Biology subjects

Li, A.

Publications and source records attributed to Li, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Memory stabilizes complex ecological systems but delays full restoration

Memory effects--defined as the capacity of system states to exert long-lasting influence on subsequent dynamics--are widely recognized as central features of complex living systems. In ecological systems, however, their consequences for stability and recovery dynamics remain poorly understood. To fill this gap, we develop a general theoretical framework that incorporates memory into the dynamics of species-rich ecological systems with complex interaction structures. Our analyses reveal that memory effects expand the stability domain, enabling systems that would otherwise be unstable to persist following perturbations, particularly in cases where instability involves oscillatory behavior. At the same time, memory can accelerate short-term recovery, allowing systems to return more rapidly toward equilibrium in the early stages after perturbation. These apparent benefits, however, come at a cost: memory effects markedly slow long-term recovery, thereby delaying full restoration, as memory retains the influence of past perturbations and hinders a full return to equilibrium. We further support these results by integrating empirical data into the framework. Together, these results reveal fundamental trade-offs mediated by memory--enhanced stability and faster short-term recovery at the expense of delayed full restoration--highlighting the dual role of memory in shaping resilience in complex ecological systems and, more broadly, complex living systems.

ecology↗

bioRxiv2026

Microglia-derived IL-18 remodels hippocampal plasticity to constrain traumatic fear memory

Post-traumatic stress disorder (PTSD) involves complex neuroimmune-synaptic crosstalk in the hippocampus. Here we show that interleukin-18 (IL-18), an extensively studied pro-inflammatory cytokine, serves a protective role against traumatic fear memory through a microglia-to-neuron signaling axis. Traumatic stress induces sustained upregulation of IL-18 in the hippocampus. Exogenous IL-18 administration attenuates fear memory, whereas blockade of IL-18 signaling exacerbates it. Mechanistically, microglial-derived IL-18 acts on neuronal IL-18R1 to restore stress-impaired synaptic plasticity and reduce perineuronal net density, thereby facilitating structural synaptic remodeling. In addition, IL-18 modulates the synaptic organization of fear memory-encoding engram cells within hippocampal ensembles. Together, these findings redefine IL-18 as a homeostatic regulator of post-trauma hippocampal synaptic function and identify the hippocampal IL-18 pathway as a potential therapeutic target for PTSD.

neuroscience↗

bioRxiv2026

An efficient and stable ascorbate/O2-driven route for L-DOPA synthesis by heme-dependent tyrosine hydroxylase

L-DOPA is a key therapeutic agent for Parkinsons disease, with growing demand due to global population aging. Here we report that heme-dependent tyrosine hydroxylase (TyrH) can utilize an ascorbate/O2 system--as an alternative to H2O2--to synthesize L-DOPA with markedly enhanced operational stability. While exogenous H2O2 rapidly inactivates TyrH within minutes, sodium ascorbate (NaAsc) enables sustained catalysis for up to 24 h, surpassing the H2O2-driven yield after only 30 min. UV-vis spectroscopy confirms that H2O2 readily degrades the heme center, whereas the heme remains intact in the presence of NaAsc. QM/MM simulations reveal that in situ generated H2O2 leads to the active species of Compound I for tyrosine hydroxylation. Through systematic optimization, we establish efficient reaction conditions (40 {micro}M TyrH, 1 mM L-Tyr, 100 mM NaAsc, pH 8.5, 40 {degrees}C), achieving >95% conversion of L-Tyr to L-DOPA within 2 h. This work not only provides a robust and sustainable biocatalytic route for L-DOPA production but also highlights the broader applicability of the ascorbate/O2 pathway in heme-enzyme catalysis.

biochemistry↗

bioRxiv2026

Time-resolved hemodynamic responses to sentence-level speech perception, production, and self-monitoring

Functional magnetic resonance imaging (fMRI) has been widely utilized to explore the neural mechanisms underlying speech processing. However, the intertwining of perception and production that exists in real-world scenarios remains underexplored due to challenges such as gradient noise and head motion artifacts from speaking. Previous research has often employed sparse-sampling designs, pausing image acquisition intermittently to present auditory stimuli or record overt speech. While this approach mitigates some challenges, it cannot capture continuous brain activity during speech processing and does not separate the mixed hemodynamic responses to external and self-generated speech occurring in succession. We overcame these limitations and continuously scanned thirty-one participants as they listened to and recited English sentences. Through independent component analysis (ICA), we decomposed each functional scan into spatially independent components (ICs), identifying task-related ICs in the superior temporal cortex, inferior frontal gyrus, and orofacial sensorimotor cortex. These ICs demonstrated time-resolved hemodynamic responses corresponding to distinct stages of speech perception, planning, and production. A linear subtraction between the IC time courses from the listening-reciting (perception-to-production) and listening (perception-only) tasks further revealed a secondary hemodynamic response to self-generated speech in the superior temporal cortex. Furthermore, we established precise temporal relationships between overt speech output and the peak, rise, and fall of hemodynamic responses for each independent component. Together, we present a methodological framework that can inform future fMRI studies on naturalistic tasks involving the perception of external auditory stimuli and monitoring of self-generated sounds.

