Brain structural plasticity is an extraordinary tool that allows the mature brain to adapt to environmental changes, to learn, to repair itself after lesions or disease, and to slow aging. A long history of neuroscience research led to fascinating discoveries of different types of plasticity, involving changes in the genetically determined structure of nervous tissue, up to the ultimate dream of neuronal replacement: a stem cell-driven “adult neurogenesis” (AN). Yet, this road does not seem a straight one, since mutable dogmas, conflicting results and conflicting interpretations continue to warm the field. As a result, after more than 10,000 papers published on AN, we still do not know its time course, rate or features with respect to other kinds of structural plasticity in our brain. The solution does not appear to be behind the next curve, as differences among mammals reveal a very complex landscape that cannot be easily understood from rodents models alone. By considering evolutionary aspects, some pitfalls in the interpretation of cell markers, and a novel population of undifferentiated cells that are not newly generated [immature neurons (INs)], we address some conflicting results and controversies in order to find the right road forward. We suggest that considering plasticity in a comparative framework might help assemble the evolutionary, anatomical and functional pieces of a very complex biological process with extraordinary translational potential.
GRAPHICAL ABSTRACT
Brief Historical Perspective: Revisiting A Never-Ending Story
Most neuronal plasticity in mammals relies on changes of synaptic contacts between pre-existing cells (synaptic strengthening, formation, elimination; Forrest et al., 2018). By considering the number of synapses in the brain (estimated in the trillions: 1015/mm3 in humans; Chklovskii et al., 2004), this can be considered the main potential for structural modification in the mammalian central nervous system (CNS). Nevertheless, this kind of plasticity does not add or replace neurons. Unlike non-mammalian vertebrates, which show remarkable neuronal cell renewal in their CNS (Ganz and Brand, 2016), the mammalian brain is far less capable of forming new neurons (Rakic, 1985; Weil et al., 2008; Bonfanti, 2011). The exception is a process called “adult neurogenesis” (AN), conferred by active stem cell niches that produce new neurons throughout life in restricted regions of the paleocortex (olfactory bulb) and archicortex (hippocampus) (Kempermann et al., 2015; Lim and Alvarez-Buylla, 2016). Yet, after 60 years of intense research and more than 10,000 peer-reviewed publications, we still do not know if our brain maintains such capability (Duque and Spector, 2019; Petrik and Encinas, 2019; Snyder, 2019). Although we have learned a lot about neural stem cell (NSC) biology and the molecular/cellular mechanisms that sustain neurogenesis in rodents (Bond et al., 2015; Kempermann et al., 2015; Lim and Alvarez-Buylla, 2016), direct analysis of human brain has produced many conflicting results (discussed in Arellano et al., 2018; Kempermann et al., 2018; Paredes et al., 2018; Parolisi et al., 2018; Petrik and Encinas, 2019). Here, we try to address such controversy by highlighting some biases and questionable interpretations, recurrent in the field, and by introducing the new concept of “immature neurons” (INs).
