Biology subjects

Duque, A.

Publications and source records attributed to Duque, A..

12 recordsLinked to original sources

bioRxiv2026

Loss of calbindin and rise in pT217-tau in aging monkey prefrontal cortical dendrites

INTRODUCTION: Tau pathology in Alzheimers disease preferentially afflicts excitatory neurons in the limbic and association cortices that utilize high levels of calcium signaling to perform cognitive operations. This includes the layer III pyramidal cells in the dorsolateral prefrontal cortex (dlPFC) that subserve higher cognition, which express the calcium-binding protein, calbindin, when young and healthy, but lose calbindin and develop tangles and degenerate in Alzheimers disease (AD). These data suggest that loss of calbindin may be associated with the emergence of tau pathology. However, the relationship between calbindin and early-stage, soluble tau pathology is challenging to study in human brains, as soluble pTau dephosphorylates within 15min postmortem. In contrast, the relationship between calbindin and soluble pT217-tau expression can be studied in aging macaques with naturally-occurring tau pathology, where perfusion fixation is possible to capture phosphorylation state in situ. METHODS: The current study used multiple-label-immunofluorescence to label MAP2-positive dlPFC layer III pyramidal cells for calbindin and pT217-tau in macaque brains across the adult age span (8-34.5yrs). The study employed a semi-automated CellProfiler workflow to identify labeled pyramidal cell dendrites the cellular compartment where tau pathology begins in AD. RESULTS: Calbindin expression decreased with age, while pT217Tau increased with age. Specifically, the ratio of calbindin/pT217-tau within a dendrite decreased with age, and was especially prominent in the aged macaques with long-term inflammatory disorders. DISCUSSION: These data suggest that the loss of calbindin in dendrites with advancing age, and especially with inflammation, contributes to the rise of tau pathology and the risk of AD.

neuroscience↗

bioRxiv2025

Human-specific features of the cerebellum and ZP2-regulated synapse development

Understanding the unique features of the human brain compared to non-human primates has long intrigued humankind. The cerebellum refines motor coordination and cognitive functions, contributing to the evolutionary development of human adaptability and dexterity. To identify shared and divergent features across primates, we conducted single-nucleus transcriptomic and chromatin accessibility profiling of the adult cerebellar cortex in humans, chimpanzees, macaques, and marmosets. We revealed human-specific transcriptomic and regulatory features, particularly those involved in synaptogenesis. Notably, we identified an enrichment of the sperm receptor zona pellucida glycoprotein 2 (ZP2) and its potential interactors, known for their roles in gamete interaction, in human granule cells. Experimental data show that ZP2 expression in human granule cells is induced by pontine mossy fibers, reducing synaptic proteins at pontocerebellar glomerular synapses, and decreasing cerebellar neuron electrophysiological activity. This unexpected co-option of ZP2 in human-specific synapse regulation provides insights into the evolutionary specialization of the human cerebellum.

neuroscience↗

bioRxiv2025

Competing Programs Shape Cortical Sensorimotor-Association Axis Development

The neocortex is organized along a dominant sensorimotor-to-association (S-A) axis, anchored by modality-specific primary sensorimotor areas at one end and transmodal association areas that form distributed networks supporting abstract cognition at the other. The developmental mechanisms shaping this axis remain elusive. Here, we present converging multispecies evidence supporting the Multinodal Induction-Exclusion in Network Development (MIND) model, in which S-A patterning is governed by competing processes of induction and exclusion, driven by opposing transcriptomically-defined identity programs emerging from different nodes. Key molecular and connectional features of association cortices arise through pericentral programs, originating around fronto-temporal poles and partially regulated by retinoic acid. They progress inward toward central territories of the naive neocortex along fronto-temporally polarized trajectories. Central programs are induced through interactions between topographically separated first-order sensorimotor thalamocortical inputs and the neocortex, promoting the formation of primary areas while excluding pericentral programs. Influenced by SATB2 and ZBTB18, these evolutionarily conserved programs compete for the same territory and create spatial compartmentalization of axon guidance, cell-cell adhesion, retinoic acid signaling, synaptogenesis, Wnt signaling, and autism risk genes. Notably, PLXNC1 and SEMA7A exhibit anti-correlated expression and repulsive functions in shaping cortico-cortical connectivity along the S-A axis. These processes of induction and exclusion establish an S-A equilibrium and topography in which primary sensorimotor areas emerge as focal islands within the broader ocean of distributed associative networks. The MIND model provides a unifying framework for understanding experimental, evolutionary, and clinical phenomena, revealing induction and exclusion as antagonistic complementary principles shaping the S-A axis and processing hierarchies.