neuroscience↗

bioRxiv2026

A Generalization of the Ternary Binding Model to Membrane-Confined Systems with Finite Copy Number

Bispecific T cell engagers and related immunotherapies are dosed using equilibrium binding models derived for well-mixed solution, yet therapeutic activity occurs at nanoscale membrane synapses with finite receptor copy numbers. Here we show that membrane confinement introduces geometry-dependent corrections to the landmark Douglass [6] ternary binding model, shifting formation half-points (TF50) by 2-10-fold at clinically relevant antigen densities. We present two complementary formulations--effective concentration and surface density--that preserve the Douglass framework while explicitly accounting for synapse geometry, surface topology, and the accessibility factor () of surface receptors. We further derive stochastic descriptions of trimer formation via the chemical master equation, demonstrating the recovery of the classical Ternary Binding Model equilibrium in appropriate limits. We illustrate the framework using the CD19-targeting BiTE blinatumomab as a case study. Accounting for microvillus-driven patchy close contact during immune surveillance yields a mechanistic explanation for why higher target antigen density can increase the dose required to achieve a fixed level of ternary formation: in the membrane-confined regime, excess target acts as a local antigen sink that sequesters drug and reduces the free fraction available for productive bridging. Rather than fitting to a single shift value, we emphasize the robust scaling and regime structure predicted by the theory (density-proportional behavior in the sink-dominated limit, and collapse toward affinity-limited behavior outside that limit). The generalized framework provides ready-to-use correction formulas and parameter-estimation guidance, establishing a rigorous foundation for antigen-density-aware dosing strategies in T cell engager pharmacology. Statement of SignificanceBispecific T cell engagers are currently interpreted largely through bulk-solution binding models, but at nanometer-scale immune synapses those models can miss a distinct, decision-relevant regime. We generalize the standard ternary binding model to membrane-confined synapses and relate whole-cell receptor counts to effective concentrations in the contact zone. In a blinatumomab case study, the framework explains a paradoxical observation: increasing target density can shift half-maximal ternary-complex formation to higher doses because abundant antigen acts as a local sink that sequesters drug. These results show when bulk affinity alone is insufficient for potency interpretation and support antigen-density-aware dosing and experiments that distinguish geometric from chemical control.

biophysics↗

bioRxiv2026

The Central Coupler of the AAA+ ATPase ClpXP Controls Intersubunit Communication and Couples the Conversion of Chemical Energy into the Generation of Force

ClpX is a clockwise hexameric helical arrangement that hydrolyzes ATP to unfold proteins and translocate them into the proteolytic chamber. We investigate the central coupler, a three -helix module conserved among AAA+ ATPases, which is proposed to enable intersubunit communication and mechanochemical coupling. Although fundamental in AAA+ ATPases, the molecular mechanism underlying these processes remains elusive in ClpX. By combining single-molecule optical tweezers, biochemical assays and single particle cryo-EM we demonstrate that the central coupler, of the second-highest subunit of the ClpX clockwise helical arrangement, positions its Arginine-finger, sensor-I and sensor-II to contact the ATP of the anticlockwise neighbor subunit to trigger its hydrolysis. Then, the central coupler of the highest subunit rapidly couples the ATP hydrolysis with the downward motion of its substrate-translocating loop, enabling fast force generation to swiftly unfold protein substrates while maximizing the thermodynamic efficiency of the motor.

