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

To the Editor: Paredes et al1,2 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. The boundaries of the zones analyzed by Paredes et al1,2 and Nogueira et al6 overlap (Figure). First, putative neural stem cells and immature neurons follow through the mammillothalamic tract (figures 9A-9C and 10D-10F in Nogueira et al6) to the anterior nuclei of the thalamus (figure A in Paredes et al2 and figure 6 in Paredes et al1) 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 al6) to the location referred to as Arc (figure 1 in Paredes et al1), 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 al6)—including the organum vasculosum laminae terminalis, another circumventricular organ6— express neurogenesis markers and are adjacent to basal forebrain nuclei at the ventral and anterior portion of the lateral ventricle7 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 al1,2 practically did not find immature neurons after infancy, and Nogueira et al6,8 found expression of neurogenesis markers in the circumventricular organs and adjacent structures of the adult human brain. Moreover, Paredes et al1,2 showed DCX expression in interneurons, and Nogueira et al6 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 al1 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