Whole-cortex in situ sequencing reveals input-dependent area identity

Area of Science:

• Neuroscience
• Molecular Biology
• Genomics

Background:

• The cerebral cortex features specialized areas with distinct cytoarchitecture, connectivity, and activity, organized into modular networks.
• Understanding how neuronal transcriptomic signatures align with spatial organization and develop over time remains a key challenge in neuroscience.

Purpose of the Study:

• To investigate the relationship between neuronal gene expression, cortical area identity, and modular network organization in the mouse brain.
• To explore the developmental mechanisms underlying transcriptomic signatures in cortical neurons, particularly the role of peripheral input.

Main Methods:

• Utilized BARseq, a high-throughput in situ sequencing technique, to analyze the expression of 104 cell-type marker genes in over 4 million cortical neurons across nine mouse forebrain hemispheres.
• Performed de novo clustering of gene expression data to identify transcriptomic types and assessed cell-type distributions following neonatal binocular enucleation.

Main Results:

• Transcriptomic types identified were consistent with previous single-cell RNA sequencing studies and highly predictive of cortical area identity.
• Cortical areas with similar transcriptomic compositions formed 'cortical modules' that overlapped with highly connected regions, indicating shared modular organization.
• Neonatal binocular enucleation led to shifts in visual area transcriptomic profiles towards neighboring areas within the same module, suggesting peripheral input refines transcriptomic identity.

Conclusions:

• The study demonstrates that large-scale in situ sequencing can reveal the brain's molecular architecture and developmental processes.
• Neuronal transcriptomic signatures are spatially organized, reflecting functional modularity and connectivity within the cerebral cortex.
• Peripheral sensory input plays a crucial role in shaping the distinct transcriptomic identities of cortical areas during development.