neuroscience↗

bioRxiv2025

Contrasting patterns of extrasynaptic NMDAR-GluN2B expression in macaque subgenual cingulate and dorsolateral prefrontal cortices

Expression of the N-methyl-D-aspartate receptor, particularly when containing the GluN2B subunit (NMDAR-GluN2B) varies across the prefrontal cortex (PFC). In humans, the subgenual cingulate cortex (SGC) contains among the highest levels of NMDAR-GluN2B expression, while the dorsolateral prefrontal cortex (dlPFC) exhibits a more moderate level of NMDAR-GluN2B expression. NMDAR-GluN2B are commonly associated with ionotropic synaptic function and plasticity, and are essential to the neurotransmission underlying working memory in the macaque dlPFC in the layer III circuits afflicted in schizophrenia. However, NMDAR-GluN2B can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked to neurodegenerative processes. The SGC is an early site of tau pathology in sporadic Alzheimers Disease (sAD), which mirrors its high NMDAR-GluN2B expression. Additionally, the SGC is hyperactive in depression, which is treated with NMDAR antagonists. Given the clinical relevance of NMDAR in the SGC and dlPFC, the current study used immunoelectron microscopy (immunoEM) to quantitatively compare the synaptic and extrasynaptic expression patterns of NMDAR-GluN2B across excitatory and inhibitory neuron dendrites in the rhesus macaque SGC and dlPFC. We found a larger population of extrasynaptic NMDAR-GluN2B in dendritic shafts and spines of putative pyramidal neurons in SGC as compared to the dlPFC, while the dlPFC had a higher proportion of synaptic NMDAR-GluN2B. In contrast, in putative inhibitory dendrites from both areas, extrasynaptic expression of NMDAR-GluN2B was far more frequently observed over synaptic expression. These findings may provide insight into varying cortical vulnerability to alterations in excitability and to neurodegenerative forces. Scope StatementNMDAR are ionotropic receptors that contribute to neurotransmission and second messenger signaling events. NMDAR can induce a diverse array of neuronal events, in part due to variation in subunit composition and subcellular localization of receptor expression. Expression of the GluN2B subunit varies across the prefrontal cortex in humans. This subunit is highly expressed in the subgenual cingulate, an area associated with mood and emotion, and more moderately expressed in the dorsolateral prefrontal cortex, an area associated with cognitive processes. Extrasynaptic NMDAR, which often contain with the GluN2B subunit, have been linked to detrimental cellular events like neurodegeneration. Here, using high resolution electron microscopy in rhesus macaques, we found evidence that extrasynaptic NMDAR-GluN2B expression may be more prominent in subgenual cortex than in the dorsolateral prefrontal cortex. Conversely, synaptic NMDAR-GluN2B may be more prominent in the dorsolateral prefrontal cortex, consistent with their essential contribution to neuronal firing during working memory. These findings may help to illuminate the propensity of the subgenual cortex to tonic hyperactivity in major depression and its vulnerability to neurodegeneration in Alzheimers disease, and may help to explain how rapid acting antidepressants exert therapeutic action across diverse neural circuits.

neuroscience↗

bioRxiv2024

Dysregulated calcium signaling in the aged macaque entorhinal cortex associated with tau hyperphosphorylation.

