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Extensive migration of young neurons into the infant human frontal lobe

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Science  07 Oct 2016:
Vol. 354, Issue 6308, aaf7073
DOI: 10.1126/science.aaf7073

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Building the human brain

As the brain develops, neurons migrate from zones of proliferation to their final locations, where they begin to build circuits. Paredes et al. have discovered that shortly after birth, a group of neurons that proliferates near the ventricles migrates in chains alongside circulatory vessels into the frontal lobes (see the Perspective by McKenzie and Fishell). Young neurons that migrate postnatally into the anterior cingulate cortex then develop features of inhibitory interneurons. The number of migratory cells decreases over the first 7 months of life, and by 2 years of age, migratory cells are not evident. Any damage during migration, such as hypoxia, may affect the child's subsequent physical and behavioral development.

Science, this issue p. 81; see also p. 38

Structured Abstract


Inhibitory interneurons balance the excitation and inhibition of neu­ral networks and therefore are key to normal brain function. In the developing brain, young interneurons migrate from their sites of birth into distant locations, where they functionally integrate. Although this neuronal migration is largely complete before birth, some young inhibitory interneurons continue to travel and add to cir­cuits in restricted regions of the juvenile and adult mammalian brain. For example, postna­tally migrating inhibitory neurons travel from the walls of the lateral ventricle, along the rostral migratory stream (RMS) into the olfac­tory bulb. In humans, an additional ventral route branching off the RMS, the medial mi­gratory stream (MMS), takes young neurons into the medial prefrontal cortex. It has been suggested that recruitment of neurons during postnatal life could help shape neural circuits according to experience. Specifically, inhibi­tory interneuron maturation during postnatal development is associated with critical peri­ods of brain plasticity. We asked whether neuronal recruitment continues into early childhood in the frontal lobe, a region of the human brain that has greatly increased in size and complex­ity during evolution.


Migrating young neurons per­sist for several months after birth in an exten­sive region of the subventricular zone (SVZ) around the anterior lateral ventricles in the human brain. Are all these young neurons migrating into the RMS and MMS, or do they have other destinations? Using high-reso­lution magnetic resonance imaging (MRI), histology, and time-lapse confo­cal microscopy, we observed the migration of many young inhibitory interneurons around the dorsal anterior walls of the lateral ven­tricle and into multiple cortical regions of the human frontal cortex. We determined the location and orientation of these young neu­rons, demonstrated their active translocation, and inferred their fates in the postnatal anterior forebrain.


A large collection of cells express­ing doublecortin (DCX), a marker of young migrating neurons, traveled and integrated within the infant frontal lobe. This migratory stream, which was most prominent during the first 2 months after birth and persisted until at least 5 months, formed a caplike structure surround­ing the anterior body of the lateral ventricle. We refer to this population of young neurons as the Arc. This structure could also be visualized by brain MRI. Young neurons in the Arc appeared to move long dis­tances in distinct regions around the ventricu­lar wall and the developing white matter. The orientation of elongated DCX+ cells suggested that migratory neurons closer to the ventricu­lar wall dispersed tangentially. In contrast, migratory neurons within the developing white matter tended to be orientated toward the overlying cortex. These cells expressed markers of interneurons, and their entry into the anterior cingulate cortex (a major target of the Arc used for quantification) was corre­lated with the emergence of specific subtypes of γ-aminobutyric acid (GABA)­–expressing interneurons (neuropeptide Y, somatostatin, calretinin, and calbindin). Ex­pression of transcription factors associated with specific sites of origin suggested that these neurons arise from ventral telencephalon progenitor domains.


Widespread neuronal mi­gration into the human frontal lobe continues for several months after birth. Young neu­rons express markers of cortical inhibitory interneurons and originate outside the cortex, likely in the ventral forebrain. The postnatal recruitment of large populations of inhibitory neurons may contribute to maturation and plasticity in the human frontal cortex. Defects in the migration of these neurons could result in circuit dysfunction associated with neurodevelopmental disorders.

Widespread neuronal migration into the human frontal lobe continues during postnatal life.

(A) Sagittal schematic of the newborn forebrain shows prominent collections of young migratory neurons (illustrated in green) adjacent to the lateral ventricle (LV) and in the overly­ing white matter. Directional axes: D, dorsal; A, anterior. (B and C) DCX+ cells coexpress GABA and GAD67, markers of inhibitory interneurons (marked by arrows).


The first few months after birth, when a child begins to interact with the environment, are critical to human brain development. The human frontal lobe is important for social behavior and executive function; it has increased in size and complexity relative to other species, but the processes that have contributed to this expansion are unknown. Our studies of postmortem infant human brains revealed a collection of neurons that migrate and integrate widely into the frontal lobe during infancy. Chains of young neurons move tangentially close to the walls of the lateral ventricles and along blood vessels. These cells then individually disperse long distances to reach cortical tissue, where they differentiate and contribute to inhibitory circuits. Late-arriving interneurons could contribute to developmental plasticity, and the disruption of their postnatal migration or differentiation may underlie neurodevelopmental disorders.

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