neurogenesis

Adult Neurogenesis

  • 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.

References: 

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Kozorovitskiy, Y. & Gould, E.J. 2004. Dominance Hierarchy Influences Adult Neurogenesis in the Dentate Gyrus. The Journal of Neuroscience,24(30), 6755-6759.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. Santarelli, L. et al. 2003. Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants. Science, 301(5634), 805-809.
  18. Song, H., Stevens, C.F. & Gage, F.H. 2002. Astroglia induce neurogenesis from adult neural stem cells. Nature, 417, 39-44.
  19. 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.
  20. 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.
  21. 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.

 

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Coping with cognitive decline in MS

Cognitive impairment affects 40-65% of people with MS. Why? In the past year, a number of studies have helped us build a better picture of the precise nature of cognitive problems that may affect multiple sclerosis sufferers:

  • poorer performance on executive function tasks is fully explained by slower processing speed (which is presumably a function of the degradation in white matter characteristic of MS)
  • slowing in processing speed is associated with weaker connections between the executive area and the brain regions involved in carrying out cognitive tasks
  • cognitive reserve helps counter the decline in memory and cognitive efficiency
  • brain reserve (greater brain volume, ie less shrinkage) helps counter the decline in cognitive efficiency
  • working memory capacity explains the link between cognitive reserve and long-term memory
  • subjective cognitive fatigue is linked to the time spent on the task, not on its difficulty
  • mnemonic training helps protect against cognitive decline, but appears to be less helpful in those with slow processing speed.

What all this implies is that a multi-pronged approach is called for, involving:

  • working memory training
  • training in effective memory strategies
  • practice in breaking down cognitive tasks into more manageable chunks of time
  • practice in framing tasks to accommodate slower processing speed
  • physical and mental activities that encourage neurogenesis (growing more neurons) and synaptogenesis (growing more connections).

Here's some more detail on those studies:

Slow processing speed accounts for executive deficits in MS

A study of 50 patients with MS and 28 healthy controls found no differences in performance on executive function tasks when differences in processing speed were controlled for. In other words, although MS patients performed more poorly than controls on these tasks, the difference was fully accounted for by the differences in processing speed. There were no differences in performance when there was no processing speed component to the task. Similarly, MS patients with a greater degree of brain atrophy performed more poorly than those with less atrophy, but again, this only occurred when there was a processing speed aspect to the task, and was fully accounted for by processing speed differences.

http://www.eurekalert.org/pub_releases/2014-09/kf-kfs091614.php

[3939] Leavitt VM, Wylie G, Krch D, Chiaravalloti ND, DeLuca J, Sumowski JF. Does slowed processing speed account for executive deficits in multiple sclerosis? Evidence from neuropsychological performance and structural neuroimaging. Rehabilitation Psychology [Internet]. 2014 ;59(4):422 - 428. Available from: http://doi.apa.org/getdoi.cfm?doi=10.1037/a0037517

Functional connectivity factor in cognitive decline in MS

A brain imaging study involving 29 participants with relapsing-remitting MS and 23 age- and sex- matched healthy controls found that, as expected, those with MS were much slower on a processing speed task, although they were as accurate as the controls. This slowing was associated with weaker functional connections between the dorsolateral prefrontal cortex (the executive area) and the regions responsible for carrying out the task. It's thought that this is probably due to decreased white matter (white matter degradation is symptomatic of MS).

http://www.eurekalert.org/pub_releases/2015-07/cfb-srb070715.php

[3938] Hubbard NA, Hutchison JL, Turner MP, Sundaram S, Oasay L, Robinson D, Strain J, Weaver T, Davis SL, Remington GM, et al. Asynchrony in Executive Networks Predicts Cognitive Slowing in Multiple Sclerosis. Neuropsychology. 2015 .