Tau pathology in sporadic Alzheimers disease (AD) follows a distinct pattern, beginning in the entorhinal cortex (ERC) and spreading to interconnected brain regions. Early-stage tau pathology, characterized by soluble phosphorylated tau, is difficult to study in human brains post-mortem due to rapid dephosphorylation. Rhesus macaques, which naturally develop age-related tau pathology resembling human AD, provide an ideal model for investigating early tau etiology. This study examines the molecular processes underlying tau pathology in the macaque ERC, focusing on calcium and inflammatory signaling pathways. Our findings reveal age-related decreases in PDE4 phosphodiesterases that hydrolyze cAMP and increases in calpain-2 and GCPII that occur in parallel with early-stage tau hyperphosphorylation at multiple epitopes (pS214-tau, pT181-tau, pT217-tau). These findings suggest that dysregulated calcium signaling in ERC, beginning in middle-age, primes tau for hyperphosphorylation, potentially driving the early stages of AD, advancing our understanding of how ERC vulnerabilities contribute to neurodegeneration in AD.

neuroscience↗

bioRxiv2024

Dopamine D1 receptor expression in dlPFC inhibitory parvalbumin neurons may contribute to higher visuospatial distractibility in marmosets versus macaques

Marmosets and macaques are common non-human primate models of cognition, yet marmosets appear more distractible and perform worse in cognitive tasks. The dorsolateral prefrontal cortex (dlPFC) is pivotal for sustained attention, and prior macaque research suggests that dopaminergic modulation and inhibitory parvalbumin (PV) neurons could contribute to distractibility. Thus, we compared the two species using a visual fixation task with distractors, performed molecular and anatomical analyses in dlPFC, and linked functional microcircuitry with cognitive performance using computational modeling. We found that marmosets are more distractible than macaques, and that marmoset dlPFC PV neurons contain higher levels of dopamine-1 receptor (D1R) transcripts and protein, similar to their levels in mice. The modeling indicated that higher D1R expression in marmoset dlPFC PV neurons may increase distractibility by making dlPFC microcircuits more vulnerable to disruptions of their task-related persistent activity, especially when dopamine is released in dlPFC in response to unexpected salient stimuli. Declaration of InterestsThe authors have nothing to declare. Author ContributionsAFTA, MKPJ, TGI, and SFW designed the study; MKPJ collected and analyzed anatomical data; TGI designed the computational framework with guidance from RG and SFW; TGI performed the modeling simulations and data analysis; FM and SAM collected and analyzed transcriptomics data; GGB and DAL provided macaque brain tissue for transcriptomics performed by FM; SM and NS collected and analyzed phylogenetic transcriptomics dataset; JFM and ASN performed and analyzed the behavioral testing; IW and JMT provided the marmoset tissue for immunofluorescence; MKPJ, TGI, SFW, and AFTA wrote the first draft and all authors revised and edited subsequent drafts of the article.

neuroscience↗

bioRxiv2024

Early Developmental Origins of Cortical Disorders Modeled in Human Neural Stem Cells

The implications of the early phases of human telencephalic development, involving neural stem cells (NSCs), in the etiology of cortical disorders remain elusive. Here, we explored the expression dynamics of cortical and neuropsychiatric disorder-associated genes in datasets generated from human NSCs across telencephalic fate transitions in vitro and in vivo. We identified risk genes expressed in brain organizers and sequential gene regulatory networks across corticogenesis revealing disease-specific critical phases, when NSCs are more vulnerable to gene dysfunctions, and converging signaling across multiple diseases. Moreover, we simulated the impact of risk transcription factor (TF) depletions on different neural cell types spanning the developing human neocortex and observed a spatiotemporal-dependent effect for each perturbation. Finally, single-cell transcriptomics of newly generated autism-affected patient-derived NSCs in vitro revealed recurrent alterations of TFs orchestrating brain patterning and NSC lineage commitment. This work opens new perspectives to explore human brain dysfunctions at the early phases of development. One-sentence summaryThe temporal analysis of gene regulatory networks in human neural stem cells reveals multiple early critical phases associated with cortical disorders and neuropsychiatric traits.

