Biology subjects

Men, S.

Publications and source records attributed to Men, S..

3 recordsLinked to original sources

bioRxiv2025

Cognitive and Synaptic Impairment Induced by Deficiency of Autism Risk Gene Smarcc2 and its Rescue by Histone Deacetylase Inhibition

SMARCC2, which encodes BAF170, a core subunit of chromatin remodeling BAF complex, is one of the top-ranking risk genes for autism spectrum disorder (ASD). However, the mechanisms linking SMARCC2 haploinsufficiency to ASD remain poorly understood. Genome-wide RNA-seq analysis revealed that SMARCC2 was significantly diminished in iPSC-derived neurons from idiopathic ASD patients. ChIP-seq of SMARCC2 demonstrated its binding to many other ASD risk genes involved in transcriptional regulation. Smarcc2 deficiency in prefrontal cortex (PFC) of adolescent mice led to impaired working memory, with largely intact social and anxiety-like behaviors. Significant downregulation of genes enriched in synaptic transmission were found in PFC of Smarcc2-deficient mice by RNA-seq and qPCR profiling. In parallel, electrophysiological recordings uncovered the significant impairment of GABAergic and glutamatergic synaptic currents in Smarcc2-deficient PFC pyramidal neurons. Smarcc2 bound to HDAC2, and Smarcc2 deficiency led to the reduced global histone acetylation and H3K9ac enrichment at synaptic gene Slc1a3 (EAAT1), Slc6a1 (GAT1), and Slc32a1 (VGAT) promoters. Treatment of Smarcc2-deficient mice with romidepsin, a class I HDAC inhibitor, restored histone acetylation, working memory and some synaptic gene expression. These findings highlight the critical role of Smarcc2 in regulating cognitive and synaptic function, suggesting that targeting HDAC could alleviate deficits in Smarcc2-associated neurodevelopmental disorders.

neuroscience↗

bioRxiv2021

In Vivo Simultaneous Nonlinear Absorption Raman and Fluorescence (SNARF) Imaging of Mouse Brain Cortical Structures

AO_SCPLOWBSTRACTC_SCPLOWTwo-photon excited fluorescence (TPEF) microscopy is a widely used optical imaging technique that has revolutionized neurophotonics through a diverse palette of dyes, specialized transgenic models, easy implementation, and straightforward data analysis. However, in vivo TPEF imaging is often limited in the number of contrasts available to distinguish different cells, structures, or functions. We propose using two label-free multiphoton microscopy techniques - stimulated Raman scattering (SRS) microscopy and transient absorption microscopy (TAM) - as complementary and orthogonal imaging modalities to TPEF for in vivo brain imaging. In this study, we construct a simultaneous nonlinear absorption, Raman, and fluorescence (SNARF) microscope and image several cortical structures up to 250-300 m below the pial surface, the highest reported in vivo imaging depth for SRS or TAM. We further demonstrate the capabilities of our SNARF microscope through the quantification of age-dependent myelination, hemodynamics, vessel structure, cell density, and cell identity in vivo. Using machine learning, we report the use of label-free SRS and TAM features to predict capillary-lining cell identities with 90% accuracy. The SNARF microscope and methodology outlined herein provide a powerful platform to study several research topics, including neurovascular coupling, blood-brain barrier, neuronal and axonal degeneration in aging, and neurodegenerative diseases.

neuroscience↗

bioRxiv2021

Quantitative imaging of intracellular density with ratiometric stimulated Raman scattering microscopy

Cell size and density impact a wide range of physiological functions, including tissue homeostasis, growth regulation, and osmoregulation. Both are tightly regulated in mammalian cells. In comparison, density variation of a given cell type is much smaller than cell size, indicating that maintenance of cell type-specific density is important for cell function. Despite this importance, little is known about how cell density affects cell function and how it is controlled. Current tools for intracellular cell density measurements are limited either to suspended cells or cells growing on 2D substrates, neither of which recapitulate the physiology of single cells in intact tissue. While optical measurements have the potential to measure cell density in situ and noninvasively, light scattering in multicellular systems prevents direct quantification. Here, we introduce an intracellular density imaging technique based on ratiometric stimulated Raman scattering microscopy (rSRS). It quantifies intracellular drymass density through vibrational imaging of macromolecules. Moreover, water is used as an internal standard to correct for aberration and light scattering. We demonstrate real-time measurement of intracellular density quantification and show that density is tightly regulated across different cell types and can be used to differentiate cell types as well as cell states. We further demonstrate dynamic imaging of density change in response to osmotic challenge as well as intracellular density imaging of a 3D tumor spheroid. Our technique has the potential for imaging intracellular density in intact tissue and understanding density regulation and its role in tissue homeostasis.

biophysics↗