Brain and cognitive reserve protect against cognitive decline in MS

A study compared memory, cognitive efficiency, vocabulary, and brain volume in 40 patients with MS, at baseline and 4.5 years later. After controlling for disease progression, they found that those with better vocabulary (a proxy for cognitive reserve) experienced less decline in memory and cognitive efficiency, and those with less brain atrophy over the period showed less decline in cognitive efficiency.

Cognitive efficiency is a somewhat fuzzy concept, but essentially has to do with how much time and effort you need to acquire new knowledge; in this study, it was assessed using the Symbol Digit Modalities Test and Paced Auditory Serial Addition Task, two tests commonly used to detect cognitive impairment in MS patients.

http://www.eurekalert.org/pub_releases/2014-04/kf-mrf043014.php

[3943] Sumowski JF, Rocca MA, Leavitt VM, Dackovic J, Mesaros S, Drulovic J, DeLuca J, Filippi M. Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS. Neurology [Internet]. 2014 ;82(20):1776 - 1783. Available from: http://www.neurology.org/cgi/doi/10.1212/WNL.0000000000000433

Working memory capacity accounts for link between cognitive reserve & better memory

A study involving 70 patients with MS has found that working memory capacity explained the relationship between cognitive reserve and long-term memory, suggesting that interventions targeted at working memory may help protect against decline in long-term memory.

http://www.eurekalert.org/pub_releases/2014-09/kf-kfm090914.php

[3941] Sandry J, Sumowski JF. Working Memory Mediates the Relationship between Intellectual Enrichment and Long-Term Memory in Multiple Sclerosis: An Exploratory Analysis of Cognitive Reserve. Journal of the International Neuropsychological Society [Internet]. 2014 ;20(08):868 - 872. Available from: http://www.journals.cambridge.org/abstract_S1355617714000630

Cognitive fatigue linked to time on task, not difficulty

A study investigating cognitive fatigue in 32 individuals with MS and 24 controls has found that subjective and objective fatigue were independent of one another, and that subjective cognitive fatigue increased as time on task increased. This increase in cognitive fatigue was greater in the MS group. No relationship was found between cognitive fatigue and cognitive load. Fatigue was greater for the processing speed task than the working memory task.

In other words, the length of time spent is far more important than the difficulty of the task.

http://www.eurekalert.org/pub_releases/2015-01/kf-kfr012115.php

[3940] Sandry J, Genova HM, Dobryakova E, DeLuca J, Wylie G. Subjective cognitive fatigue in multiple sclerosis depends on task length. Frontiers in Neurology. 2014 ;5:214.

Story mnemonic training helps some

A series of small studies have found cognitive benefits for MS patients from a 10-session training program designed to build their memory skills using a modified story mnemonic. The MEMREHAB Trial involved 85 patients with MS, of whom 45 received the training. In the most recent analyses of the data, the benefits were found to be maintained six months later, but unfortunately, it appears that those with processing speed deficits gain less benefit from the training.

The training consists of four 45-minute sessions focused on building imagery skills, in which participants were given a story with highly visualizable scenes and given facilitated practice in using visualization to help them remember the story. In the next four sessions, they were given lists of words and instructed in how to build a memorable story from these words, that they could visualize. The sessions employed increasingly unrelated word lists. In the final two sessions, participants were taught how to apply the technique in real-world situations.

http://www.eurekalert.org/pub_releases/2014-08/kf-kfs080814.php

[3936] Chiaravalloti ND, DeLuca J. The influence of cognitive dysfunction on benefit from learning and memory rehabilitation in MS: A sub-analysis of the MEMREHAB trial. Multiple Sclerosis (Houndmills, Basingstoke, England). 2015 .

