologies crucial for fundamental cellular processes. Despite their significance, the molecular mechanisms governing morphology transitions remain poorly understood. To address this gap in knowledge, we investigated DNA and the human transcription factor p53 as a model system, specifically focusing on DNA-protein interactive co-condensates (DPICs)--a scenario where neither dsDNA nor the protein demonstrates phase-separation behavior individually. Through a combination of experimental assays and theoretical approaches, we elucidated: (i) the phase diagram of DPICs, identifying two distinct transition phenomena--a phase transition between viscoelastic fluid and viscoelastic solid states, and a morphology transition from droplet-like to "pearl chain"-like DPICs; (ii) the growth dynamics of DPICs. Droplet-like and "pearl chain"-like DPICs, although with dramatically distinct final morphologies and material properties, share a common initial critical microscopic cluster (CMC) size at the nanometer scale during the early stage of phase separation. These findings provide novel insights into the biophysical mechanisms underlying multi-component phase separations within cellular environments. Significance StatementNucleic acids and proteins have the capacity to form co-condensates, exhibiting various morphologies, including droplet-like and "pearl chains" formations. Despite this observation, the underlying biophysical mechanisms remain poorly understood. In this study, we employed DNA and the protein p53 as a model system. Our investigation revealed that the strength of the DNA-p53 interactions dictates the material properties of the co-condensates, leading to a transition from a viscoelastic fluid to a viscoelastic solid phase. This transition is accompanied by a morphological shift from droplet-like formations to structures resembling "pearl chains". Additionally, we explored the growth dynamics of these co-condensates and demonstrated that the strength of p53-DNA interactions influences the relaxation time of the co-condensates, thereby potentially determining their morphological features.

biophysics↗

bioRxiv2024

Human IL-6 fosters long-term engraftment of patient derived disease-driving myeloma cells in immunodeficient mice

Multiple myeloma is a largely incurable and life-threatening malignancy of antibody-secreting plasma cells. An effective and widely available animal model that recapitulates human myeloma and related plasma cell disorders is lacking. We show that busulfan-conditioned hIL-6 transgenic NSG mice (NSG+hIL6) reliably support the engraftment of malignant and pre-malignant human plasma cells including from patients diagnosed with monoclonal gammopathy of undetermined significance, pre- and post-relapse myeloma, plasma cell leukemia, and AL amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells, developed serum M spikes, and a majority developed anemia, hypercalcemia, and/or bone lesions. Single cell RNA sequencing showed non-malignant and malignant cell engraftment, the latter expressing a wide array of mRNAs associated with myeloma cell survival and proliferation. Myeloma engrafted mice given CAR T-cells targeting plasma cells or bortezomib experienced reduced tumor burden. Our results establish NSG+hIL6 mice as an effective patient derived xenograft model for study and preclinical drug development of multiple myeloma and related plasma cell disorders.

cancer biology↗

bioRxiv2023

Aberrant connective tissue sheath contraction drives premature hair follicle regression by inducing progenitor cell depletion in androgenetic alopecia

Androgenetic alopecia (AGA) is characterized by progressive miniaturization of hair, forming a distinctive patterned baldness in the scalp; yet, the mechanisms for hair miniaturization in this disease remain largely unknown. Here by single-cell transcriptome analysis, we describe a concise single-cell atlas, and identify the early changes in cell subpopulations, hair follicle (HF) stem cell fate determination and cell-cell communications in AGA anagen HF units. Thereinto, apoptotic loss of HF progenitor cells is significantly increased, correlated with HF miniaturization in AGA. Mechanistically, enhanced contraction of connective tissue sheath (CTS) activates the mechanosensitive channel PIEZO1, which triggers ectopic apoptosis of progenitor cells in human anagen HFs. Continuous CTS contraction during AGA causes long-term loss of progenitor cells via inducing persistent ectopic apoptosis through PIEZO1, eventually leading to premature hair regression. Most importantly, we show that targeting CTS contraction by ML-7, a selective myosin light chain kinase (MLCK) inhibitor, can obviously improve the growth of HFs from balding scalps of AGA patients. Our study reveals the cellular hierarchies and identifies CTS with increased muscle contraction activity as a driver of premature hair regression in AGA, highlighting CTS surrounding human HF as the therapeutic target for treating this disorder.

pathology↗

bioRxiv2023

Oblique Line Scan Illumination Enables Expansive, Accurate and Sensitive Single Protein Measurements in Solution and in Living Cells