The intense research following the “re-discovery” of AN in mammals (starting from the seminal work of Lois and Alvarez-Buylla (1994), but adding to the pioneering studies of Joseph Altman and Fernando Nottebohm) were carried out almost exclusively using mice and rats. These studies were aimed to exploit endogenous and exogenous sources of stem/progenitor cells for therapeutic purposes (Bao and Song, 2018); however, the reparative capacity of mammalian AN was not sufficient, even in rodents (Bonfanti and Peretto, 2011; Lois and Kelsch, 2014). Further studies began to reveal that the main significance of the newborn neurons is linked to physiological roles, related to learning and adaptation to a changing environment (Kempermann, 2019). What appeared interesting is the discovery that AN is highly modulated by the internal/external environment and, ultimately, by lifestyle (Vivar and van Praag, 2017; Kempermann, 2019), which opened the road to prevention of age-related problems. These results also began to highlight the importance of evolutionary aspects (and constraints) revealed by the remarkable differences that exist among mammals (Barker et al., 2011; Amrein, 2015; Feliciano et al., 2015). As stated by Faykoo-Martinez et al. (2017): “Species-specific adaptations in brain and behavior are paramount to survival and reproduction in diverse ecological niches and it is naive to think AN escaped these evolutionary pressures” (see also Amrein, 2015; Lipp and Bonfanti, 2016). Subsequently, several studies addressed the issue of AN in a wider range of species, including wild-living and large-brained mammals that displayed a varied repertoire of anatomical and behavioral features, quite different from those of mice (reviewed in Barker et al., 2011; Amrein, 2015; Lipp and Bonfanti, 2016; Paredes et al., 2016; Parolisi et al., 2018). Though still too fragmentary to support exhaustive conclusions about phylogeny (much less function), this landscape of heterogeneity directs us to re-evaluate, discuss and better contextualize the observations obtained in rodents, especially in the perspective of translation to humans (analyzed in Lipp and Bonfanti, 2016; Paredes et al., 2016; Parolisi et al., 2018; Duque and Spector, 2019; Snyder, 2019). Comparative approaches strongly indicate that there is a decrease in the remarkable plastic events that lead to whole cell changes (i.e., AN) with increasing brain size. In an evolutionary framework, the absence/reduction of neurogenesis should not be viewed as a limit, rather as a requirement linked to increased computational capabilities. Unfortunately, this same fact turns into a “necessary evil” when brain repair is needed: a requirement for stability and a high rate of cell renewal, apparently, cannot coexist (Rakic, 1985; Arellano et al., 2018). Why then do some reports claim the existence of AN in humans? Several scientists in the field warn of high profile papers published on human AN that were technically flawed, their interpretations going well beyond what the data could support; some have never been reproduced (these aspects are thoroughly reviewed in Oppenheim, 2018; Duque and Spector, 2019). Apart from the soundness of data, a strong species bias exists in the neurogenesis literature, due to an overestimation of the universality of laboratory rodents as animal models (Amrein, 2015; Lipp and Bonfanti, 2016; Bolker, 2017; Faykoo-Martinez et al., 2017; Oppenheim, 2019). There is also a common misunderstanding that the putative existence of AN in primates suggests or provides evolutionary proof that the same process exists in humans. In fact, the few existing reports are on non-human primates (common marmosets and macaca), endowed with smaller, less gyrencephalic brains and lower computational capacity, compared to apes (Roth and Dicke, 2005). Systematic, quantitative studies in apes (family Hominidae) are still lacking and most studies carried out in monkeys suggest that very low levels of hippocampal neurogenesis persist during adulthood. In Callithrix jacchus, proliferating doublecortin (DCX)+ neuroblasts were virtually absent in adults and markers of cell proliferation and immaturity declined with age (Amrein et al., 2015). In another study involving Macaca mulatta and Macaca fascicularis, the estimated rate of hippocampal neurogenesis was approximately 10 times lower than in adult rodents (Kornack and Rakic, 1999). These data, along with evidence that AN is virtually absent in cetaceans (Patzke et al., 2015; Parolisi et al., 2017), do provide strong support for declining rates of AN in large-brained mammals (Paredes et al., 2016).
The reasons for some of these misunderstandings are analyzed in the next paragraph.
Neurogenic Processes: Well-Defined Origin, Ill-Defined Markers, Uneven Outcome
Origin
The birth of neurons from NSC/radial glia cells has been well demonstrated both in embryonic and AN (Lim and Alvarez-Buylla, 2014; Berg et al., 2019). The germinal layers in the embryo and the neurogenic sites in the adult brain (subventricular zone, V-SVZ; subgranular zone, SGZ; hypothalamus) are microenvironments in which the NSCs are regulated so that new neurons can be formed. Hence, an adult neurogenic process, as we now understand it, must be sustained by an active NSC niche (Figure 1A). If we accept this definition, then the biological limits of mammalian AN are clear: it is highly restricted to small neurogenic zones, most cells proliferating outside these regions are glial cells, it is related to physiological needs and species-specific adaptations/behaviors, and it is strictly linked to the different animal species, developmental stages and ages (Bonfanti, 2016; Paredes et al., 2016).[…]
TBI Rehabilitation 