[3937] Dobryakova E, Wylie GR, DeLuca J, Chiaravalloti ND. A pilot study examining functional brain activity 6 months after memory retraining in MS: the MEMREHAB trial. Brain Imaging and Behavior [Internet]. 2014 ;8(3):403 - 406. Available from: http://link.springer.com/10.1007/s11682-014-9309-9

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Neurogenesis

Older news items (pre-2010) brought over from the old website

Neurogenesis improved in Alzheimer mice

Studies of adult neurogenesis in genetically engineered mice have revealed two main reasons why amyloid-beta peptides and apolipoprotein E4 impair neurogenesis, and identified drug treatments that can fix it. The findings point to a deficit in GABAergic neurotransmission or an imbalance between GABAergic and glutamatergic neurotransmission as an important contributor to impaired neurogenesis in Alzheimer’s. While stem cell therapy for Alzheimer’s is still a long way off, these findings are a big step toward that goal.

Gang Li et al. 2009. GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knockin Mice. Cell Stem Cell, 5 (6), 634-645.

Binggui Sun et al. 2009. Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer's Disease. Cell Stem Cell, 5 (6), 624-633.

http://www.eurekalert.org/pub_releases/2009-12/gi-gsi113009.php

Mouse study points to possible treatment for chemobrain

A mouse study has found that four commonly used chemotherapy drugs disrupt neurogenesis, and that the condition could be partially reversed with the growth hormone IGF-1. Surprising the researchers, both the drugs which cross the blood-brain barrier (cyclophosphamide and fluorouracil) and the two that don’t (paclitaxel and doxorubicin) reduced neurogenesis, with fluorouracil producing a 15.4% reduction, compared to 22.4% with doxorubicin, 30.5% with cyclophosphamide, 36% with paclitaxel. A second study of a single high dose of cyclophosphamide, a mainstay of breast cancer treatment, resulted in a 40.9% reduction. Administration of the experimental growth hormone IGF-1 helped in all cases, but was more effective with the high dose.

[1472] Janelsins MC, Roscoe JA, Michel J. Berg, Thompson BD, Gallagher MJ, Morrow GR, Charles E. Heckler, Jean-Pierre P, Opanashuk LA, Robert A. Gross. IGF-1 Partially Restores Chemotherapy-Induced Reductions in Neural Cell Proliferation in Adult C57BL/6 Mice. Cancer Investigation [Internet]. 2009 . Available from: http://informahealthcare.com/doi/abs/10.3109/07357900903405942

http://www.eurekalert.org/pub_releases/2009-12/uorm-usr121709.php

Nerve-cell transplants help brain-damaged rats recover lost ability to learn

After destroying neurons in the subiculum of 48 adult rats, some were given hippocampal cells taken from newborn transgenic mice. On spatial memory tests two months later, the rats given cell transplants performed as well as rats which had not had their subiculums damaged; however, those without transplants had significantly impaired performance. The new cells were found to have mainly settled in the dentate gyrus, where they appeared to promote the secretion of two types of growth factors, namely BDNF and basic fibroblast growth factor (bFGF).

Rekha, J. et al. 2009. Transplantation of hippocampal cell lines restore spatial learning in rats with ventral subicular lesions. Behavioral Neuroscience, 123(6), 1197-1217.

http://www.eurekalert.org/pub_releases/2009-12/apa-nth120909.php

Adult neurogenesis important for discriminating things that are close

A mouse study adds to our understanding of the role of adult neurogenesis — the birth of new brain cells in adults. Mice whose ability to grow new brain cells in the dentate gyrus was removed were able to learn a new location of a food reward in an eight-armed radial maze, but only when the new location was far enough from the original location. This inability to discriminate close locations was confirmed in a touch screen experiment. Computer modeling suggested that this benefit of new neurons might also apply to temporal information, helping us distinguish events occurring closely in time.