neuroscience↗

bioRxiv2023

Nanoscale imaging of pT217-tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early-stage neurodegeneration

Structured Abstract INTRODUCTIONpT217-tau is a novel fluid-based biomarker that predicts onset of Alzheimers disease (AD) symptoms, but little is known about how pT217-tau arises in brain, as soluble pT217-tau is dephosphorylated postmortem in humans. METHODSWe utilized multi-label immunofluorescence and immunoelectron-microscopy to examine the subcellular localization of early-stage pT217-tau in entorhinal and prefrontal cortices of aged macaques with naturally-occurring tau pathology and assayed pT217-tau levels in plasma. RESULTSpT217-tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to CSF/blood. Plasma pT217-tau levels increased across the age-span and thus can serve as a biomarker in macaques. DISCUSSIONThese data help to explain why pT217-tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker.

neuroscience↗

bioRxiv2023

Origin and Development of the Claustrum in Rhesus Macaque

Understanding the claustrums functions has recently progressed thanks to new anatomical and behavioral studies in rodents, which suggest that it plays an important role in attention, salience detection, slow-wave generation, and neocortical network synchronization. Nevertheless, knowledge about the origin and development of the claustrum, especially in primates, is still limited. Here, we show that neurons of rhesus macaque claustrum primordium are generated between embryonic day E48 and E55 and express some neocortical molecular markers, such as NR4A2, SATB2, and SOX5. However, in the early stages, it lacks TBR1 expression, which separates it from other surrounding telencephalic structures. We also found that two waves of neurogenesis (E48 and E55) in the claustrum, corresponding to the birthdates of layers 6 and 5 of the insular cortex, establish a "core" and "shell" cytoarchitecture, which is potentially a basis for differential circuit formation and could influence information processing underlying higher cognitive functions of the claustrum. In addition, parvalbumin-positive interneurons are the dominant interneuron type in the claustrum in fetal macaque, and their maturation is independent of that in the overlaying neocortex. Finally, our study reveals that the claustrum is likely not a continuance of subplate neurons of the insular cortex, but an independent pallial region, suggesting its potentially unique role in cognitive control. Significance StatementThe claustrum is believed to have a role in many high cognitive functions. However, the origin and development of this mysterious structure remain unknown, and the understanding of its relationship with the neocortex is ambiguous. Here we examined neuron origin and development of claustrum in rhesus macaque during the prenatal and postnatal periods. We found that the claustrum is formed as an independent telencephalic area as early as E55, and it seems not related to the subplate of the insula, although it shares some molecular characteristics with the neocortex. The claustrum excitatory neurons are generated sequentially around E48 and E55 and build a "core and shell" structure that may be a basic computing neuronal circuit unit underlying higher cognitive functions.

neuroscience↗

bioRxiv2023

Major axes of variation in tree demography across global forests

The future trajectory of global forests is closely intertwined with tree demography, and a major fundamental goal in ecology is to understand the key mechanisms governing spatial-temporal patterns in tree population dynamics. While historical research has made substantial progress in identifying the mechanisms individually, their relative importance among forests remains unclear mainly due to practical limitations. One approach is to group mechanisms according to their shared effects on the variability of tree vital rates and to quantify patterns therein. We developed a conceptual and statistical framework (variance partitioning of Bayesian multilevel models) that attributes the variability in tree growth, mortality, and recruitment to variation in species, space, and time, and their interactions, categories we refer to as organising principles (OPs). We applied the framework to data from 21 forest plots covering more than 2.9 million trees of approximately 6,500 species. We found that differences among species, the species OP, proved a major source of variability in tree vital rates, explaining 28-33% of demographic variance alone, and in interaction with space 14-17%, totalling 40-43%. The average variability among species declined with species richness across forests, indicating that diverse forests featured smaller interspecific differences in vital rates supporting the theory that the range of vital rates is similar across global forests. Decomposing the variance in vital rates into the proposed OPs showed that taxonomy is crucial to predicting and understanding tree demography on large forest plots. A focus on how variance is organized in forests can facilitate the construction of more targeted models with clearer expectations of which covariates might drive a vital rate. This study therefore highlights the most promising avenues for future research, both in terms of understanding the relative contributions of groups of mechanisms to forest demography and diversity, and for improving projections of forest ecosystems.

