Reviewing the Reserve Supply of Immature Neurons in the Adult Brain

To what degree can the adult brain restructure and regenerate itself? In one sense the components of the central nervous system, brain included, are clearly among the least regenerative of tissues in mammalian species. In another sense the brain is capable of significant compensatory change following damage. Further, the normal operation of the brain over time depends upon the plasticity of neural circuits in response to changing circumstances: learning, memory, and so forth.

The authors of today's open access research propose that these capacities for regeneration and change may arise not just from a supply of daughter cells created by neural stem cell populations, but also from a reserve population of immature neurons that are generated during early development and then retained throughout life. This hypothesis lacks solid evidence, but it is this sort of speculation - what is this apparently inactive cell population actually doing? - that drives further investigations.

Looking at the broader picture, it is a question of great interest to researchers in the field as to whether or not it is possible to upregulate the existing mechanisms of repair and plasticity in the central nervous system. Are there comparatively simple signal or regulatory proteins that can be targeted to change cell behavior in ways that provoke greater regeneration and maintenance in the aging brain? This is an open question for human medicine, though it is certainly the case that many studies in mice have provided promising data over the years. It remains to be seen as to where that work will lead.

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

The aging of the brain, especially in the light of a progressive increase of life expectancy, will impact the majority of people during their lifetime, putting at stake their later life and that of their relatives. This cannot be seen only as a health problem for patients but as a more general, worrisome, social, and economic burden. In spite of fast and substantial advancements in neuroscience/neurology research, resolutive therapeutic solutions are lacking.

For a long time, some hopes have been recognized in structural plasticity: The possibility for a "generally static" brain to undergo structural changes throughout life that may go beyond the modifications of synaptic contacts between pre-existing neuronal elements. During the last five decades, the discovery that the genesis of new neurons (adult neurogenesis) can still occur in some regions of the central nervous system (CNS) supported such hopes, suggesting that young, fresh neurons might replace the lost/damaged ones.

The real roles and functions of adult neurogenesis are far from being elucidated, and it appears clear that the new neurons can mainly serve physiological functions within the neural circuits, rather than being useful for repair. Interestingly, and adding further complexity, non-newly generated, immature neurons sharing the same molecular markers of the newly born cells are also present in the mature brain.

Independently from any specific physiological function (at present unknown), the novel population of "immature" neurons (nng-INs) raise interest in the general context of mammalian structural plasticity, potentially representing an endogenous reserve of "young", plastic cells present in cortical and subcortical brain regions. Finding more about such cells, especially regarding their topographical and phylogenetic distribution, their fate with increasing age, and the external/internal stimuli that might modulate them, would open new roads for preventive and/or therapeutic approaches against age-related brain damage and cognitive decline.

A current hypothesis is that in the large-brained, long-living humans the neurons generated at young ages might mature slowly, maintaining plasticity and immaturity for very long periods. Hence, immature neurons, intended as both newly generated (in neurogenic sites) and non-newly generated (nng-INs in cortex and subcortical regions), might represent a form of "reserve" of young neurons in the absence of continuous cell division. In this context, solid evidence suggests that "adult" neurogenesis in mammals should not be considered as a constitutive, continuous process taking place at the same rate throughout life, but rather as an extension of embryonic neurogenesis, which can persist for different postnatal periods by decreasing (even ceasing) at different ages and in different brain regions.

There is no sharp boundary between developmental processes and subsequent tissue maintenance and aging processes and some events, such as adult neurogenesis, have all the hallmarks of late developmental processes. In that sense, adult neurogenesis is not at all similar to the cell renewal/regenerative processes known to occur in other stem cell systems, such as the skin, blood, or bone; rather, it is characterized by progressive neural stem cell/progenitor depletion, the cell addition being directed at the completion of organ or tissue formation, not at the replacement of lost cells. This aspect is more prominent and precocious in large-brained mammals, especially humans.


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