Modeling Neurogenesis

It's been years since we learned the falsity of that old claim, "you're born with all the neurons you'll ever have," but the molecular mechanisms of neurogenesis have remained fairly mysterious. The functional role of neurogenesis remains unclear as well; why is adult neurogenesis primarily limited to the subgranular zone of the dentate gyrus in hippocampus? A better understanding of the biological conditions that signal adult neurogenesis could inform computational models of this process, and perhaps clarify the role that neurogenesis serves in these specific brain regions. These are the issues tackled by Liedo, Alonso, and Grubb in the current online edition of Nature Reviews Neuroscience.

Adult hippocampal neurogenesis is known to be increased in cab drivers, rats placed in an enriched environment, and even in certain seed-catching birds. This suggests that some mechanism identifies the need to learn and remember more spatial locations in these populations, and then presumably signals the development of new neurons. Indeed, new neurons have been shown to be more sensitive to novel inputs than other neurons, suggesting that they are actively generated, under some conditions, in response to novelty.

These new neurons are also more excitable than their elders, in part due to the fact that new neurons are excited by a neurotransmitter that is normally inhibitory - GABA. This excitatory effect appears to be crucially linked to chloride ion channels, in that blocking these channels results in GABA becoming inhibitory in new neurons as it is in older neurons. NMDA receptor activation also appears necessary for new cell survival; interestingly, survival is improved not by some absolute magnitude of NMDA activation, but rather an amount that is high with respect to a neuron's elder neighbors. New neurons also show increased long-term potentiation. Functionally speaking, these characteristics all make sense: new neurons must be "immune" to inhibition (so that they can more fairly compete with established neurons for representing new inputs) but must also show that they are actually needed (i.e., they are receiving a large amount of excitatory input relative to others).

On a molecular level, neurogenesis may occur in a process roughly similar to the following: astrocytes actively express growth proteins dependent on the local patterns of neural activity and the local neural density, which then upregulate the proliferation of adult hippocampal stem cells and encourage them to adopt a specific fate as neurons. The expression of WNT proteins also has a role in promoting neurogenesis. Interestingly, neurons appear to promote the differentiation of these stem cells into oligodendrocytes without an increase in neurogenesis, suggesting a possible pathway for negative feedback in the production of new neurons from adult neural stem cells. This view of neurogenesis is consistent with an emerging view of the active role astrocytes may play in neural functioning. For far more details on the molecular mechanisms of neurogenesis, see this excellent in press article from Nature Reviews Neuroscience.

The CA3 region of the hippocampus has been studied as a possible candidate for creating the kinds of distributed representations that likely underlie memory functions. If the CA3 detects these representations are beginning to overlap, and are hence less distributed, it may be subject to catastrophic interference in memory recall - in which memories may overwrite others. Neurogenesis in the hippocampus could therefore be a way of maintaining capacity for distributed representations and avoiding catastrophic interference. In fact, the neurons generated by astrocytic signalling of progenitor cells (which are of both inhibitory and excitatory types) send axonal projections into CA3.

This view is also compatible with evidence that adult neurogenesis may contribute to the learning and memory functions of hippocampus, as well as with computational models of both olfactory bulb circuitry (in which neurogenesis better orthogonalizes new sensory representations and may relate to improved olfactory discrimination) and the dentate gyrus layer of hippocampal networks (in which neurogenesis reduces inteference between stored representations and hence improves recall). Other computational models of neurogenesis, such as the cascade correlation algorithm, are not as biologically constrained and work on slightly different principles: new units are added to better orthogonalize existing representations rather than prepare for better orthogonalization of new ones. See this excellent review for more information on computational models of neurogenesis.

In summary, the current evidence appears to converge on an understanding of neurogenesis as a response to low neural density or astrocyte dependent brain activity, with the possible purpose of preparing a network with the ability to recruit new units if necessary. As pointed out by Liedo, Alonso, and Grubb, this might be considered a form of "metaplasticity" - in other words, changes that facilitate further changes.

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