Single-molecule localization microscopy (SMLM) techniques, such as single-molecule tracking (SMT), enable in situ measurements in cells from which data-rich metrics can be extracted. SMT has been successfully applied to a variety of biological questions and model systems, aiming to unravel the spatiotemporal regulation of molecular mechanisms that govern protein function, downstream pathway effects, and cellular function. While powerful, SMLM often suffers from low throughput and illumination inhomogeneity, along with microscope and user-induced technical biases. Due to technical limitations in scaling SMLM techniques, a tradeoff between spatiotemporal resolution and throughput has been made historically, restricting broad application of these technologies. Here we address these limitations using Oblique Line Scan (OLS), a robust single-objective light-sheet based illumination and detection modality that achieves nanoscale spatial resolution and sub-millisecond temporal resolution across a 250 x 190 m field of view. We demonstrate OLS-enabled SMT on Halo-Tagged proteins in living cells capturing protein motion up to 14 m2 /s. By exploiting the adaptability of the acquisition frame rate and the improved rejection of out of focus light, we extend the utility of OLS beyond cellular compartments with in-solution SMT (isSMT) for single-molecule measurement of ligand-protein interactions and disruption of protein-protein interactions (PPI). We illustrate the versatility of OLS by showcasing two-color SMT, STORM, and single molecule fluorescence recovery after photobleaching (FRAP). OLS expands the range of SMLM applications and paves the way for robust, high-throughput single-molecule investigations of protein dynamics required for drug screening and systems biology studies, both in cells and in solution.

biophysics↗

bioRxiv2023

WRN Inhibition Leads to its Chromatin-Associated Degradation Via the PIAS4-RNF4-p97/VCP Axis

Synthetic lethality, the concept in which the co-occurrence of two genetic events leads to cell death while either single event alone does not, is an attractive strategy for targeted cancer therapies. A recent example of synthetic lethality as a therapeutic paradigm is the observation that cancer cells with high levels of microsatellite instability (MSI-H) are dependent on the Werner (WRN) RecQ helicase for survival. However, the mechanisms that regulate WRN spatiotemporal dynamics are not fully understood. In this study, we used our single molecule tracking (SMT) platform in combination with a recently disclosed WRN inhibitor to gain insights into WRNs dynamic localization within the nuclei of live cancer cells. We observe that WRN inhibition results in the helicase becoming trapped on chromatin, requiring p97/VCP for extraction and shuttling to the proteasome for degradation. Interestingly, this sequence of events resulting in WRN degradation appears to be MSI-H dependent. Using a phenotypic screen, we identify the PIAS4-RNF4 axis as the pathway responsible for WRN degradation and show that co-inhibition of WRN and SUMOylation has an additive toxic effect in MSI-H cells. Taken together, our work elucidates a novel regulatory mechanism for WRN. Gaining a deeper understanding into this regulatory pathway for WRN can aid in the identification of new high value targets for targeted cancer therapies.

molecular biology↗

bioRxiv2023

Cultivation of host-adapted Cryptosporidium parvum and Cryptosporidium hominis using enteroids for cryopreservation of isolates and transcriptomic studies of infection

Cryptosporidium hominis and Cryptosporidium parvum are major causes of severe diarrhea in humans. Comparative studies of them are hampered by the lack of effective cultivation and cryopreservation methods, especially for C. hominis. Here, we described adapted murine enteroids for the cultivation of one C. parvum IId subtype and nonhuman primate-adapted C. hominis Ib, Im, and In subtypes, which allowed the complete development of the pathogens, producing oocysts infectious to mice. Using the system, we developed a novel cryopreservation method for Cryptosporidium isolates. In comparative RNA-seq analyses of C. hominis cultures, the enteroid system generated significantly more transcriptomic responses of both pathogen and host genes than the conventional HCT-8 cell system. In particular, the infection was shown to upregulate PI3K-Akt, Wnt, Ras,TNF, NF-{kappa}B, IL-17, MAPK, and innate immunity signaling pathways and downregulate Wnt and Hippo signaling pathways, host cell metabolism, and parasites in enteroid cultures had significantly higher expression of genes involved in oocyst formation. Therefore, the new culture model provides a valuable tool for comparative studies of the biology of divergent Cryptosporidium species. IMPORTANCE The two dominant species for human cryptosporidiosis, Cryptosporidium hominis and Cryptosporidium parvum, differ significantly in host range and virulence. Up to date, biological studies of Cryptosporidium spp. are almost exclusively done with bovine-adapted IIa subtypes of C. parvum, which is the species with effective laboratory animal models and in vitro cultivation methods. Here, we describe modified procedures for the generation of murine enteroids for successful cultivation of both nonhuman primate-adapted C. hominis subtypes and a C. parvum IId subtype, producing oocysts infective to mice. In addition, we have developed a novel cryopreservation method using the system for long-term storage of Cryptosporidium isolates. RNA-seq analyses of C. hominis cultures indicate that the enteroid culture system generates host and pathogen transcriptomic responses similar to those in natural infection. This new development alleviates a technical bottleneck in cryptosporidiosis research, and provides an example for other difficult-to-culture pathogens of major public health importance.

