Newly Generated and Non-Newly Generated “Immature” Neurons in the Mammalian Brain: A Possible Reservoir of Young Cells to Prevent Brain Aging and Disease?

Abstract

Brain plasticity is important for translational purposes since most neurological disorders and brain aging problems remain substantially incurable. In the mammalian nervous system, neurons are mostly not renewed throughout life and cannot be replaced. In humans, the increasing life expectancy explains the increase in brain health problems, also producing heavy social and economic burden. An exception to the “static” brain is represented by stem cell niches leading to the production of new neurons. Such adult neurogenesis is dramatically reduced from fish to mammals, and in large-brained mammals with respect to rodents. Some examples of neurogenesis occurring outside the neurogenic niches have been reported, yet these new neurons actually do not integrate in the mature nervous tissue. Non-newly generated, “immature” neurons (nng-INs) are also present: Prenatally generated cells continuing to express molecules of immaturity (mostly shared with the newly born neurons). Of interest, nng-INs seem to show an inverse phylogenetic trend across mammals, being abundant in higher-order brain regions not served by neurogenesis and providing structural plasticity in rather stable areas. Both newly generated and nng-INs represent a potential reservoir of young cells (a “brain reserve”) that might be exploited for preventing the damage of aging and/or delay the onset/reduce the impact of neurological disorders.

Brain Structural Plasticity: From Adult Neurogenesis to Immature Neurons

“…Reports in mammals living longer than mice indicate that the cells generated in their hippocampi mature across longer time courses (3 months in sheep, 6 months in monkeys, with respect to 3-4 weeks in rodents; Kornack and Rakic, 1999;Kohler et al, 2011;Brus et al, 2013; Figure 1D), thus suggesting that a slow, delayed maturation of neurons might replace neurogenic processes at certain ages. This hypothesis is coherent with the "preference" of INs in the relatively large sheep brain (Piumatti et al, 2018) and points to the possibility of a "reservoir of young neurons" in the mature brain of large-brained species (Palazzo et al, 2018;Rotheneichner et al, 2018;La Rosa et al, 2019).…”

Understanding the Real State of Human Adult Hippocampal Neurogenesis From Studies of Rodents and Non-human Primates

“…Although the exact nature and function of these INM+ cells in non-neurogenic regions remain unclear, some interesting hypotheses have been proposed, for example, the cells are in a state of arrested development (Gomez-Climent et al, 2010), in the process of continuous maturation of dormant precursors (Rotheneichner et al, 2018), and are a reservoir of young cells for the adult/aging brain (La Rosa et al, 2019).…”

“…Taken together, studies on AHN are entering a new era, in which knowledge of rodent studies are not simply applied to understand human AHN, but species differences in brain size, lifespan, and ways of life, and identity of INM-expressing cells must be considered to understand the true state and function of human AHN (Amrein et al, 2011;Faykoo-Martinez et al, 2017;La Rosa et al, 2019;Oppenheim, 2019;Seki et al, 2019;Snyder, 2019). Furthermore, comprehensive analyses of postnatally born neurons, both in infants and in adults, and INM-expressing neurons, regardless of their origin, will enable us to understand the state and function of human AHN and plasticity.…”

Phylogenetic variation in cortical layer II immature neuron reservoir of mammals

“…The cINs can progressively mature through the lifespan, ultimately losing the markers for immaturity ( Rotheneichner et al, 2018 ; Benedetti et al, 2020 ). They are considered as a potential reservoir of young, plastic neuronal phenotypes ( Piumatti et al, 2018 ; Bonfanti and Nacher, 2012 ; La Rosa et al, 2019 ), which might represent a form of slow, delayed neurogenesis (‘neurogenesis without division’) if ultimately integrated into circuits ( Rotheneichner et al, 2018 ; Benedetti et al, 2020 ; König et al, 2016 ). These immature cells were initially discovered in cortical layer II of the mouse and rat piriform cortex (reviewed in Bonfanti and Nacher, 2012 ).…”