ecology↗

bioRxiv2022

Molecular programs of regional specification and neural stem cell fate progression in developing macaque telencephalon

Early telencephalic development involves patterning of the distinct regions and fate specification of the neural stem cells (NSCs). These processes, mainly characterized in rodents, remain elusive in primates and thus our understanding of conserved and species-specific features. Here, we profiled 761,529 single-cell transcriptomes from multiple regions of the prenatal macaque telencephalon. We defined the molecular programs of the early organizing centers and their cross-talk with NSCs, finding primate-biased signaling active in the antero-ventral telencephalon. Regional transcriptomic divergences were evident at early states of neocortical NSC progression and in differentiated neurons and astrocytes, more than in intermediate transitions. Finally, we show that neuropsychiatric disease- and brain cancer-risk genes have putative early roles in the telencephalic organizers activity and across cortical NSC progression. One-Sentence SummarySingle-cell transcriptomics reveals molecular logics of arealization and neural stem cell fate specification in developing macaque brain

neuroscience↗

bioRxiv2019

Revisiting the regulation of the capsular polysaccharide biosynthesis gene cluster in Staphylococcus aureus

In Staphylococcus aureus, the capsular polysaccharide (CP) protects against phagocytosis, but also hinders adherence to endothelial cells and matrix proteins. Its biosynthesis is tightly controlled resulting in a heterogeneous phenotype within a population and CP being mainly detectable in non-growing cells. Capsular biosynthesis genes are encoded by a conserved capA-P operon whose expression is driven by an upstream promoter element (Pcap) in front of capA. The organization of Pcap is poorly understood, as is the interplay of different regulators that influence the early-Off/late-Heterogeneous cap transcription pattern. Here, we demonstrate that Pcap contains a main SigB-dependent promoter. The SigB consensus motif overlaps with a previously described inverted repeat that is crucial for cap expression. The essentiality of the inverted repeat is derived from this region acting as a SigB binding site rather than as an operator site for the proposed cap activators RbsR and MsaB. Furthermore, Pcap contains an extensive upstream region harboring a weak SigA-dependent promoter and binding sites for the cap repressors SaeR, CodY and Rot. We show that heterogeneous CP synthesis is determined by the combination of SigB activity and repressor binding to the upstream region. The direct SigB dependency and the upstream repressors are also sufficient to explain the temporal gene expression pattern at the transcriptional level. However, CP synthesis remains growth phase-dependent even when capA transcription is rendered constitutive, suggesting additional post-transcriptional regulatory circuits. Thus, the interference of multiple repressors with SigB-dependent promoter activity as well as post-transcriptional mechanisms ensure the appropriate regulation of CP synthesis.\n\nImportanceThe majority of bacterial pathogens produce an array of polysaccharides on their surface which are important virulence factors and thus serve as attractive vaccine candidates. However, the synthesis and assembly of these structures is highly variable and tightly regulated at various levels. In the human pathogen Staphylococcus aureus, the synthesis of the capsular polysaccharide (CP) is dependent on a complex regulatory network which ensures that CP is produced only in a fraction of stationary phase cells. Here, we determined main regulators that drive the peculiar CP expression pattern. We found that the interplay of the transcriptional repressors Sae, CodY and Rot with the alternative Sigma factor B is responsible for early-Off/late-Heterogeneous expression at the transcriptional level. The data also implicates post-transcriptional mechanisms that may act to avoid conflict in precursor usage by machineries involved in either synthesis of CP or other glycopolymers in growing bacterial cells.

microbiology↗