Humans and dolphins: Decline and fall of adult neurogenesis

Pre-clinical research is carried out on animal models, mostly laboratory rodents, with the ultimate aim of translating the acquired knowledge to humans. In the last decades, adult neurogenesis (AN) has been intensively studied since it is viewed as a tool for fostering brain plasticity, possibly repair. Yet, occurrence, location, and rate of AN vary among mammals: the capability for constitutive neuronal production is substantially reduced when comparing small-brained, short living (laboratory rodents) and large-brained, long-living species (humans, dolphins). Several difficulties concerning scarce availability of fresh tissues, technical limits and ethical concerns did contribute in delaying and diverting the achievement of the picture of neurogenic plasticity in large-brained mammals. Some reports appeared in the last few years, starting to shed more light on this issue. Despite technical limits, data from recent studies mostly converge to indicate that neurogenesis is vestigial, or possibly absent, in regions of the adult human brain where in rodents neuronal addition continues into adult life. Analyses carried out in dolphins, mammals devoid of olfaction, but descendant of ancestors provided with olfaction, has shown disappearance of neurogenesis in both neonatal and adult individuals. Heterogeneity in mammalian structural plasticity remains largely underestimated by scientists focusing their research in rodents. Comparative studies are the key to understand the function of AN and the possible translational significance of neuronal replacement in humans. Here, we summarize comparative studies on AN and discuss the evolutionary implications of variations on the recruitment of new neurons in different regions and different species

Adult neurogenesis 20 years later: physiological function vs. brain repair

The discovery that mammalian brains contain neural stem cells which perform adult neurogenesis - the production and integration of new neurons into mature neural circuits - has provided a fully new vision of neural plasticity. On a theoretical basis, this achievement opened new perspectives for therapeutic approaches in restorative and regenerative neurology. Nevertheless, in spite of striking advancement concerning the molecular and cellular mechanisms which allow and regulate the neurogenic process, its exploitation in mammals for brain repair strategies remains unsolved. In non-mammalian vertebrates, adult neurogenesis also contributes to brain repair/regeneration. In mammals, neural stem cells do respond to pathological conditions in the so called "reactive neurogenesis", yet without substantial regenerative outcome. Why, even in the presence of stem cells in the brain, we lack an effective reparative outcome in terms of regenerative neurology, and which factors hamper the attainment of this goal? Essentially, what remains unanswered is the question whether (and how) physiological functions of adult neurogenesis in mammals can be exploited for brain repair purposes

Major unsolved points in adult neurogenesis: doors open on a translational future?

The ultimate goal of exploiting adult neurogenesis (AN) as a source of cell replacement is far from being achieved. In spite of many data gathered during the last two decades on homeostatic and reactive neurogenesis, it is evident that such knowledge is not sufficient for granting translational outcomes. By asking the question whether AN research field has to be considered as a dead end in such a perspective, here we review some major unresolved issues: multifaceted evolutionary constraints emerged in mammals, stem/progenitor cell type/availability and tissue permissivity, the possible impact on other brain functions and/or interplay with other forms of plasticity, and relevance in humans. We suggest that full understanding of AN biological processes is an essential step to their possible exploitation for brain repair, and that further fundamental, multidisciplinary research is required before translational outcomes can be reached. Scientist's attitude and their communication skills are also important. To avoid overestimation of AN reparative potential, more distant goals of cell replacement should be kept clearly distinct from restorative approaches involving AN plasticity, both representing translational perspectives