Biology subjects

Li, X.-N.

Publications and source records attributed to Li, X.-N..

8 recordsLinked to original sources

bioRxiv2026

A thalamostriatal brake counteracts cortical recruitment of striatal ensembles in levodopa-induced dyskinesia

Levodopa-induced dyskinesia (LID) is a disabling complication of Parkinsons disease therapy, yet how upstream circuits recruit and restrain dyskinesia-linked striatal ensembles remains unclear. Using FosTRAP-based ensemble access in a unilateral 6-hydroxydopamine mouse model, we identified secondary motor cortex (M2) and parafascicular thalamus (PF) as dominant afferents with opposing functions. Projection-wide M2 activation promoted dyskinesia, whereas PF activation suppressed ongoing dyskinesia and shifted behavior toward non-dyskinetic states. Chronic levodopa reduced overall presynaptic terminal abundance while preserving putative contacts onto ensemble neurons, thereby increasing effective pathway-to-ensemble coupling. This remodeling followed distinct pathway rules: M2 contacts became spatially dispersed and biased toward NMDAR-mediated excitation, whereas PF inputs recruited stronger polysynaptic inhibition. Dyskinesia preferentially re-engaged ensemble-projecting M2 neurons, but reactivated PF neurons were topographically segregated from PF neurons directly innervating the ensemble. Accordingly, selective M2-to-ensemble stimulation promoted dyskinesia, whereas selective PF-to-ensemble stimulation was ineffective. Finally, ensemble-restricted Grin1 knockdown reduced peak dyskinesia and weakened M2-driven dyskinesia. These findings define LID as a targetable imbalance between cortical ensemble recruitment and thalamostriatal restraint.

neuroscience↗

bioRxiv2026

Microglial pruning of extinction-ensemble synapses preserves fear memory

Fear extinction suppresses learned fear without erasing the original memory, yet how competing fear and extinction ensembles are selectively updated remains unknown. Here, we show that microglia preserve fear memory by selectively editing extinction-ensemble synapses during retrieval. In medial prefrontal cortex, microglial processes, but not somata, expand, ramify, and tighten their engagement with extinction-ensemble dendrites and spines, where they preferentially engulf excitatory postsynaptic material and bias spine remodeling toward elimination. This selectivity is instructed by local find-me, eat-me, and dont-eat-me cues: purinergic signaling recruits microglial processes, phosphatidylserine exposure licenses engulfment of extinction-ensemble synapses, and CD47-SIRP protects fear ensembles from removal. Weakening microglial recruitment or engulfment, or removing this protection, accelerates extinction without impairing fear acquisition. These findings identify microglial processes as active gatekeepers of ensemble competition and reveal a neuroimmune mechanism that preserves fear memory by limiting extinction. In BriefDuring memory updating, microglial processes selectively engage extinction-ensemble synapses rather than globally pruning active circuits. Local recruitment, engulfment, and protection cues determine this choice, allowing microglia to preserve fear memory by limiting extinction. HighlightsO_LIExtinction retrieval selectively recruits microglial processes to extinction ensembles. C_LIO_LIMicroglia preferentially engulf excitatory postsynaptic material from extinction ensembles. C_LIO_LILocal "find-me," "eat-me," and "dont-eat-me" cues determine synapse selection. C_LIO_LIDisrupting microglial pruning facilitates extinction without impairing fear learning. C_LI

neuroscience↗

bioRxiv2026

Ancestral Musaceae karyotype reconstruction provides insights into chromosome evolution and bract coloration

The banana family (Musaceae) exhibits remarkable diversity in both karyotype structure and bract coloration, yet the evolutionary dynamics of chromosomes and the genomic and regulatory basis underlying color diversification remain poorly understood. Here, we present a telomere-to-telomere (T2T), gap-free genome assembly of Musa exotica, an ornamental species with brightly colored bracts occupying an early-branching lineage within sect. Callimusa (Musa L.). By integrating this high-quality genome with other available Musaceae genomes, we reconstruct the ancestral Musaceae karyotype (AMK) for the first time, inferring a haploid chromosome number of n = 17. Comparative genomic analyses reveal recurrent, highly complex lineage-specific inter-chromosome rearrangements across extant Musaceae lineages, leading to inferred stepwise reductions in chromosome number to n = 11, 10, and 9. Notably, closely related species share similar rearrangement patterns, suggesting conserved evolutionary trajectories shaped by lineage-specific structural remodeling. Strikingly, rearrangement-associated regions are enriched for functionally important genes, particularly structural genes (CHS and F3H) and regulatory transcription factors (MYB and bHLH) involved in the anthocyanin biosynthesis pathway. Integrative transcriptomic and regulatory analyses further demonstrate coordinated activation of anthocyanin biosynthetic genes (CHS, CHI, F3'5'H, and ANS) in bracts, with expression divergence largely decoupled from gene dosage and predominantly driven by transcriptional regulation. Co-expression analyses reveal extensive MYB- and bHLH-enzyme interactions, underscoring their central role in modulating pathway activity and bract coloration diversity. Collectively, our findings suggest a link between genome structural evolution to trait diversification, offering a refined framework for understanding genome evolution and phenotypic diversification in Musaceae and other monocots. SignificanceWe reconstructed the ancestral Musaceae karyotype and revealed extensive lineage-specific chromosome rearrangements underlying karyotype evolution. Rearrangement-associated regions are enriched for anthocyanin biosynthetic and regulatory genes, suggesting that genome structural evolution may have contributed to bract coloration diversification in Musaceae. Integrative transcriptomic analyses further indicate that variation in anthocyanin-mediated bract coloration is more closely associated with transcriptional regulation than with gene dosage alone.

