- Neurogenesis occurs in two main areas in the adult brain: the hippocampus and the olfactory bulb.
- The transformation of a new cell into a neuron appears to crucially involve a specific protein called WnT3, that's released by support cells called astrocytes.
- A chemical called BDNF also appears critical for the transformation into neurons.
- Most recently, T-cells have also been revealed as important for neurogenesis to occur.
- The extent and speed of neurogenesis can also be enhanced by various chemicals. Nerve growth factors appear to enhance the proliferation of precursor cells (cells with the potential to become neurons), and the prion protein that, damaged, causes mad cow disease, appears in its normal state to speed the rate of neurogenesis.
- The integration of the new neuron into existing networks appears to need a brain chemical called GABA.
- Indications are that moderate alcohol may enhance neurogenesis, but excess alcohol certainly has a negative effect. Most illegal drugs have a negative effect, but there is some suggestion cannabinoids may enhance neurogenesis. Antidepressants also seem to have a positive effect, while stress and anxiety reduce neurogenesis. However, positive social experiences, such as being of high status, can increase neurogenesis. Physical activity, mental stimulation, and learning, have all been shown to have a positive effect on neurogenesis.
What is neurogenesis?
Neurogenesis — the creation of new brain cells — occurs of course at a great rate in the very young. For a long time, it was not thought to occur in adult brains — once you were grown, it was thought, all you could do was watch your brain cells die!
Adult neurogenesis (the creation of new brain cells in adult brains) was first discovered in 1965, but only recently has it been accepted as a general phenomenon that occurs in many species, including humans (1998).
Where does adult neurogenesis occur?
It's now widely accepted that adult neurogenesis occurs in the subgranular zone of the dentate gyrus within the hippocampus and the subventricular zone (SVZ) lining the walls of the lateral ventricles within the forebrain. It occurs, indeed, at a quite frantic rate — some 9000 new cells are born in the dentate gyrus every day in young adult rat brains — but under normal circumstances, at least half of those new cells will die within one or two months.
The neurons produced in the SVZ are sent to the olfactory bulb, while those produced in the dentate gyrus are intended for the hippocampus.
Adult neurogenesis might occur in other regions, but this is not yet well-established. However, recent research has found that small, non-pyramidal, inhibitory interneurons are being created in the cortex and striatum. These new interneurons appear to arise from a previously unknown class of local precursor cells. These interneurons make and secrete GABA (see below for why GABA is important), and are thought to play a role in regulating larger types of neurons that make long-distance connections between brain regions.
How does neurogenesis occur?
New neurons are spawned from the division of neural precursor cells — cells that have the potential to become neurons or support cells. How do they decide whether to remain a stem cell, turn into a neuron, or a support cell (an astrocyte or oligodendrocyte)?
Observation that neuroblasts traveled to the olfactory bulb from the SVZ through tubes formed by astrocytes has led to an interest in the role of those support cells. It's now been found that astrocytes encourage both precursor cell proliferation and their maturation into neurons — precursor cells grown on glia divide about twice as fast as they do when grown on fibroblasts, and are about six times more likely to become neurons.
Adult astrocytes are only about half as effective as embryonic astrocytes in promoting neurogenesis.
It’s been suggested that the role of astrocytes may help explain why neurogenesis only occurs in certain parts of the brain — it may be that there’s something missing from the glial cells in those regions.
The latest research suggests that the astrocytes influence the decision through a protein that it secretes called Wnt3. When Wnt3 proteins were blocked in the brains of adult mice, neurogenesis decreased dramatically; when additional Wnt3 was introduced, neurogenesis increased.
How are these new neurons then integrated into existing networks? Mouse experiments have found that the brain chemical called GABA is critical. Normally, GABA inhibits neuronal signals, but it turns out that with new neurons, GABA has a different effect: it excites them, and prepares them for integration into the adult brain. Thus a constant flood of GABA is needed initially; the flood then shifts to a more targeted pulse that gives the new neuron specific connections that communicate using GABA; finally, the neuron receives connections that communicate via another chemical, glutamate. The neuron is now ready to function as an adult neuron, and will respond to glutamate and GABA as it should.