microbiology↗

bioRxiv2023

Spatially resolved molecular and cellular atlas of the mouse brain

A comprehensive atlas of genes, cell types, and their spatial distribution across a whole mammalian brain is fundamental for understanding function of the brain. Here, using snRNA-seq and Stereo-seq techniques, we generated a mouse brain atlas with spatial information for 308 cell clusters with single-cell resolution involving over 6 million cells as well as for 29,655 genes. We have identified new astrocyte clusters, and demonstrated that distinct cell clusters exhibit preference for cortical subregions. In addition, we identified 155 genes exhibiting regional specificity in the brainstem, and 513 long non-coding RNA exhibited regional specificity in the adult brain. Parcellation of brain regions based on spatial transcriptomic information showed large overlap with that by traditional method. Furthermore, we have uncovered 411 transcription factor regulons with spatiotemporal specificity during development. Thus, our study has discovered genes and regulon with spatiotemporal specificity, and provided a high-resolution spatial transcriptomic atlas of the mouse brain.

neuroscience↗

bioRxiv2023

Xanthomonas euvesicatoria effector XeAvrRxo1 triggers a Rxo1-mediated defense response in Nicotiana benthamiana and its chaperone Xe4429 functions as an antitoxin, an expression repressor, and an enhancer of XeAvrRxo1 secretion

Xanthomonas euvesicatoria (X. euvesicatoria) is the causal agent of bacterial spot disease that threatens pepper and tomato production around the globe. X. euvesicatoria gene Xe4428 encodes a type III effector (T3E) that shares 89.67% amino acid identity with Xanthomonas oryzae pv. oryzicola (Xoc) T3E AvrRxo1. Deletion of Xe4428 in the genome of X. euvesicatoria (strain Xcv85-10) compromised its virulence to infect pepper and Nicotiana benthamiana plants. Transient co-expression of Xe4428 and Rxo1 on pepper and N. benthamiana plant leaves results in a robust hypersensitive reaction. Thus, Xe4428, renamed as XeAvrRxo1, is a bona fide orthologue of XocAvrRxo1 that possesses both virulence and avirulence functions. Expression of XeAvrRxo1 in E. coli and X. euvesicatoria is toxic to both bacterial cells. Another X. euvesicatoria gene Xe4429, encodes a putative chaperone of XeAvrRxo1, which can interact with XeAvrRxo1 to suppress its toxicity in X. euvesicatoria and E. coli bacterial cells. Xe4429 also binds to the promoter region of XeavrRxo1 and represses its transcription/translation in X. euvesicatoria bacterial cells. In addition, expression of Xe4429 can enhance the secretion and translocation of XeAvrRxo1 into plant cells. Therefore, Xe4429 functions as an antitoxin, a transcription repressor, and a type III chaperone that is capable of enhancing the secretion and translocation of XeAvrRxo1 during pathogenesis.

pathology↗

bioRxiv2023

In-bore MRI-compatible Transrectal Ultrasound and Photoacoustic Imaging

Prostate cancer (PCa) is known as one of the most prevalent and fatal cancer types. This report describes an MRI-compatible photoacoustic/ultrasound (PA/US) imaging platform to improve the diagnosis of PCa. In the proposed solution, PA imaging, which offers real-time, non-ionizing imaging with high sensitivity and specificity, is combined with MRI, aiming to overcome PAs limited field of view (FOV) and make PA scalable for translation to clinical settings. Central to the design of the system is a reflector-based transrectal probing mechanism composed of MRI-compatible materials. The linear transducer with a center hole for optical fiber delivery can be mechanically actuated to form a multi-angled scan, allowing PA/US imaging from varied cross-sectional views. Performance assessment was carried out in phantom and ex-vivo settings. We confirmed the MRI compatibility of the system and demonstrated the feasibility of its tri-modal imaging capability by visualizing a tubing phantom containing contrast agents. The ex-vivo evaluation of targeted tumor imaging capability was performed with a mouse liver sample expressing PSMA-positive tumors, affirming the systems compatibility in spectroscopic PA (sPA) imaging with biological tissue. These results support the feasibility of the in-bore MRI-compatible transrectal PA and US and the potential clinical adaptability.

