Expanded Neuronal Migration Supports Region-specific Distribution of Inhibitory Neurons in the Gyrencephalic Brain

Neurodevelopmental mechanisms have evolved to support the formation of more complex brain structures, such as the neocortex. While there are increasing examples of persistent migration of GABAergic inhibitory neurons (interneurons) in the neonatal brain, the breadth and impact of postnatal neuronal migration in the cortex remain unknown. Here, we demonstrate that neonatal gyrencephalic brains harbor an expanded subventricular zone, termed the Arc, defined by a tiered arrangement of neuroblasts and vascular enrichment at the ventricular wall. The Arc is a neonatal reservoir of diverse immature inhibitory subpopulations that supply higher cognitive cortical regions. Migration from the Arc is primarily related to the caudal ganglionic eminence and results in higher VIP+ neuron densities in the cingulate and temporal cortex of the piglet and human brains. Our findings indicate the Arc is a developmental structure present in phylogenetically divergent species and supports the expansion of postnatal neuronal migration, contributing to regional patterning of cortical interneurons in gyrencephalic brains. The recruitment of Arc-derived neuroblasts provides a mechanism to postnatally influence plasticity and has neuroprotective implications for late-migratory neurons given the presence of perinatal injuries, such as hypoxia-ischemia. Overall design: To explore the molecular and cellular diversity of the Arc, we performed single-nucleus RNA sequencing (snRNA-seq) on the human Arc using sub-dissected ventricular tissue from 3 postmortem human brains between gestational week (GW) 30 to 39 (Fig.2a). We obtained the transcriptional profiles of 28,550 single nuclei (Extended Data Fig.4a-c)