Biology subjects

Silberfeld, A.

Publications and source records attributed to Silberfeld, A..

5 recordsLinked to original sources

bioRxiv2025

Perfect imperfections: seeking molecular and cellular asymmetries in the mouse brain

Although perfect symmetry is a mathematical ideal, many Bilateria exhibit left-right asymmetries of body, brain and behavior that are adaptive 1-3. In the human brain, various aspects of cognition are lateralized, including language 4 and handedness 5, which rely on left hemisphere dominance in most people. Brain hemispheric specialization can support parallel processing, neural efficiency, and action selection 3,6, while atypical structural or functional asymmetries are often found in neuropsychiatric disorders 7-10. Mice may be useful models for studying brain asymmetry because they show hemispheric differences of structure 11,12 and neurophysiology 13, but the extent to which molecular and cellular differences are involved remains unknown. We applied spatial transcriptomics with single molecule resolution to coronal sections from 31 adult mouse brains, to assess left-right differences of gene expression and cell types. Sections were chosen to capture the hippocampus and auditory cortex, as these two regions have shown the most prior evidence for functional asymmetry 13-15. In the hippocampus, Crhr1 (Corticotropin-Releasing Hormone Receptor 1) was more highly expressed in the pyramidal layers of CA1, CA3 and the dentate gyrus of the left hemisphere compared to the right. In the auditory cortex, three principal components capturing transcriptomic variation showed hemispheric differences, including prominent contributions from genes that have shown associations with human brain asymmetry. Overall cellular density and cell type proportions generally showed no significant hemispheric differences, with Car3 cortical excitatory neurons showing the most laterality. The transcriptional left-right differences that we found may relate to functional asymmetries for learning, memory and hearing. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/675542v1_ufig1.gif" ALT="Figure 1"> View larger version (119K): org.highwire.dtl.DTLVardef@1530502org.highwire.dtl.DTLVardef@16dd244org.highwire.dtl.DTLVardef@107950corg.highwire.dtl.DTLVardef@ca52a3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMolecular and cellular basis of functional brain asymmetry is barely known C_LIO_LISpatial transcriptomics with cellular resolution applied to mouse brain coronal sections C_LIO_LIGenes implicated in human brain asymmetry showed hemispheric differences in mice C_LIO_LINo hemispheric differences of cell type abundances C_LI

neuroscience↗

bioRxiv2024

Left-Right Brain-Wide Asymmetry of Neuroanatomy in the Mouse Brain

Left-right asymmetry of the human brain is widespread through its anatomy and function. However, limited microscopic understanding of it exists, particularly for anatomical asymmetry where there are few well-established animal models. In humans, most brain regions show subtle, population-average regional asymmetries in thickness or surface area, alongside a macro-scale twisting called the cerebral petalia in which the right hemisphere protrudes anteriorly past the left. Here, we ask whether neuroanatomical asymmetries can be observed in mice, leveraging 6 mouse neuroimaging cohorts from 5 different research groups ([~]3,500 animals). We found an anterior-posterior pattern of volume asymmetry with anterior regions larger on the right and posterior regions larger on the left. This pattern appears driven by similar trends in surface area and positional asymmetries, with the results together indicating a small brain-wide twisting pattern, similar to the human cerebral petalia. Furthermore, the results show no apparent relationship to known functional asymmetries in mice, emphasizing the complexity of the structure-function relationship in brain asymmetry. By establishing a signature of anatomical brain asymmetry in mice, we aim to provide a foundation for future studies to probe the mechanistic underpinnings of brain asymmetry seen in humans - a feature of the brain with extremely limited understanding. Significance StatementThe human brain shows significant left-right anatomical asymmetry. Understanding its microscopic basis has implications for studies of autism and schizophrenia, evolution, embryonic brain development, and the relationship between structure and function in the brain. One of the biggest challenges to understanding this aspect of the brain is that animal models are limited. Here we show a brain-wide twisting pattern of asymmetry in the mouse brain using over 3,500 animals from six independent cohorts. These findings provide a basis for using mice to interrogate the microscopic underpinnings of anatomical asymmetry in humans and a roadmap for exploring anatomical asymmetry in additional species.

neuroscience↗

bioRxiv2023

The universe is asymmetric, the mouse brain too.

