Searching for alternatives to brain regeneration

Brain regeneration from an evolutionary perspective: Brain regeneration (the full restoration of tissue after loss from injury or disease) is the most sought after goal for researchers working in developmental neurobiology. It also appears to be the most challenging to achieve when considering the mammalian brain. Whereas remarkable regenerative capacities can be present in the central nervous systems of many non-mammalian vertebrates (e.g., fish, amphibians), these kinds of processes appear to be dramatically reduced in mammals (Bonfanti, 2011). The reasons for such differences across animal classes are not completely understood, yet, some clear aspects have emerged from the study of well-established models like the teleost fish brain (Lange and Brand, 2020), which has: i) multiple, widespread stem cell niches that provide continuous, physiological cell renewal, as well as regeneration after lesioning; ii) additional neural elements that can de-differentiate after injury and re-acquire stem cell properties; iii) the ability to re-activate developmental programs in order to provide regenerative capacity. Studies on regeneration in various tissues and organs across animal species indicate that physiological and lesion-induced regeneration requires the coexistence of some (if not all) of the above-mentioned aspects, which, in the mammalian brain, are either absent or restricted to very small neurogenic niches. The most intuitive explanation for differences in brain regeneration across animal classes, apart from causal reasons, is the need for more neuroanatomical complexity linked to increased computational capabilities that often occurs in parallel with increased brain size. The “complexity” of large brains appears to be incompatible with substantial cell renewal/regeneration, a process that would be biologically expensive and somehow in contrast with the requirement for “stability” of the neural circuits (e.g., to retain long-term memories related to multiple previous experiences in long-living organisms). The current state of knowledge is still a mix of evidence and theories that are blurred by the frequently irregular patterns of evolution, but it does point to an important, underestimated issue: phylogenetic variations in the location, amount, rate, and type of brain plasticity in mammals. Stem cell-driven adult neurogenesis and brain plasticity in mammals: Since its initial discovery, adult neurogenesis has been considered a turning point in our understanding of brain regeneration. Most mammalian brains host at least two active neurogenic sites (three, considering the hypothalamus) where multipotent neural stem cells generate new neurons capable of maturing and undergoing functional integration within restricted brain regions. Initially, this discovery was viewed in terms of a typical stem cell system, such as those existing in skin and blood, and was interpreted as a possible source of new neurons that could join pre-existing elements to replace neuronal cells damaged/lost in neurodegenerative disorders. However, it is now evident that mammalian neural stem cell niches produce only a few types of neurons, and that these are selectively integrated in very specific neural circuits. Moreover, neurogenic sites hosting the stem cells progressively decrease in number and activity across the lifespan of the animals. This decrease occurs very early in large-brained mammals, including humans, where it leads to substantial exhaustion of the stem cell niches in adolescence (Parolisi et al., 2018). The disappointment regarding the potential of stem cells to contribute to brain regeneration is understandable, especially considering the huge effort by the scientific community over the years. In addition, the substantial differences emerging between mice and humans have important implications for the use of rodent models to study brain plasticity in a translational perspective. Nevertheless, mammalian brains possess other forms of plasticity that are not confined within small, restricted regions but ubiquitously present, and congruent with the need for stability in the number/type of neurons, e.g., the well-known synaptic and dendritic/axonal plasticity. These structural changes consist of adjustments of small components of pre-existing cells and do not provide “true” brain regeneration in terms of neuronal replacement and/or neural tissue reconstruction (Figure 1A, top).Figure 1: Different ways for achieving structural plasticity in the adult mammalian brain.Stem cell-driven genesis of new neurons (adult neurogenesis) and synaptic/axonal plasticity (A, top) represent two extremes of plastic events in the brain. Non-newly generated “immature” neurons (A, bottom), as a form of delayed neurogenesis without division, might be considered as an intermediate form of plasticity providing new elements for the pre-existing neural circuits in the absence of active stem cell niches/neural progenitors. Note that a similar outcome (the addition of a new neuron in the circuits) can be obtained through different plastic processes, not all of which involve stem/progenitor cells (high top: color code indicating different maturational states of neurons; dark blue indicates newly formed elements). (B) Specific types of plasticity such as “classic” adult neurogenesis (top) or “immature” neurons (bottom) can coexist, yet, with highly different distributions and amounts. The numbers of immature neurons can vary remarkably in mammals, with phylogenetic variation between small-brained and large-brained species (La Rosa et al., 2020b). Asterisk, the reduction in adult neurogenesis rates across mammalian species has not yet been assessed through systematic, comparable approaches.From the evolutionary point of view, it makes sense to shift from adult neurogenesis to forms of structural modification that meet the increasing, intrinsic need for stability; however, this comes at the cost of lost regenerative capacity. Why, the