Neocortical Debate

Credit: Jennifer Nunn

After the long standing dogma of no new neurons in the adult brain came crashing down, a wave of publications concerning neurogenesis and its locations flooded the neuroscience community.  It is important to define neurogenesis for the purpose of the debate. Neurogenesis is defined as the proliferation, migration and integration of new neurons. Proliferation is the actual replication of new neurons. Migration is the path and action they must follow to arrive at their target area. Integration is key and is the acceptance of the new neuron into a previously existing neuronal circuit, giving it a function.  Expression of a factor of the mature neuronal phenotype called NeuN, must be with in the neocortex.

Hippocampal neurogenesis has been proven by use of multiple techniques, verified by multiple labs all over the world. Neurons have been shown to proliferate, migrate and integrate into the hippocampus with known involvement in learning and memory. The olfactory bulb is an area under the frontal lobe of the brain that deals with sensory information concerning olfaction (smell).  Researchers have utilized numerous techniques in order to confirm the existence of neurogenesis in the olfactory bulb.  The functional role of newly generated neurons that migrate to the olfactory blub is speculated to be involved with adaption to new smells. Functionality is again established because the olfactory sense must be able to adapt to new smells and must therefore be a more plastic and changeable circuit. This page is dedicated to another brain region called the neocortex.

If these other regions in the brain show neurogenesis, why not the neocortex?

The goal of science is the empirical observation of a phenomenon. Conclusions drawn from these data must the product of valid, reproducible experimental results. Neocortical neurogenesis is a different argument in a sense than hippocampal and olfactory neurogenesis because it  does not have the solid case evidence supporting it. Methods, research techniques, cell labeling, etc… all come into question when inconsistent results are found from these labs. Therefore a systematic, objective, analytical approach must be taken towards the research. The first steps begin by looking at the methodologies (for example: confocal microscopy) used, experimental designs or techniques used that could  account for differences in results. Analysis of conclusions drawn from the results obtained also undergo inspection. Everything methods, results and analysis of results must be closely scrutinized for error or confounding variable before any conclusions can be drawn.

Cortical column development in mammals Credit: Flickr.com http://www.flickr.com/photos/mark-ashton-smith/4187284211/

The arguments below are organized by their main points

A statement below each addresses the opposing side’s view of the point


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Pro: Neocortical Neurogenesis

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  • Multiple techniques have shown the same results;  such as 3Htd, BrdU, fluorescent and confocal  microscopy with Z-sectioning analysis, fluorescent retrograde tracers. If these techniques were good enough to prove hippocampal neurogenesis, why would they not good enough to prove neocortical? Found: (Gould 1999, 2007, Dayer 2005) Not Found: (Rakic 1984, Kornack 2001, Koketsu 2003, Bhardwaj 2006)

These neuronal markers, used to identify cell differentiation have been found to be non-specific. That is to say these “neuronal” markers, mark cells that are not neurons i.e. astrocytes and oligodendrocytes, types of glia within the brain. Hippocampal neurogenesis was proven by multiple labs, techniques and methods that lead to the general contention of its existence. Neocortical research is not there yet.   

For more information about these markers: Click Here

For more information about immunohistochemistry: Click Here


  • Lack of descriptive nature of the housing conditions does not allow for effective replication of the experiment. Environment has been proven to be a factor in increasing rates of neurogenesis, so lack of details concerning the environment could prove to be pertinent. (Gould 2007)

Much of the research does not have descriptive methods making the experiments unverifiable and unreplicable. Environment has been shown to be a huge factor in neurogenesis. More attention is being paid to the environmental conditions and enriched environments of subjects which will lead to better descriptions of methods to hopefully enhance replicability.


  • Gould showed a possible migratory pathway for neurons to migrate from their place of origin, the subventricular zone. A migratory stream would explain another stage of of neurogenesis, i.e how the cells travel to their destination. (Gould 1999)

If there was a migratory pathway as large as Gould hypothesized, it would be visible under a light microscope in the prefrontal cortex. No such pathway has been found in all pre-frontal cortical examination. The cells Gould showed in figures concerning the migratory pathway look a lot like neuroendothelial cells. Subjectivity in the analysis of these cells cannot be definitive proof.

  • Studies that have not shown neocortical neurogenesis have not followed the same methods as those that have found neocortical neurogenesis. If different methods are leading to different results, then the results should not be in question. The methods chosen should be examined. Found: (Gould 1999, 2007, Dayer 2005) Not Found: (Rakic 1984, Kornack 2001, Koketsu 2003, Bhardwaj 2006)

This argument goes both ways. All experiments cannot be retested and proven by other labs constantly. There is no available grant money to re-do other people’s experiments. It is a flaw in the system however there are more studies 21-11 (Gould 2007) showing negative results for neocortical neurogenesis.

