Letter: Extensive Migration of Young Neurons Into the Infant Human Frontal Lobe.

To the Editor:

Paredes et al[1,2] showed, in a manuscript published recently in Science, that human postnatal neurogenesis occurs in noncanonical niches in the frontal lobe and that immature interneurons migrate long distances even in the postmortem brain. These immature interneurons are likely to be postmitotic neurons born principally in the medial ganglionic eminence (MGE; Figure A).[1,3,4] The MGE is a fetal brain structure located anterosuperior to the hypothalamus that vanishes after birth.[5] An elusive connection with this process of postnatal neurogenesis involves neurons that potentially arise after birth from the structures without blood–brain barrier (ie, the circumventricular organs, located principally in the hypothalamus) and follow through the neural circuits sustained by basal membrane in the ependyma, pia mater, and blood vessels.[6] This connection comprehends only anatomical locations where neurogenesis markers are expressed. Nonetheless, this knowledge may serve as a starting point to overcome the differences observed in the studies discussed here and to develop methods aiming at neuroregeneration.

FIGURE.

Connections between hypothalamus zones that express neurogenesis markers and migratory routes of immature interneurons in the frontal lobe. Panel A shows that the counterpart locations of the medial ganglionic eminence (MGE) in the adult mammalian brain (structures in yellow; reprinted with permission from O’Connell and Hofmann[10]) are anterior (left-hand figure) and superior (right-hand figure) to the hypothalamus (hy), including the preoptic area (poa). Panel B is a sagittal view of an adult human brain specimen (adapted from Nogueira et al[6]). The zone underneath the green ellipse encompasses adult counterpart locations of MGE, which display a dense DCX expression in the infant brain.[1,2] This zone overlaps partially with the zone of the septal area and anterior hypothalamus (yellow ellipse), which expresses neurogenesis markers in the adult human brain.[6] Note that the paraolfactory (po) and paraterminal (pt) gyri are regarded part of the septal area. The neural circuit formed from the mammillothalamic tract to the anterior thalamic nuclei (yellow arrow)[6] and next to the anterior cingulate gyrus (cg; green arrow)[1,2] expresses neurogenesis markers in the postnatal human brain. Panel C is an immunohistochemistry image of glial fibrillary acid protein stained in red and DAPI stained in blue in a coronal slice of the body of the lateral ventricle (lv; adapted from Nogueira et al[6]). This figure illustrates that the zone encompassing the choroid plexus (cp), fornix (fx), and subcallosal zone (scz), which expresses neurogenesis markers in adults,[6] reaches the adult counterpart location of the infant brain zone referred to as Arc,[1,2] from which immature interneurons migrate toward the cingulate gyrus. Legend: ac, anterior commissure; bcn, body of the caudate nucleus; BNST, bed nucleus of the stria terminalis; cc, corpus callosum; cf, column of the fornix; fm, forame of Monro; ic, internal capsule; LS, lateral septum; mb, mammillary body; NAcc, nucleus accumbens; oc, optic chiasm; sg, straight gyrus; sp, septum pellucidus; st, stria terminalis; Str, striatum; th, thalamus; VP, ventral pallidum. Scale bar: 5000 μm.

The boundaries of the zones analyzed by Paredes et al[1,2] and Nogueira et al[6] overlap (Figure). First, putative neural stem cells and immature neurons follow through the mammillothalamic tract (figures 9A-9C and 10D-10F in Nogueira et al[6]) to the anterior nuclei of the thalamus (figure A in Paredes et al[2] and figure 6 in Paredes et al[1]) and next to the anterior cingulate gyrus (figure 3 in Paredes et al;[1]Figure B this letter). Second, putative neural stem cells and immature neurons arise from the choroid plexus, which is a circumventricular organ, follow through the fornix (figures 23-25 in Nogueira et al[6]) to the location referred to as Arc (figure 1 in Paredes et al[1]), and reach principally the sulci of the cingulate gyrus (figures 3 and S1G in Paredes et al;[1]Figure C this letter). Finally, the septal nuclei and anterior hypothalamus (figures 12-15 in Nogueira et al[6])—including the organum vasculosum laminae terminalis, another circumventricular organ[6]—express neurogenesis markers and are adjacent to basal forebrain nuclei at the ventral and anterior portion of the lateral ventricle[7] that display dense expression of DCX, an immature neuron marker (figures 1A-1B and S5C in Paredes et al;[1]Figure B this letter).

The boundary between the septal nuclei and the anterior hypothalamus, including the preoptic area, is the location that could be explored to assess the major caveat in the comparison described here. The caveat is that Paredes et al[1,2] practically did not find immature neurons after infancy, and Nogueira et al[6,8] found expression of neurogenesis markers in the circumventricular organs and adjacent structures of the adult human brain. Moreover, Paredes et al[1,2] showed DCX expression in interneurons, and Nogueira et al[6] showed DCX expression in neuronal fibers with long projections.

One might speculate that this difference occurs because the MGE vanishes after birth and the formation of interneurons that migrate postnatally ceases, but the neurogenesis from the circumventricular organs to the counterpart location of the MGE in the postnatal brain (Figure A) persists. The organotypic culture of postmortem human brain developed by Paredes et al[1] is a novel method that can be used to assess adult neurogenesis in the hypothalamus.

The fetal hypothalamus contributes to the migration of MGE-produced interneurons because it forms an inhibitory environment for this migration that contrasts with the permissive environment formed by cortical areas.[3] If adult neurogenesis is revealed in the human hypothalamus, perhaps its stimulation could recapitulate the interaction between the hypothalamus and MGE and trigger neurogenesis from the counterpart location of the MGE in adults (Figure A). This would be an approach to pursue treatment for neuropsychiatric conditions that involve interneurons such as epilepsy, schizophrenia, and autism.[9,10]

Disclosures

National Council for Scientific and Technological Development (CNPq), Brazil, grant #401002/2013-6. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.