evolutionary biology↗

bioRxiv2024

An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits

Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

neuroscience↗

bioRxiv2023

ALS-causing SOD1 mutations H46R and G85R form similar novel amyloid fibril structures and promote ferroptosis in cells

More than two hundred genetic mutations of Cu, Zn-superoxide dismutase (SOD1) have been identified in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the selective death of motor neurons through ferroptosis. Two ALS-causing SOD1 mutations, H46R and G85R, are metal-binding region mutants with reduced affinity for metal ions. Here, we generated amyloid fibrils from the apo forms of H46R and G85R under reducing conditions and determined their structures using cryo-EM. We built models for the fibril cores, comprising residues 85-153 for H46R and 82-153 for G85R. These mutations disrupt crucial interactions in the wild-type SOD1 fibril, resulting in amyloid fibrils with distinct structures compared to the wild-type fibril. Remarkably, H46R and G85R form similar novel amyloid fibril structures. The fibril cores display a serpentine fold containing seven or eight {beta}-strands, which are stabilized by a hydrophobic cavity. In the G85R fibril core, Arg85 and Asp101 form a salt bridge for stabilization. We demonstrate that fibril seeds from H46R and G85R cause more severe mitochondrial impairment and significantly promote ferroptosis in neuronal cells, compared with those from wild-type SOD1. Our findings reveal how different SOD1 mutations can result in similar amyloid fibril structures and contribute to ALS pathology.

biochemistry↗

bioRxiv2021

Familial prion disease-related mutation E196K displays a novel amyloid fibril structure revealed by cryo-EM

Prion diseases are caused by the conformational conversion of prion protein (PrP) from its cellular form (PrPC) into a protease-resistant, aggregated form (PrPSc). 42 different familial mutations were identified in human PrP, which lead to genetic prion diseases with distinct clinical syndromes. Here we report cryo-EM structure of an amyloid fibril formed by full-length human PrP with E196K mutation, a familial Creutzfeldt-Jakob disease-related mutation. This mutation disrupts key interactions in wild-type PrP fibril and results in a rearrangement of the overall structure, forming an amyloid fibril with a conformation distinct from wild-type PrP fibril. The E196K fibril consists of two protofibrils intertwined into a left-handed helix. Each subunit forms five {beta}-strands stabilized by a disulfide bond and an unusual hydrophilic cavity. Two pairs of amino acids (Lys194 and Glu207; Lys196 and Glu200) from opposing subunits form four salt bridges to stabilize the zigzag interface of the two protofibrils. Furthermore, the E196K fibril exhibits a significantly lower conformational stability and protease resistance activity than the wild-type fibril. Our results provide direct structural evidences of the diverse mammalian prion strains and fibril polymorphism of PrP, and highlight the importance of familial mutations in determining the different prion strains.

biochemistry↗

bioRxiv2020

C11orf95-RELA Reprograms 3D Epigenome in Supratentorial Ependymoma

Supratentorial ependymoma (ST-EPN) is a type of malignant brain tumor mainly seen in children. Since 2014, it has been known that an intrachromosomal fusion C11orf95-RELA is an oncogenic driver in ST-EPN1 but the molecular mechanisms of oncogenesis are unclear. Here we show that the C11orf95 component of the fusion protein dictates DNA binding activity while the RELA component is required for driving the expression of ependymoma-associated genes. Epigenomic characterizations using ChIP-seq and HiChIP approaches reveal that C11orf95-RELA modulates chromatin states and mediates chromatin interactions, leading to transcriptional reprogramming in ependymoma cells. Our findings provide important characterization of the molecular underpinning of C11orf95-RELA fusion and shed light on potential therapeutic targets for C11orf95-RELA subtype ependymoma.

cancer biology↗

bioRxiv2020

LiBis: An ultrasensitive alignment method for low-input bisulfite sequencing

The cell-free DNA (cfDNA) methylation profile in liquid biopsies has been utilized to diagnose early-stage disease and estimate therapy response. However, in typical clinical settings, only very small amounts of cfDNA can be purified. Whole-genome bisulfite sequencing (WGBS) is the gold standard to measure DNA methylation; however, WGBS using small amounts of fragmented DNA introduces a critical challenge for data analysis, namely a low mapping ratio. This, in turn, generates low sequencing depth and low coverage for CpG sites genome wide. The lack of informative CpGs has become a bottleneck for the clinical application of cfDNA-based WGBS assays. Hence, we developed LiBis (Low-input Bisulfite Sequencing), a novel method for low-input WGBS data alignment. By dynamically clipping initially unmapped reads and remapping clipped fragments, we judiciously rescued those reads and uniquely aligned them to the genome. By substantially increasing the mapping ratio by up to 88%, LiBis dramatically improved the number of informative CpGs and the precision in quantifying the methylation status of individual CpG sites. The high sensitivity and cost effectiveness afforded by LiBis for low-input samples will allow the discovery of genetic and epigenetic features suitable for downstream analysis and biomarker identification using liquid biopsy.Competing Interest StatementThe authors have declared no competing interest.List of AbbreviationsLiBislow-input bisulfite sequencing alignmentcfDNAcell-free DNAWGBSwhole-genome bisulfite sequencingCpGcytosine nucleotide followed by a guanine nucleotidectDNAcirculating tumor DNAHTMLHyperText Markup LanguageHPVHuman papillomavirusView Full Text

bioinformatics↗