[501] Gage FH, Bussey TJ, Clelland CD, Choi M, Romberg C, Clemenson GD, Fragniere A, Tyers P, Jessberger S, Saksida LM, et al. A Functional Role for Adult Hippocampal Neurogenesis in Spatial Pattern Separation. Science [Internet]. 2009 ;325(5937):210 - 213. Available from: http://www.sciencemag.org/cgi/content/abstract/325/5937/210

http://www.eurekalert.org/pub_releases/2009-07/si-nbc070609.php

Baby neurons time-stamp new memories

Since its discovery ten years, adult neurogenesis has been a fruitful area of research, but although we know it’s important for learning and memory, we’re still a little vague on how. Now a new computational model suggests that immature cells are very excitable, easily provoked into firing, while older neurons are more discriminating. The dentate gyrus is designed to separate new memories into separate events (pattern separation), but the indiscriminate excitability of newborn neurons means they link events and memories that happen around the same time (pattern integration) instead. As the brain cells mature, they settle down and join established neural circuits, taking on their proper role, but clusters of neurons that "grew up" around the same time still retain the memories forged in their youth. Which is why independent events that have nothing in common but the fact that they occurred at the same time are connected in our minds: baby neurons have ‘time-stamped’ them.

[785] Aimone JB, Wiles J, Gage FH. Computational Influence of Adult Neurogenesis on Memory Encoding. Neuron [Internet]. 2009 ;61(2):187 - 202. Available from: http://www.cell.com/neuron/abstract/S0896-6273(08)01019-2

http://www.the-scientist.com/blog/display/55385/
http://www.eurekalert.org/pub_releases/2009-01/si-nbc012209.php

New brain cells are essential for learning

It was only a short time ago that it was accepted wisdom that new neurons were only created during childhood and that being an adult meant facing the gradual death, without replacement, of those neurons. Then, nearly a decade ago, it was discovered that adult brains could create new brain cells, albeit in a very limited way. However, it still hasn’t been clear how important adult neurogenesis is for learning and memory. Now a mouse study makes it clear that in one of the two regions in which neurogenesis takes place, it really is necessary. The study is the first to simultaneously study the two brain regions that produce new neurons, the subventricular zone and the dentate gyrus. Continual cell death was observed in the olfactory bulb, suggesting that newly born neurons (from the subventricular zone) are necessary to take their place. Neurons in the dentate gyrus, however, did not die regularly. However, when neurogenesis was knocked out in the olfactory bulb, no deficits occurred in smell memory, while the same action in the dentate gyrus did result in problems with spatial memory. The findings perhaps open up more questions than they answer — such as how odor memory is maintained when neurons in the olfactory bulb are being continuously replaced.

[1087] Kageyama R, Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M, Mori K, Ikeda T, Itohara S. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci [Internet]. 2008 ;11(10):1153 - 1161. Available from: http://dx.doi.org/10.1038/nn.2185

http://www.the-scientist.com/blog/display/54993/
http://www.newscientist.com/channel/being-human/dn14630-new-brain-cells-are-essential-for-learning.html

Injection of human umbilical cord blood helps aging brain

A rat study has found that a single intravenous injection of human umbilical cord blood mononuclear cells in aged rats significantly improved the microenvironment of the aged hippocampus and rejuvenated the aged neural stem/progenitor cells. The increase in neurogenesis seemed to be due to a decrease in inflammation. The results raise the possibility of cell therapy to rejuvenate the aged brain.

[686] Bachstetter A, Pabon M, Cole M, Hudson C, Sanberg P, Willing A, Bickford P, Gemma C. Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain. BMC Neuroscience [Internet]. 2008 ;9(1):22 - 22. Available from: http://www.biomedcentral.com/1471-2202/9/22

http://www.physorg.com/news124384387.html

REM sleep deprivation reduces neurogenesis

And in another sleep study, rats deprived of REM sleep for four days showed reduced cell proliferation in the dentate gyrus of the hippocampus, where most adult neurogenesis takes place. The finding indicates that REM sleep is important for brain plasticity.

[507] Guzman-Marin R, Suntsova N, Bashir T, Nienhuis R, Szymusiak R, McGinty D. Rapid eye movement sleep deprivation contributes to reduction of neurogenesis in the hippocampal dentate gyrus of the adult rat. Sleep [Internet]. 2008 ;31(2):167 - 175. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18274263

http://www.eurekalert.org/pub_releases/2008-02/aaos-fdo012808.php

Adult neurogenesis confirmed in primates

A study with marmosets has confirmed that the rate at which new neural cells form in the hippocampus (neurogenesis) begins to decline soon after reaching adulthood. This is the first study to confirm the finding from rodent studies in primates, and confirms that findings from rodent studies regarding ways of enhancing adult neurogenesis can be applied to primates.

