bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.03.29.437585

Chromatin accessibility dynamics of neurogenic niche cells reveal a reversible decline in neural stem cell migration during aging

Yeo, R. W.·Zhou, O. Y.·Zhong, B.·Sharmin, M.·Ruetz, T. J.·Kundaje, A.·Dunn, A. R.·Brunet, A.
View original source ↗Export metadata ↓

Abstract

Aging is accompanied by a deterioration in the regenerative and repair potential of stem cell niches in the brain1-5. However, the mechanisms underlying this decline are largely unknown. Here we characterize genome-wide chromatin accessibility in young and old neurogenic niche cells in vivo, revealing defects in neural stem cell (NSC) adhesion and migration during aging. Interestingly, chromatin accessibility at cell adhesion and migration genes decreases with age in quiescent NSCs but increases with age in activated (proliferative) NSCs, and this is accompanied by corresponding expression changes in these genes. We experimentally validate that quiescent and activated NSCs exhibit opposing adhesion and migration behaviors with age: quiescent NSCs become less adhesive (and more migratory) whereas activated NSCs and progeny become more adhesive (and less migratory) during aging. We also show that the ability of activated NSCs and progeny to mobilize out of the niche during in vivo neurogenesis diminishes during aging. Using tension sensors with single molecule resolution, we find that one of the cellular mechanisms by which aging impairs the migration of old activated NSCs and progeny involves increased force-producing adhesions. We identify inhibition of the cytoskeletal-regulating kinase ROCK6, 7 as a way to reduce force-producing adhesions and restore migration in old activated NSCs in vitro. Interestingly, inhibition of ROCK in the neurogenic niche of old mice boosts neurogenesis to the olfactory bulb in vivo. These results have important implications for restoring the migratory potential of NSCs and progeny and for improving neurogenesis in the aged brain.

Source connections

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Yeo, R. W., Zhou, O. Y., Zhong, B., Sharmin, M., Ruetz, T. J., Kundaje, A., Dunn, A. R., Brunet, A.. 2021-03-29. Chromatin accessibility dynamics of neurogenic niche cells reveal a reversible decline in neural stem cell migration during aging. https://doi.org/10.1101/2021.03.29.437585

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗
bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗
bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