Hemispheric brain asymmetry is a basic organizational principle of the human brain and has been implicated in various psychiatric conditions, including autism spectrum disorder. Brain asymmetry is not a uniquely human feature and is observed in other species such as the mouse. Yet, asymmetry patterns are generally nuanced, and substantial sample sizes are required to detect these patterns. In this pre-registered study, we use a mouse dataset from the Province of Ontario Neurodevelopmental Network, which comprises structural MRI data from over 2000 mice, including genetic models for autism spectrum disorder, to reveal the scope and magnitude of hemispheric asymmetry in the mouse. Our findings demonstrate the presence of robust hemispheric asymmetry in the mouse brain, such as larger right hemispheric volumes towards the anterior pole and larger left hemispheric volumes toward the posterior pole, opposite to what has been shown in humans. This suggests the existence of species-specific traits. Further clustering analysis identified distinct asymmetry patterns in autism spectrum disorder models, a phenomenon that is also seen in atypically developing participants. Our study shows potential for the use of mouse models in studying the biological bases of typical and atypical brain asymmetry but also warrants caution as asymmetry patterns seem to differ between humans and mice.

neuroscience↗

bioRxiv2023

Activity-Induced MeCP2 Phosphorylation Regulates Retinogeniculate Synapse Refinement

Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelopmental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MeCP2 causes miswiring of neural circuits due to defects in the brains capacity to respond to changes in neuronal activity and sensory experience. Here we show that MeCP2 is phosphorylated at four residues in the brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from that previously reported for Mecp2 null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period. SIGNIFICANCE STATEMENTRett syndrome (RTT) is an X-linked neurodevelopmental disorder that predominantly affects girls. RTT is caused by loss of function mutations in a single gene MeCP2. Girls with RTT develop normally during their first year of life, but then experience neurological abnormalities including breathing and movement difficulties, loss of speech, and seizures. This study investigates the function of the MeCP2 protein in the brain, and how MeCP2 activity is modulated by sensory experience in early life. Evidence is presented that sensory experience affects MeCP2 function, and that this is required for synaptic pruning in the brain. These findings provide insight into MeCP2 function, and clues as to what goes awry in the brain when the function of MeCP2 is disrupted.

neuroscience↗

bioRxiv2022

Reconstruction and deconstruction of human somitogenesis in vitro

The body of vertebrates displays a segmental organization which is most conspicuous in the periodic organization of the vertebral column and peripheral nerves. This metameric organization is first implemented when somites, which contain the precursors of skeletal muscles and vertebrae, are rhythmically generated from the presomitic mesoderm (PSM). Somites then become subdivided into anterior and posterior compartments essential for vertebral formation and segmental patterning of the peripheral nervous system1-4. How this key somitic subdivision is established remains poorly understood. Here we introduce novel tridimensional culture systems of human pluripotent stem cells (PSCs), called Somitoids and Segmentoids, which can recapitulate the formation of epithelial somite-like structures with antero-posterior (AP) identity. Using these systems, we identified a key organizing function of the segmentation clock in converting temporal rhythmicity into the spatial regularity of anterior and posterior somitic compartments. We show that an initial salt-and-pepper expression pattern of the segmentation gene MESP2 in the newly formed segment is transformed into defined compartments of anterior and posterior identity via an active cell sorting mechanism. Moreover, we demonstrate a large degree of independence of the various patterning modules involved in somitogenesis including the segmentation clock, somite epithelialization and AP polarity patterning. Together we put forward a novel framework accounting for the symmetry breaking process initiating somite polarity patterning. Our work provides a valuable platform to decode general principles of somitogenesis and advance knowledge of human development.

developmental biology↗