Neurogenesis isn’t over…??

Neurogenesis isn’t over. At least that is what researchers at Columbia University say.
Let’s sum up what happened so far. The human hippocampus, the counterpart of which in rodents is regarded as one of the two adult neurogenic niches, has been long thought to not be able to produce such a big number of neurons in adult individuals. At least until when the Frisén lab showed with ¹⁴C dating that it indeed generates in average 700 newborn neurons per day. In March of this year another adult neurogenesis-leading lab, the Alvarez-Buylla lab, published a paper showing that the human hippocampus generates very few neurons after childhood, and the number of proliferating cells sharply declines too (see the comment we published on April 11^th).

Not long after it, Cell Stem Cell published the work of Boldrini and colleagues – Human hippocampal neurogenesis persists throughout aging. In this paper, researchers performed immunohistochemical analyses of post-mortem tissue from subjects of different ages, from 14 to 79 years. Particular care was put into the description of exclusion criteria for the samples, from an extensive anamnesis to a drug screening. One big difference between the two works, is that Boldrini and colleagues regionally divided the Dentate Gyrus (DG) into anterior, mid and posterior DG rather than analysing the whole structure altogether.

Given this categorisation, immunostaining for the transcription factor Sox2 – necessary for the proliferation and maintenance of neural stem cells, revealed a decline with age exclusively in the anterior DG. The total population of proliferating cells seemed instead to remain stable, possibly due to the presence of dividing cells from other lineages. Whilst the PSA-NCAM marker alone - identifying cells of the neuronal lineage from neuroblasts to granule neurons, seems to decline in the anterior DG, the number of newborn neurons based on the expression of Doublecortin (DCX) remained stable.

Additionally, the group investigated age-related angiogenesis levels in the neurogenic niche. They used the marker Nestin, together with the proliferative marker Ki67, as an indicator of newly generated capillaries. Interestingly, the number of new capillaries was reduced to half in the eldest subjects, while their level of maturation dropped sharply.
This new work on human hippocampal neurogenesis helps shedding more light on the possibility to have newborn neurons generated and integrated in the hippocampal system after childhood. It is interesting to note that the data gathered by Boldrini and colleagues hint for differences in the proliferating and neurogenic abilities of different regions of the DG. It appears indeed that rostral and medial areas of the DG are harbouring similar numbers of neural stem cells, neuroblasts (DCX-positive) and neuronal cells in subject of different ages. Conversely, the anterior part of the DG, described as the most rostral part of it going until the beginning of the lateral geniculate, shows a decline in the number of these cell types with age. Such kind of distinction between different rostro-caudal parts of the neurogenic niche hasn’t so far been described and might be one reason for the variability of data reported by different groups. Nonetheless, this work doesn’t keep into account the fact that cells positive for DCX might belong to different lineages and would be better to describe newborn neurons as PSA-NCAM/DCX-double positive cells (indicating newborn neurons committed to the neurogenic lineage) with the typical morphology of neuroblasts.

Another novel finding described is the decline of angiogenesis in the area of the anterior DG. Blood vessels are in fact supplying the niche with nutrients and factors that could have an impact in the maintenance of the neural stem cells present and their activation. Thus, it is possible that the decline in angiogenesis is linked to the reduction in the pool of quiescent neural stem cells or in their activation to produce neurons. However, such link has yet to be proven.

This paper is thereby supporting other works stating that neurogenesis is still present in adults and doesn’t decline with age. It is definitely difficult to handle human tissue and post mortem fixation. Moreover, immunofluorescent stainings of human markers can be less trivial than the murine counterparts. What is for sure, is that the field of adult neurogenesis has never been as exciting and inflamed as now. For sure this isn’t the last report to be expected and proof is the mini review published online last week by the journal Cell Stem Cell. For sure you should continue reading those books stacked on your night table and running along the river (enriched environment and running are both linked to increased hippocampal neurogenesis in rodents). If it won’t give you more neurons it might make you healthier and more satisfied.

Written by Chiara Galante; Edited by Radhika Menon. Featured image: confocal picture of mouse adult hippocampus with DCX-positive newborn neurons, courtesy of Chiara Galante (acquired at the Microscopy facility/IMB Mainz).