Human brains teach us a surprising lesson

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Science  07 Oct 2016:
Vol. 354, Issue 6308, pp. 38-39
DOI: 10.1126/science.aai9379

The unique cognitive abilities of humans have long captured the imagination of philosophers and neuroscientists alike. But which features of the human brain set us apart from other mammals? Most likely, our intellectual advantages result from a relative expansion of cortical regions responsible for associative and executive function (1). However, the question of how this cortical expansion is achieved during human development has remained unresolved. A major clue came from the elucidation of neurogenic events taking place during the later phases of embryonic human brain development. This began with the recognition that the human cortical subventricular zone is greatly expanded relative to that of lower mammals. This evolutionary innovation allowed for the marked expansion of associative cortex, especially the frontal lobes. Subsequently, a thorough investigation of the fetal human cortex revealed the existence of a number of distinct excitatory neuronal progenitor types (e.g., outer radial glia) that were identified as key to driving a remarkable burst of late neurogenesis (2). However, the cortex is able to function only when excitatory and inhibitory activities in the brain are balanced. On page 81 of this issue, Paredes et al. (3) identify a population of interneurons that migrate to the cortex during infancy to establish inhibitory circuits.

In rodents, inhibitory cortical interneurons are predominantly generated in the ventral telencephalon and then migrate into the cortex (4). There is also considerable postnatal neurogenesis of GABAergic interneurons that contributes to the olfactory bulb and, to a limited extent, the anterior forebrain (5). By contrast, previous human studies (6) hinted that inhibitory interneurons in humans could arise from within the cortical primordium itself. However, subsequent studies did not find evidence for cortically derived interneurons in humans (7, 8). Furthermore, postnatal neurogenesis within humans appears to be considerably more modest than in rodents (9). Paredes et al. have now uncovered an alternative mechanism by which embryonically derived but uncommitted cortical interneurons integrate postnatally into the human cortex.

Paredes et al. examined postmortem human brain samples from infants between birth and 3 months of age. They discovered a periventricular complex of morphologically and biochemically identified young migrating neurons, which they named Arc cells for their characteristic trajectory from the ventricle. Arc cells appeared to form a fourtier assemblage that originated as a compact accumulation in the cortical subventricular zone (SVZ) and extended into chains of migrating neurons. The presence of these neurons in the SVZ is noteworthy, as the SVZ is the embryonic epicenter of pyramidal cell neurogenesis. During migration, Arc cells associated with blood vessels and formed finger-like chains connected by adherent junctions, reminiscent of migratory cells in the rodent cortex. Paredes et al. were able to label this population with adenovirus carrying green fluorescent protein, and then used video microscopy to capture them in the act of migration.

Embedded Image

The dynamic integration of cells continues postnatally in the frontal lobe of humans.


The authors found that migratory Arc cells primarily expressed markers associated with the inhibitory neurotransmitter γ-aminobutyric acid (GABA). However, unlike previous findings in rodents, actively proliferating cells were absent, which suggests that these migrating GABAergic neurons are already generated before birth. Cortical interneurons are renowned for their diversity, which has been shown to relate to their region of origin (10). The Arc populations identified appear to run the gamut of different interneuron subtypes, which in rodents are known to arise from distinct ventral telencephalic progenitor zones. The source and precise timing of the origin of migrating Arc cells, and how they are assembled in the cortex, remain open questions.

Studies on human brain development are technically difficult and typically rely on piecemeal data. The heroic effort needed to histologically examine and track virally labeled Arc cells using the meager human samples available should not be underestimated. By overcoming the inherent difficulties involved in such studies, Paredes et al. have begun to scratch the surface of how this novel mode of circuit integration could influence human brain development. Despite the sparseness of their data, both indirect and direct lines of evidence support their conclusions. With striking symmetry, Arc cells migrate in a manner indistinguishable from their embryonic predecessors, making a strong but circumstantial case for their findings. More important, the authors were able to support their histologic evidence with T2 signal intensity in magnetic resonance images of developing and postnatal human brains, which allowed them to detect migratory streams of cells, providing an important in vivo correlate for their conclusions. The cross-correlation between high-resolution in vitro analysis and lower-resolution in vivo imaging is extremely promising. It suggests that with modest improvements, noninvasive clinical studies will allow us to explore the postnatal migration of cells within the human brain.

What are the implications of these findings for our understanding of brain development? With a shift in focus from neurogenesis to maturation, the authors raise the question of what aspects of brain development we have missed. The loss of markers of young migrating neurons such as doublecortin by 6 months implies that shortly after birth the residual migration of interneurons is complete. Nonetheless, it remains possible that a postmigratory but immature interneuron population is retained within the young brain for months or perhaps years. If humans possess an “interneuron reserve,” its potential to contribute to plasticity under normal or pathophysiological conditions may be considerable. Accumulated evidence indicates that specific interneuron populations control critical-period plasticity within the brain (11). Moreover, transplantation studies pioneered by this same group have indicated that the grafting of interneuron precursors can reopen critical-period plasticity (12). The present data suggest that these findings, rather than being epiphenomena, may reflect the underlying biology of how our brains are assembled.

References and Notes

Acknowledgments: We thank C. Mayer and R. Machold for critical reading and insightful comments on the manuscript. Supported by the Simons Foundation and NIH grants MH071679, MH111529, NS074972, and NS081297 (G.F.), and by NIH grant T32MH015174-39 (M.M.).
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