The creation and development of new neurons in the adult brain is very much a "hot" topic right now — it's still very much a work-in-progress. However, it is clear that other brain chemicals are also involved. An important one is BDNF (brain-derived neurotrophic factor), which seems to be needed during the proliferation of hippocampal precursor cells to trigger their transformation into neurons.
Other growth factors have been found to stimulate proliferation of hippocampal progenitor cells: FGF-2 (fibroblast growth factor-2) and EGF (epidermal growth factor).
Recently it has been discovered that the normal form of the prion protein which, when malformed, causes mad cow disease, is also involved in neurogenesis. These proteins, in their normal form, are found throughout our bodies, and particularly in our brains. Now it seems that the more of these prion proteins that are available, the faster neural precursor cells turn into neurons.
The immune system's T cells (which recognize brain proteins) are also critically involved in enabling neurogenesis to occur. Among mice given environmental enrichment, only those with healthy T-cells had their production of new neurons boosted.
Factors that influence neurogenesis
A number of factors have been found to affect the creation and survival of new neurons. For a start, damage to the brain (from a variety of causes) can provoke neurogenesis.
Moderate alcohol consumption over a relatively long period of time can also enhance the formation of new nerve cells in the adult brain (this may be related to alcohol's enhancement of GABA's function). Excess alcohol, however, has a detrimental effect on the formation of new neurons in the adult hippocampus. But although neurogenesis is inhibited during alcohol dependency, it does recover. A pronounced increase in new neuron formation in the hippocampus was found within four-to-five weeks of abstinence. This included a twofold burst in brain cell proliferation at day seven of abstinence.
Most drugs of abuse such as nicotine, heroine, and cocaine suppress neurogenesis, but a new study suggests that cannabinoids also promote neurogenesis. The study involved a synthetic cannabinoid, which increased the proliferation of progenitor cells in the hippocampal dentate gyrus of mice, in a similar manner as some antidepressants have been shown to do. The cannabinoid also produced similar antidepressant effects. Further research is needed to confirm this early finding.
If antidepressants promote neurogenesis, it won't be surprising to find that chronic stress, anxiety and depression are associated with losing hippocampal neurons. A rat study has also found that stress in early life can permanently impair neurogenesis in the hippocampus.
Showing the other side of this picture, perhaps, an intriguing rat study found that status affected neurogenesis in the hippocampus, with high-status animals having around 30% more neurons in their hippocampus after being placed in a naturalistic setting with other rats.
Also, a study into the brains of songbirds found that birds living in large groups have more new neurons and probably a better memory than those living alone.
Both physical activity and environmental enrichment (“mental stimulation”) have been shown to affect both how many cells are born in the dentate gyrus of rats and how many survive. Learning that uses the hippocampus has also been shown to have a positive effect, although results here have been inconsistent.
Inconsistent results from studies looking at neurogenesis are, it is suggested, largely because of a confusion between proliferation and survival. Neurogenesis is measured in terms of these two factors, which researchers often fail to distinguish between: the generation of new brain cells, and their survival. But these are separate factors, that are independently affected by various factors.
The inconsistency found in the effects of learning may also be partly explained by the complex nature of the effects. For example, during the later phase of learning, when performance is starting to plateau, neurons created during the late phase were more likely to survive, but neurons created during the early phase of more rapid learning disappeared. It’s speculated that that this may be a “pruning” process by which cells that haven’t made synaptic connections are removed from the network.
And finally, rodent studies suggest a calorie-restricted diet may also be of benefit.
It's not all about growing new neurons
A few years ago, we were surprised by news that new neurons could be created in the adult brain. However, it’s remained a tenet that adult neurons don’t grow — this because researchers have found no sign that any structural remodelling takes place in an adult brain. Now a mouse study using new techniques has revealed that dramatic restructuring occurs in the less-known, less-accessible inhibitory interneurons. Dendrites (the branched projections of a nerve cell that conducts electrical stimulation to the cell body) show sometimes dramatic growth, and this growth is tied to use, supporting the idea that the more we use our minds, the better they will be.
- Aberg, E., Hofstetter, C., Olson, L. & Brené, S. 2005. Moderate ethanol consumption increases hippocampal cell proliferation and neurogenesis in the adult mouse. International Journal of Neuropsychopharmacology, 8(4), 557-567.