Rat neocortical column development Credit: Flicker.com http://www.flickr.com/photos/76865535@N00/2072968621/

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Con: Neocortical Neurogenesis

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  • Since we cannot enter the brain and physically see new neurons at work, we must use markers that would bind to certain new ‘immature’ neurons and not the previously established ones.

Markers are not perfect, however we have proven hippocampal and olfactory neurogenesis with the same markers. NeuN is a factor expressed by mature neurons. Double-band microscopy is a technique used to look at brain tissue and may not be sensitive enough for NeuN, which would underestimate the amount of new neurons found. (Kornack and Rakic 2001)

  • BrdU is a marker of DNA synthesis and not necessarily a marker of cell proliferation. DNA synthesis and modifications occur in normative cell function. This allows the possibility BrdU to incorporate into DNA during these normative processes not indicative of cell proliferation. Furthermore, dosages and number of injections affects of numbers of BrdU labeled cells and is not a standardized procedure. In addition cell may be taking up BrdU as result of saturation rather than proliferation. (Taupin 2007)

BrdU labeling in the absence of mitosis has been shown in an intact adult brain . The absence of double labeled BrdU and NeuN cells at short time points after BrdU injection would not lead to progenitor cells incorporating the BrdU, dividing, and then differentiating into neurons.

  • In the adult brain, neurogenesis occurs in region specific damaged area. In areas suffering from ischemic stroke, the proliferation of cells is specific the area of the damaged blood vessel. In Huntington’s disease there is site specific proliferation in the damaged caudate nucleus and the subependymal label layers. There is a lack of evidence for definitive migratory pathway from known sites of cell proliferation to the neocortex. (Rakic 2002, Sinai 2004)

There is evidence of some amount of migration. For example in the olfactory bulb there is a evidence of some migration from the proliferation area (subventricular zone) to the olfactory bulb. The olfactory bulb has long been proven as an area for neurogenesis.


  • There is no known functionality of new neurons in the neocortex. Some possibilities such as memory have been hypothesized but there is no evidence to support these claims. Therefore integration has not been proven. (Gould 2001, 2007)

The neocortex in a very dynamic part of the brain. It is the outer layer of the brain which is full of neuronal cell bodies It is involved with many functions such as sensory, motor, spatial reasoning and language. Determined functionality is not a necessary for neurogenesis as long as the new neuron migrates and integrates into a system.

Cortical neurons Credit: Flickr.com http://www.flickr.com/photos/mikeeconomo/3953697153/



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Conclusions

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There are many problems with finding sufficient evidence for neocortical neurogenesis. First,there is not one big science lab enforcing the best methods for each experiment that lead to infallible results. All the information we have comes from all over the world from different labs, with different protocols and experimental flaws. A core tenet of science is to be as exact and control for extraneous variables as much as possible. When multiple labs that have attacked a problem in more than one way and have gotten similar results, that favors external validity of the results. With neocortical neurogenesis, it has proved to be beyond difficult to get scientists to agree on certain sets of methods because none are perfect. That being said as long as the shortcomings of any given experiment are addressed appropriately the field can move forward. Discussion and critique move all fields forward. It inspires experimentation and the best work from scientists.

Significant problems plague neocortical neurogenesis being proven. The body of research on this topic has utilized non-standardize methods and therefore has inconclusive results. It would unwise to draw scientific conclusions from these results. Post mortem analysis allows time for significant degradation of the neurons and chemical factors in the brain. Labeling techniques are inexact because effects of all the chemical interactions with the biological systems are not understood. Multiple techniques have not given similar results creating descention among the analyst. One technique could overestimate the number of new functional neuron, another could underestimate or increase the number of labeled cells. However, with multiple techniques and similar methods, hippocampal and olfactory neurogenesis have been proven. Neocortical neurogenesis has not been disproven. For example, it is still may be that there is a migratory stream of neurons that lead to the neocortex. But at this point it is possibility and not proven fact. The majority of the research has not found neocortical neurogenesis and functionality has yet to be established for these new neurons. (Gould 2007)

Insufficient and inconsistent results combined with unclear research methods maintain the unproven status of neocortical neurogenesis.

Page By: Jennifer Nunn

For more information about this topic and the papers referenced: Click Here