biophysics↗

bioRxiv2026

End-to-end bimodal anti-counterfeiting by informational DNA nanoparticles

The superior stealth properties and high information density make DNA a sought-after candidate in the field of molecular steganography. Here, we developed the InfinMark end-to-end DNA steganography framework for anti-counterfeiting applications by combining the characteristics of both the Internet of Things (IoT) and DNA-of-Things (DoT). InfinMark includes five modules: Information Transcoding, Fingerprint Writing, Nano-encapsulation, Invisible Marking, and Multi-level Rapid Authentication. It ensures precise anti-counterfeiting information reading and writing through a dynamic DNA-compatible transcoding algorithm, achieves seamless embedding by developing scalable nanoparticle manufacture methods, and supports cross-scenario on-site verification, ultimately granting it comprehensive anti-counterfeiting capabilities spanning from source labeling to terminal tracing. By addressing the bottlenecks in IoT and DoT integration, lifecycle tracking, as well on-site product authentication, this research constructs a full-chain bimodal anti-counterfeiting system, thereby showcasing the practical application of informational DNA nanoparticles in various aspects of production and daily life.

synthetic biology↗

bioRxiv2026

Deep Learning Reveals Persistent Individual Signatures in Bat Echolocation Calls of the Greater Leaf-nosed Bat

Intraspecific variation is a prerequisite for natural selection and can manifest in various phenotypic traits, including vocal signals. However, classifying individuals based on their vocalizations, or acoustic individual identification (AIID), remains a significant challenge. This is particularly true for species that use rapidly varying echolocation calls for orientation. Here, we demonstrate that deep learning can overcome the limitation of traditional methods and reveal persistent individual signatures within bat echolocation calls. We recorded echolocation calls from 34 individuals of the greater leaf-nosed bat (Hipposideros armiger) under controlled laboratory conditions, with 19 individuals recorded repeatedly over three months. We show that a convolutional neural network (CNN) dramatically outperforms a traditional method, achieving an average identification accuracy of 84% for single calls and 91% for call sequences. In contrast, the traditional Discriminant Functional Analysis method achieved accuracies of only 39% and 47%, respectively. Through systematically altering the temporal structure of echolocation calls in input sequences, we found that temporal patterning enhances individual classification accuracy, suggesting it contributes to the encoding of individual-specific information. This study revealed that echolocation calls of H. armiger can contain stable, individual identity that were previously undetectable. Our findings highlight the potential of deep learning for non-invasive AIID and provide a methodological basis for future studies aiming to monitor animals in more dynamic environments.

zoology↗

bioRxiv2026

An Intermediate Mesoderm Premyogenic Niche Supports Early Human Myogenic Lineage Progression

Transient cell states that precede and support human myogenic lineage commitment, and the intrinsic and extrinsic signals that control them, remain poorly defined in vitro. Here, we used longitudinal single-nucleus profiling, together with a SIX1:H2B-GFP hPSC reporter for lineage tracing, resolved previously uncaptured transient intermediates and sequential waves of human myogenesis across differentiation and in vivo. We show that hPSC-directed myogenesis gives rise in parallel to paraxial mesoderm and a transient PAX8+ intermediate mesoderm population that forms a 3-dimensional pre-myogenic niche supporting the PAX3-to-PAX7 myogenic progenitor transition. LIANA+ analysis further identified a temporally restricted BMP7-BMPR1B interaction, together with laminin-linked signaling, between PAX8+ niche cells and skeletal muscle progenitors before commitment. We further show that dynamic SIX1 cofactor switching, including EYA3 activity, is required for PAX3-to-PAX7 progression, and that disruption of this program compromises multi-lineage niche integrity. Together, these findings define how transient niche populations and intrinsic regulatory networks coordinate early human myogenic lineage progression and provide a human in vitro platform to study parallel intermediate and paraxial mesoderm development during myogenesis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/715044v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@189294dorg.highwire.dtl.DTLVardef@1f6b669org.highwire.dtl.DTLVardef@41cc68org.highwire.dtl.DTLVardef@1d2cb42_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISIX1+PAX8+ niche progenitors promote myogenic differentiation via BMP7- and laminin-dependent signaling. C_LIO_LILoss of SIX1-EYA3 activity disrupts the pre-myogenic niche and impairs the PAX3-to-PAX7 transition C_LIO_LIMulti-omics single-cell optimal transport resolves previously uncaptured transient intermediates and sequential waves of human myogenesis C_LIO_LISIX1 lineage tracing identifies CREB5 as a top regulator of the PAX7+ state in human myogenesis C_LI

cell biology↗

bioRxiv2026

Neuronal expression of Retinoid-Related Orphan Receptor Gamma (RORγ) and revisiting its role in the Central Nervous System