- Bull, N.D. & Bartlett, P.F. 2005. The Adult Mouse Hippocampal Progenitor Is Neurogenic But Not a Stem Cell. Journal of Neuroscience, 25, 10815-10821.
- Dayer, A.G., Cleaver, K.M., Abouantoun, T. & Cameron, H.A. 2005. New GABAergic interneurons in the adult neocortex and striatum are generated from different precursors. Journal of Cell Biology, 168, 415-427.
- Döbrössy, M.D., Drapeau, E., Aurousseau, C., Le Moal, M., Piazza, P.V. & Abrous, D.N. 2003. Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date. Molecular Psychiatry, 8, 974-982.
- Ge, S., Goh, E.L.K., Sailor, K.A., Kitabatake, Y., Ming, G-L. & Song, H. 2005. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature advance online publication; published online 11 December 2005
- Hairston, I.S., Little, M.T.M., Scanlon, M.D., Barakat, M.T., Palmer, T.D., Sapolsky, R.M. & Heller, H.C. 2005. Sleep Restriction Suppresses Neurogenesis Induced by Hippocampus-Dependent Learning. Journal of Neurophysiology, 94 (6), 4224-4233.
- Jiang, W. et al. 2005. Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. Journal of Clinical Investigation, 115, 3104-3116.
- Johnson, R.A., Rhodes, J.S., Jeffrey, S.L., Garland, T. Jr., & Mitchell, G.S. 2003. Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running. Neuroscience, 121(1), 1-7.
- Karten, Y.J.G., Olariu, A. & Cameron, H.A. 2005. Stress in early life inhibits neurogenesis in adulthood. Trends in Neurosciences, 28 (4), 171-172.
- Kozorovitskiy, Y. & Gould, E.J. 2004. Dominance Hierarchy Influences Adult Neurogenesis in the Dentate Gyrus. The Journal of Neuroscience,24(30), 6755-6759.
- Lee, J., Duan, W., Long, J.M., Ingram, D.K. & Mattson, M.P. 2000. Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats. Journal of Molecular Neuroscience, 15(2), 99-108.
- Lie, D-C., Colamarino, S.A., Song, H-J., Désiré, L., Mira, H., Consiglio, A., Lein, E.S., Jessberger, S., Lansford, H., Dearie, A.R. & Gage, F.H. 2005. Wnt signalling regulates adult hippocampal neurogenesis. Nature, 437, 1370-1375.
- Lipkind, D., Nottebohm, F., Rado, R. & Barnea, A.2002. Social change affects the survival of new neurons in the forebrain of adult songbirds. Behavioural Brain Research, 133 (1), 31-43.
- Lombardino, A.J., Li, X-C., Hertel, M & Nottebohm, F. 2005. Replaceable neurons and neurodegenerative disease share depressed UCHL1 levels. PNAS, 102(22), 8036-8041.
- Nixon, K. & Crews, F.T. 2004. Temporally Specific Burst in Cell Proliferation Increases Hippocampal Neurogenesis in Protracted Abstinence from Alcohol. Journal of Neuroscience, 24, 9714-9722.
- Prickaerts, J., Koopmans, G., Blokland, A. & Scheepens, A. 2004. Learning and adult neurogenesis: Survival with or without proliferation? Neurobiology of Learning and Memory, 81, 1-11.
- Santarelli, L. et al. 2003. Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants. Science, 301(5634), 805-809.
- Song, H., Stevens, C.F. & Gage, F.H. 2002. Astroglia induce neurogenesis from adult neural stem cells. Nature, 417, 39-44.
- Steele, A.D., Emsley, J.G., Özdinler, P.H., Lindquist, S. & Macklis, J.D. 2006. Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. PNAS, 103, 3416-3421.
- Yoshimura, S. et al. 2003. FGF-2 regulates neurogenesis and degeneration in the dentate gyrus after traumatic brain injury in mice. Journal of Clinical Investigation, 112, 1202-1210.
- Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N., Cohen, H., Kipnis, J. & Schwartz, M. 2006. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nature Neuroscience, 9, 268-275.
For more, see the research reports