Biology subjects

Ghizoni, E.

Publications and source records attributed to Ghizoni, E..

4 recordsLinked to original sources

bioRxiv2026

A multimodal single-cell atlas of the adolescent brain reveals gene regulatory networks linking development to disease risk

Adolescence represents a critical window of brain maturation when many neuropsychiatric disorders first emerge, yet the molecular mechanisms driving this developmental period remain incompletely understood. To address this gap, we generated a high-resolution multimodal cell atlas of the developing adolescent brain using paired single-nucleus RNA and ATAC sequencing (snRNA-seq + snATAC-seq) from cortex, hippocampus, and amygdala tissue of six donors aged 6-15 years, profiling 88,658 high-quality nuclei. Integrative analyses identified 36 enhancer-driven gene regulatory networks (eGRNs) with significant age-dependent dynamics in the transition from childhood to adolescence. The majority of adolescence-associated eGRNs were active in oligodendrocytes and their precursors, reflecting active oligodendrogenesis and myelin remodeling during this developmental period. Notably, age-associated cis-regulatory elements were enriched for expression quantitative trait loci (eQTLs) and colocalized with genetic variants linked to both neurodevelopmental and neurodegenerative disorders, suggesting that regulatory networks may be shared across normal adolescent brain development and disease vulnerability. This multimodal cell atlas provides a valuable resource for understanding the human adolescent brain and offers new insights into the molecular origins of neuropsychiatric disorders.

neuroscience↗

bioRxiv2024

Cell type mapping of mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy using single-nucleus multiomics

ObjectiveMild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) are brain lesions associated with focal epilepsy and characterized by increased oligodendroglial density, heterotopic neurons, and hypomyelination in the white matter. While previous studies have implicated somatic mutations in the SLC35A2 gene, the cellular and molecular mechanisms underlying MOGHE pathogenesis remain elusive. To address this gap, this study aimed to systematically characterize the cell type composition and molecular alterations of MOGHE lesions at cellular resolution using single-nucleus multiomics profiling. MethodsWe performed single-nucleus multiomics sequencing to obtain paired gene expression and chromatin accessibility profiles of > 31,000 nuclei from gray matter and white matter regions of MOGHE lesions, and compared the results with publicly available neurotypical control datasets. ResultsThe analysis of gray and white matter regions from two MOGHE patients revealed significant cellular composition alterations, including the presence of heterotopic neurons and disease-specific oligodendrocytes populations within the subcortical white matter. MOGHE-specific oligodendrocytes were characterized by the upregulation of synaptic functions and enhanced neuron communication, denoting a possible role in synaptic support and the mediation of glial-neuron interactions in the disease. On the other hand, MOGHE heterotopic neurons were characterized by the upregulation of genes associated with neuronal migration and the Wnt signaling pathway, suggesting a mechanism underlying their atypical localization. SignificanceThis high-resolution cell type mapping of MOGHE lesions in clinical samples unveils neuronal and glial populations affected by the disease, and provides novel insights into the pathophysiological mechanisms of MOGHE. Key PointsO_LIWe provide a multimodal cellular atlas of the human cortical and subcortical regions affected in MOGHE C_LIO_LIMOGHE-associated oligodendrocytes showed upregulation of synaptic functions and enhanced neuron communication C_LIO_LINeuronal migration and Wnt signaling are upregulated in MOGHE heterotopic neurons C_LI

neuroscience↗

bioRxiv2024

Multimodal single-cell sequencing of the human cortex reveals neuronal vulnerability and activated glial cell states in focal cortical dysplasia

Focal Cortical Dysplasia (FCD) is a neurodevelopmental condition characterized by malformations of the cerebral cortex that often cause drug-resistant epilepsy. In this study, we performed multi-omics single-cell profiling to map the chromatin accessibility and transcriptome landscapes of FCD type II, generating a comprehensive multimodal single-cell dataset comprising 61,525 cells from 11 clinical samples of lesions and controls. Our findings revealed profound chromatin, transcriptomic, and cellular alterations affecting neuronal and glial cells in FCD lesions, including the selective loss of upper-layer excitatory neurons, significant expansion of oligodendrocytes and immature astrocytic populations, and a unique neuronal subpopulation harboring dysmorphic neurons. Furthermore, we uncovered activated microglia subsets, particularly in FCD IIb cases. This comprehensive study unveils neuronal and glial cell states driving FCD development and epileptogenicity, enhancing our understanding of FCD and offering new directions for targeted therapy development.

neuroscience↗

bioRxiv2023

Identifying cellular markers of focal cortical dysplasia type II with cell-type deconvolution and single-cell signatures

Focal cortical dysplasia (FCD) is a brain malformation that causes medically refractory epilepsy. FCD is classified into three categories based on structural and cellular abnormalities, with FCD type II being the most common and characterized by disrupted organization of the cortex and abnormal neuronal development. In this study, we employed cell-type deconvolution and single-cell signatures to analyze bulk RNA-seq from multiple transcriptomic studies, aiming to characterize the cellular composition of brain lesions in patients with FCD IIa and IIb subtypes. Our deconvolution analyses revealed specific cellular changes in FCD IIb, including neuronal loss and an increase in reactive astrocytes (astrogliosis) when compared to FCD IIa. Astrogliosis in FCD IIb was further supported by a gene signature analysis and histologically confirmed by glia fibrilla acidic protein (GAP) immunostaining. Overall, our findings demonstrate that FCD II subtypes exhibit differential neuronal and glial compositions, with astrogliosis emerging as a hallmark of FCD IIb. These observations, validated in independent patient cohorts and confirmed using immunohistochemistry, offer novel insights into the involvement of glial cells in FCD type II pathophysiology and may contribute to the development of targeted therapies for this condition.

neuroscience↗