Retinoid-related orphan receptor gamma (ROR{gamma}) is a lineage-defining transcription factor for T helper 17 (Th17) cells and has long been considered selectively expressed within the immune system. However, accumulating evidence has implicated Th17 cells and other ROR{gamma}-expressing immune populations in embryonic brain development and central nervous system (CNS) function. Notably, ROR{gamma}-Cre-mediated deletion of the tuberous sclerosis complex (TSC) has been reported to cause spontaneous seizures and premature lethality, leading to the conclusion that ROR{gamma}-expressing immune cells directly regulate CNS physiology. Using multiple ROR{gamma}-based reporter mouse lines, we identified unexpected and widespread neuronal labeling throughout the forebrain and cerebellum. ROR{gamma}-Cre:GFPf/ mice exhibited robust GFP expression in neurons despite the absence of detectable T cells in the brain. Neuronal recombination was evident prenatally and independently validated using the mT/mG reporter line, indicating transient ROR{gamma} expression in embryonic neurons. In contrast, a ROR{gamma}-GFP reporter showed no detectable ROR{gamma} expression in the postnatal brain, either at baseline or following pilocarpine-induced status epilepticus. These findings demonstrate that ROR{gamma} expression is not restricted to the immune lineage and reveal previously unrecognized developmental expression in the embryonic brain. Consequently, seizures observed following ROR{gamma}-Cre-mediated deletion of TSC1 are unlikely to arise from ROR{gamma}-expressing immune cell-dependent mechanisms but instead reflect direct neuronal loss of TSC1. Our results call for careful reinterpretation of prior studies attributing CNS phenotypes to ROR{gamma}-expressing immune cells based on ROR{gamma}-Cre-driven genetic models. SignificanceThis work identifies transient neuronal ROR{gamma} expression as a critical confounder in immune-targeted genetic studies and reveals a previously unrecognized embryonic expression of ROR{gamma} in neurons that may contribute to neurodevelopment. Our findings further raise the possibility that embryonic neurons represent unintended off-targets when deploying therapeutic strategies involving ROR{gamma} ligands.

neuroscience↗

bioRxiv2026

Histone neutralization protects the ischemic brain against stroke-associated pneumonia

Bacterial pneumonia aggravates ischemic stroke via mechanisms that still remain to be determined. In ischemic stroke patients and mice exposed to middle cerebral artery occlusion, we show that stroke-associated pneumonia markedly worsens clinical stroke outcome. In mice, pneumonia induced 3 days after stroke impaired neurological recovery and increased brain neutrophil infiltrates, blood-brain barrier breakdown, cerebral microvascular thrombosis, and progressive brain atrophy. The antibiotic amoxicillin only partially ameliorated pneumonia-associated neurological deficits and neutrophil infiltrates. Neutrophils were critical mediators of pneumonia-induced blood-brain barrier breakdown and microvascular thrombosis. Notably, administration of a neutralizing anti-histone antibody during pneumonia--unlike degradation or blockade of neutrophil extracellular trap formation or myeloperoxidase inhibition--restored long-term neurological recovery and prevented brain atrophy in stroke-associated pneumonia mice. This study identifies extracellular histones as key drivers of secondary inflammatory brain injury and establishes histone neutralization as a therapeutic strategy with an extended treatment window in the post-acute stroke phase. One Sentence SummaryNeutralizing extracellular histones reverses pneumonia-driven secondary brain injury and restores long-term recovery after ischemic stroke.

neuroscience↗

bioRxiv2026

Not all mantra meditations are equal: Emergence of divergent alpha oscillatory dynamics across mantras

The study of contemplative practices has evolved into a mature field, yet current taxonomies tend to classify all mantra-based meditation approaches as a single category, overlooking potentially different neural states induced by different mantras or different instructions. To address this gap, we conducted a study of 50 novice subjects practicing two types of mantra-based meditation over a six week period to evaluate changes in Electroencephalography (EEG) during and after meditation. Participants were randomly assigned to meditating with the Hare Krishna (HK) and Sa-Ta-Na-Ma (SA) mantras. Using spectral parameterization, we assessed the effects of each type of meditation on individual alpha power (IAP), individual alpha frequency (IAF) and center of gravity (CoG). The results revealed marked differences in alpha dynamics between the two practices. On the one hand, the HK group exhibited widespread IAP decrease and an IAF/CoG increase during mantra meditation that was maintained during rest after the meditation, which became more pronounced after training in the HK meditation. On the other hand, the SA group showed a localized IAP reduction during meditation and significant reduction of IAF during meditation after training. We suggest that the higher cognitive demands of HK induce a more activating, attentionally focused state, whereas SA promotes a more relaxed state. Additional psychological data show that both meditation groups had reduction in stress. Thus, these findings challenge the monolithic classification of mantra meditation and highlight the importance of differentiating practices according to their mechanisms, particularly for their targeted application in mental health contexts.