bioengineering↗

bioRxiv2023

Obesity status and its relative factors of captive Asian elephants (Elephas maximus) in China based on body condition assessment

Obesity is a common health problem in captive wildlife. Since the obesity status of captive Asian elephants (Elephas maximus) in China has not previously been investigated, we recorded seven relevant variables (sex, age, daily feed supply, proportion of high-calorie feed, outdoor enclosure area, outdoor time, and foot disorder) related to obesity in 204 captive Asian elephants through field investigation of 43 elephant-raising facilities. Assessment of obesity was based on visual body condition scoring for each individual. It revealed that obesity was prevalent for captive Asian elephants (especially elephants in zoos) in China. Over 70% of captive Asian elephants in China were overweight or in obesity to various degrees. Statistical analysis showed that for elephants in zoos, insufficient outdoor time might be the primary potential cause of obesity. We suggested facilities to extend the outdoor time and control the supply of high-calorie feed (e.g., fruits, vegetables, pellets, etc.) for captive elephants, thereby alleviating obesity through increased exercise and a suitable energy intake. Moreover, all facilities should implement positive reinforcement training to facilitate regular physical examinations, including foot health checks and blood sampling. This training would improve the ability to collect more precise information relating to elephant health, obesity, and the evaluation of animal welfare.

zoology↗

bioRxiv2023

Evidence for impaired hippocampal circuitry in schizophrenia and its link to memory dysfunction

Pattern separation and pattern completion are opposing yet complementary components of mnemonic processing that heavily rely on the hippocampus. It has been shown that processing within the dentate gyrus (DG) subfield promotes pattern separation while operations within the CA3 subfield are important for pattern completion. Schizophrenia has been associated with anatomical and functional hippocampal abnormalities, including within the DG and CA3. We hypothesized that an impairment in hippocampal circuitry in individuals with first-episode schizophrenia leads to deficits in pattern separation (mnemonic discrimination) and pattern completion (recognition memory), that these deficits contribute to delusions, and that antipsychotic treatment improves circuit functioning. We measured behavioral and neural responses during the identification of new, repeated, and similar stimuli using high-resolution fMRI in 45 medication-free or minimally-treated patients with first-episode schizophrenia and 49 matched controls. We found recognition memory and pattern separation deficits in patients and a negative association between memory performance and the severity of delusions. Neural analyses revealed deficits in both univariate BOLD responses and multivariate patterns in the hippocampus during mnemonic discrimination in patients compared to controls. Importantly, by investigating the association between trial-level neural activity and behavior before and after treatment, we found that antipsychotics normalized DG activity during pattern separation and CA3 activity during pattern completion. Lastly, trial-level cortical responses during mnemonic discrimination predicted performance in patients at baseline, suggesting a compensatory role. This study provides new insight into the impact of schizophrenia and antipsychotic treatment on memory systems and uncovers systems-level contributions to pattern separation and pattern completion.

neuroscience↗

bioRxiv2023

Social buffering switches fear to safety encoding by oxytocin recruitment of central amygdala "buffer neurons"

The presence of a companion can reduce fear, but the precise neural mechanisms underlying this social buffering of fear (SBF) are incompletely known. We studied SBF encoding in the amygdala of rats that were fear-conditioned (FC) to auditory conditioned stimuli (CS). Pharmacological, opto,- and/or chemogenetic interventions showed that oxytocin (OT) signaling from hypothalamus-to-central amygdala (CeA) projections was required for acute fear reduction in the presence, and SBF retention 24h later in the absence of the companion. Single-unit recordings with optetrodes revealed fear-encoding CeA neurons (characterized by increased CS responses after FC) were inhibited by SBF and blue light (BL) stimulation of OTergic projections. Other CeA neurons developed CS responses only after SBF that persisted during SBF retention. Their baseline activity was enhanced by BL and exposure to the companion. SBF thus switches the CS from encoding "fear" to "safety" by OT-mediated recruitment of a distinct group of CeA "buffer neurons".

neuroscience↗