Some immature neurons in the cerebral cortex of mammals might wait for years before they become activated and finish their development.
The history of adult neurogenesis – the ability of the developed brain to generate new neurons – is somewhat convoluted. In ground-breaking experiments at MIT in the early 1960s, Joseph Altman and Gopal Das injected thymidine that had been labeled with tritium into the brains of young rats: when labeled thymidine was later observed in neurons, the obvious explanation was that these neurons had been generated by the adult brain (Altman and Das, 1965). Altman and Das had speculated that ‘some’ progenitor cells must have been responsible, but it was only with the discovery of neural stem cells in the early 1990s that the origins of adult neurogenesis became clear (Cameron et al., 1993; Gage, 2000).
Many fish and birds can form new neurons from stem cells in their entire brain and throughout their life (Kaslin et al., 2008), but mammals seem to lack this ability – or have only limited potential to do so. The reduced regenerative capacity that might arise from this has been interpreted as the price that mammals pay for the unsurpassed complexity of the neocortex.
Neuronal development in the embryo is mainly a preset process that is defined by decisive cell divisions at the stem cell level. However, extrinsic regulation and behavioral activity have extensive influence in the adult brain, and control adult neurogenesis in mammals at many levels. But what if new neurons could also develop from other cells within the neurogenic lineage, such as dormant intermediate cells waiting to become activated? A similar mechanism can, for example, be found in human oocytes, where germ cell proliferation ceases well before sexual maturity and further development originates from dormant cells many years later.
Now, in eLife, Luca Bonfanti and colleagues – including Chiara La Rosa as first author – report new insights into this theory by describing immature neurons in the cortex of different mammals (La Rosa et al., 2020). Although first classified in 2008, we still know little about these cortical immature neurons, especially about their functional relevance (Gómez-Climent et al., 2008; Bonfanti and Nacher, 2012). These cells are created before birth but seem to be arrested in a state that lacks the final leap in maturation required for full functionality. It is thought that they could serve as a dormant reservoir of cells beyond the proliferative precursor cell stage, and as a delayed starting point for neurogenesis dissociated from stem cell division. Neurogenesis without cell division would presumably be faster and safer than the risky process of proliferation followed by differentiation (which requires many checkpoints in its early stages).
The researchers – who are based at the University of Turin and other research institutes in Italy, Spain, Switzerland, the UK and the US – studied the distribution and properties of cortical immature neurons in 80 brains across a phylogenetically diverse range of mammal species. They discovered that the larger the brain, the greater the number of immature neurons in the second cortical layer just below the brain surface (and thus far away from the niche for precursor cells near the ventricular wall). Moreover, brains with more folds contained greater densities of immature neurons across their neocortex (Figure 1).
La Rosa et al. suggest that these cells provide a reservoir of undifferentiated neurons, which may represent a mechanism for plasticity that varies among mammalian species. Immature cortical neurons could be adaptable and help maintain cognitive processes throughout life. Indeed, previous studies in adult mice revealed that immature neurons in the piriform cortex showed signs of both immaturity and synaptic plasticity (Klempin et al., 2011). Their further development remains to be proven, but is a fascinating hypothesis and has interesting implications for the role of brain plasticity in health and disease.
Dormant immature neurons could also play a role in adult neurogenesis of the human hippocampus (Kempermann et al., 2018), which shares many similarities in learning and memory with its rodent counterpart, but might show different dynamics in adult neurogenesis. Consequently, adult mammals with large brains – especially humans – might not necessarily lack adult neurogenesis (or have very low levels of it); they may simply delay the maturation of new neurons for decades. In theory, this process could allow quicker adaptive responses than adult neurogenesis, which has to be stimulated at the stem cell level.
The study of La Rosa et al. supports such speculations, inviting further research on the exact nature of these immature neurons: How do they maintain their supposedly dormant state? How do they end this state, if ever? And what is their ultimate fate and function? Maybe they are not as dormant as we are tempted to think?
Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in ratsThe Journal of Comparative Neurology 124:319–335.https://doi.org/10.1002/cne.901240303
Proliferation, neurogenesis and regeneration in the non-mammalian vertebrate brainPhilosophical Transactions of the Royal Society B: Biological Sciences 363:101–122.https://doi.org/10.1098/rstb.2006.2015
Downloads (link to download the article as PDF)
Download citations (links to download the citations from this article in formats compatible with various reference manager tools)
Open citations (links to open the citations from this article in various online reference manager services)
Early life adversity (ELA) is associated with increased risk for stress-related disorders later in life. The link between ELA and risk for psychopathology is well established but the developmental mechanisms remain unclear. Using a mouse model of resource insecurity, limited bedding (LB), we tested the effects of LB on the development of fear learning and neuronal structures involved in emotional regulation, the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). LB delayed the ability of peri-weanling (21 days old) mice to express, but not form, an auditory conditioned fear memory. LB accelerated the developmental emergence of parvalbumin (PV)-positive cells in the BLA and increased anatomical connections between PL and BLA. Fear expression in LB mice was rescued through optogenetic inactivation of PV-positive cells in the BLA. The current results provide a model of transiently blunted emotional reactivity in early development, with latent fear-associated memories emerging later in adolescence.
Hippocampal firing is organized in theta sequences controlled by internal memory processes and by external sensory cues, but how these computations are coordinated is not fully understood. Although theta activity is commonly studied as a unique coherent oscillation, it is the result of complex interactions between different rhythm generators. Here, by separating hippocampal theta activity in three different current generators, we found epochs with variable theta frequency and phase coupling, suggesting flexible interactions between theta generators. We found that epochs of highly synchronized theta rhythmicity preferentially occurred during behavioral tasks requiring coordination between internal memory representations and incoming sensory information. In addition, we found that gamma oscillations were associated with specific theta generators and the strength of theta-gamma coupling predicted the synchronization between theta generators. We propose a mechanism for segregating or integrating hippocampal computations based on the flexible coordination of different theta frameworks to accommodate the cognitive needs.