neuroscience↗

bioRxiv2026

Loss of PTPRK in hepatocytes reduces steatosis and carcinogen-induced tumour development in obesity

Protein tyrosine phosphatases are crucial regulators of metabolism with specific roles in different tissues. To investigate hepatocyte-specific function of protein tyrosine phosphatase receptor type K (PTPRK), we generated mice carrying floxed Ptprk alleles and crossed them with Alb-Cre mice (Ptprk{Delta}Hep mice). Under chow feeding, Ptprk{Delta}Hepmice were largely comparable to littermate controls. In contrast, Ptprk{Delta}Hepmice fed a high-fat, high-fructose, high-cholesterol diet exhibited reduced steatosis, lower hepatic PPAR{gamma}, and blunted hepatocyte hypertrophy, accompanied by improved systemic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps. We identified PTPRK-interacting proteins enriched for metabolic functions associated with glycolysis and lipid biosynthesis using pull downs from primary hepatocyte lysates. In line with these findings, Ptprk{Delta}Hep mice developed fewer tumours than controls in an obesity and carcinogen-induced hepatocellular carcinoma (HCC) model. Our data show that under nutrient excess PTPRK is functionally engaged in hepatocytes to support PPAR{gamma}-linked steatotic growth, insulin resistance, and tumour initiation, highlighting PTPRK as a potential therapeutic target in MASLD-associated HCC.

pathology↗

bioRxiv2026

A synaptic locus of song learning

Learning by imitation is the foundation for verbal and musical expression, but its underlying neural basis remains obscure. A juvenile male zebra finch imitates the multisyllabic song of an adult tutor in a process that depends on a song-specialized cortico-basal ganglia circuit, affording a powerful system to identify the synaptic substrates of imitative motor learning. Plasticity at a particular set of cortico-basal ganglia synapses is hypothesized to drive rapid learning-related changes in song before these changes are subsequently consolidated in downstream circuits. Nevertheless, this hypothesis is untested and the synaptic locus where learning initially occurs is unknown. By combining a computational framework to quantify song learning with synapse-specific optogenetic and chemogenetic manipulations within and directly downstream of the cortico-basal ganglia circuit, we identified the specific cortico-basal ganglia synapses that drive the acquisition and expression of rapid vocal changes during juvenile song learning and characterized the hours-long timescale over which these changes consolidate. Furthermore, transiently augmenting postsynaptic activity in the basal ganglia briefly accelerates learning rates and persistently alters song, demonstrating a direct link between basal ganglia activity and rapid learning. These results localize the specific cortico-basal ganglia synapses that enable a juvenile songbird to learn to sing and reveal the circuit logic and behavioral timescales of this imitative learning paradigm.

neuroscience↗

bioRxiv2026

Calcium interaction with Nav1.5 via FGF12A and CaM binding

Voltage-gated Na+ (Nav) channels, including Nav1.5, are responsible for the initiation of cardiac and neuronal action potentials. Regulation of Nav1.5 inactivation is linked to multiple accessory proteins that bind its C-terminal domain (CTD) including calmodulin (CaM) and intracellular fibroblast growth factors (iFGF). Previous results demonstrate that Ca2+-bound CaM preferentially binds to iFGF12A. The role of intracellular Ca2+ ([Ca2+]i) in regulating Nav1.5 gating, either directly or via auxiliary proteins like CaM, is controversial. We hypothesize that CaM binding to the Nav1.5 CTD and iFGF12A synergistically alters channel inactivation in a previously unobserved calcium-dependent manner. We performed Fluorescence Resonance Energy Transfer (FRET) imaging in live cells to observe the interaction between the Nav1.5 alpha subunit, CaM and iFGF12A. At resting [Ca2+]i, a 2-fold difference between acceptor and donor FRET efficiency was observed, implying that a single CaM acceptor is present on the Nav1.5 CTD even in the presence of FGF12A. After increasing [Ca2+]i, the donor and acceptor FRET efficiencies equalize, suggesting a 2:1:1 ratio between CaM, FGF12A, and the Nav1.5 CTD. We then compared the voltage-dependent gating kinetics of Nav1.5 with FGF12A in the presence/absence of calcium. With low [Ca2+]i, the steady-state inactivation of Nav1.5 with FGF12A was significantly shifted toward hyperpolarized potential compared to resting [Ca2+]i. Thus, the FGF12A:CaM complex confers a Ca2+-dependent mechanism enabling FGF12A modulates the Nav1.5 steady-state inactivation. Additionally, the ability of multiple subunits to bring CaM to the Nav1.5 CTD implies biological redundancy to prevent major alteration to Nav1.5 inactivation in the absence of CaM.

biophysics↗

bioRxiv2026

Dopamine Accumulation Dynamics Control Time Perception

Accurate timing is fundamental to perception and behavior, and the dopaminergic system plays a key role. According to the dopamine clock hypothesis, elevated dopamine accelerates the interval clock, while reduced levels slow it. However, optogenetic activation of substantia nigra pars compacta (SNc) dopaminergic neurons paradoxically disrupts this model, suggesting greater complexity. To resolve this paradox, we monitored ventral tegmental area (VTA) dopamine activity in mice performing a time perception task. We observed a ramping-to-threshold pattern, where slower ramping corresponded to longer durations. Optogenetic activation accelerated time estimation, whereas inhibition prolonged it. Systemic dopamine elevation had no effect, but reuptake inhibition accelerated timing. Strikingly, prolonged high dopamine levels slowed time estimation, correlating with slower accumulation due to increased reuptake. Our findings challenge the dopamine clock hypothesis, demonstrating that time perception depends not on absolute dopamine levels but on their temporal accumulation dynamics. This revised framework reconciles previous contradictions and highlights the role of dopamine accumulation rates in temporal cognition.

neuroscience↗

bioRxiv2026

Topoisomerase I inhibition suppresses nuclear blebbing via RNA Pol II stalling and nuclear stiffening

Abnormal nuclear blebbing occurs in many human diseases and causes nuclear rupture and dysfunction. Nuclear blebbing is caused by chromatin motion via RNA Pol II transcriptional activity and nuclear mechanical weakening. Camptothecin, a topoisomerase I inhibitor, rapidly suppresses nuclear blebbing within hours. We find that camptothecin does not decrease RNA Pol II phosphorylation, but does decrease newly synthesized RNA, likely by stalling RNA Pol II. However, camptothecin treatment suppresses nuclear blebbing more drastically than inhibition of transcription activity by alpha amanitin, suggesting a second mechanism of nuclear blebbing suppression. Dual micromanipulation nuclear force measures revealed camptothecin treatment increased chromatin-based nuclear stiffness but not lamin-based strain stiffening. Thus, inhibition of topoisomerase I via camptothecin drastically suppresses nuclear blebbing by both stalling RNA Pol II and increasing chromatin-based nuclear stiffness. Summary statementInhibition of topoisomerase I suppresses nuclear blebbing by stalling RNA Pol II activity and increasing chromatin-based nuclear spring constant.

cell biology↗

bioRxiv2026

A single-cell transcriptomic atlas of the periventricular proliferative zone in the late gestation fetal brain in the pigtail macaque

BackgroundThe fetal brain undergoes rapid changes in late gestation, when waves of neurogenesis and gliogenesis shape cortical circuitry. The periventricular proliferative region and adjacent white matter are enriched in neuroprogenitor cells, newborn neurons, and interneurons, which is challenging to study in the late gestation human fetal brain. The nonhuman primate (NHP) provides a powerful translational model to overcome this limitation, given its close similarity to human neurodevelopmental trajectories. The study objective was to construct a single-cell RNA-Seq (scRNA-Seq) atlas of the late-gestation fetal brain of the pigtail macaque (Macaca nemestrina), focused on the periventricular proliferative zone. MethodsA sample of the lateral ventricular wall, subventricular zone, and overlying white/gray matter was dissociated into single cells and processed through the 10X Genomics pipeline, followed by SoupX removal of ambient RNA, and Seurats pipeline to aggregate, cluster and annotate single-cell populations. Monocle3 was used to determine pseudotime and map lineage progression. ResultsThis analysis captured diverse populations of neuroprogenitors, newborn neurons, developing lineages of excitatory and inhibitory neurons, oligodendrocyte and astrocyte lineages, and resident immune and endothelial cells. ConclusionsSingle-cell populations from the third-trimester nonhuman primate fetal brain are highly similar to those in the human fetus. This late-gestation single-cell atlas of the periventricular proliferative zone provides a unique reference for progenitor, neuronal, glial, vascular, and immune cell states during a critical window of primate neurodevelopment, enabling mechanistic interrogation of how inflammatory, infectious, or hypoxic insults disrupt vulnerable neurogenic niches.

genomics↗