[1373] Leuner B, Kozorovitskiy Y, Gross CG, Gould E. Diminished adult neurogenesis in the marmoset brain precedes old age. Proceedings of the National Academy of Sciences [Internet]. 2007 ;104(43):17169 - 17173. Available from: http://www.pnas.org/content/104/43/17169.abstract

http://www.physorg.com/news111690164.html
http://www.eurekalert.org/pub_releases/2007-10/pu-bcg101207.php

Research explains how lead exposure produces learning deficits

A rat study has shown how exposure to lead during brain development produces learning deficits — by reducing neurogenesis, and by altering the normal development of newly born neurons in the hippocampus. Dendrites (branches from neurons that make the connections with other neurons) were shorter and twisted in lead-exposed rats.

[738] Verina T, Rohde CA, Guilarte TR. Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats. Neuroscience [Internet]. 2007 ;145(3):1037 - 1047. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17276012

http://www.eurekalert.org/pub_releases/2007-04/jhub-reh040307.php

New research shows why too much memory may be a bad thing

People who are able to easily and accurately recall historical dates or long-ago events may have a harder time with word recall or remembering the day's current events. A mouse study reveals why. Neurogenesis has been thought of as a wholly good thing — having more neurons is surely a good thing — but now a mouse study has found that stopping neurogenesis in the hippocampus improved working memory. Working memory is highly sensitive to interference from information previously stored in memory, so it may be that having too much information may hinder performing everyday working memory tasks.

[635] Saxe MD, Malleret G, Vronskaya S, Mendez I, Garcia DA, Sofroniew MV, Kandel ER, Hen R. Paradoxical influence of hippocampal neurogenesis on working memory. Proceedings of the National Academy of Sciences [Internet]. 2007 ;104(11):4642 - 4646. Available from: http://www.pnas.org/content/104/11/4642.abstract

Full text is available at http://www.pnas.org/cgi/reprint/104/11/4642

http://www.physorg.com/news94384934.html
http://www.sciencedaily.com/releases/2007/03/070329092022.htm
http://www.eurekalert.org/pub_releases/2007-03/cumc-nrs032807.php

Sleep deprivation affects neurogenesis

A rat study has found that rats deprived of sleep for 72 hours had higher levels of the stress hormone corticosterone, and produced significantly fewer new brain cells in a particular region of the hippocampus. Preventing corticosterone levels from rising also prevented the reduction in neurogenesis.

[642] Mirescu C, Peters JD, Noiman L, Gould E. Sleep deprivation inhibits adult neurogenesis in the hippocampus by elevating glucocorticoids. Proceedings of the National Academy of Sciences [Internet]. 2006 ;103(50):19170 - 19175. Available from: http://www.pnas.org/content/103/50/19170.abstract

http://news.bbc.co.uk/2/hi/health/6347043.stm

Why neurogenesis is so much less in older brains

A rat study has revealed that the aging brain produces progressively fewer new nerve cells in the hippocampus (neurogenesis) not because there are fewer of the immature cells (neural stem cells) that can give rise to new neurons, but because they divide much less often. In young rats, around a quarter of the neural stem cells were actively dividing, but only 8% of cells in middle-aged rats and 4% in old rats were. This suggests a new approach to improving learning and memory function in the elderly.

[1077] Hattiangady B, Shetty AK. Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus. Neurobiology of Aging [Internet]. 2008 ;29(1):129 - 147. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17092610

http://www.eurekalert.org/pub_releases/2006-12/dumc-sca121806.php

Neurogenesis not the sole cause of enriched environment effects

The creation of new neurons in the hippocampus (adult neurogenesis) and improved cognitive function have been repeatedly found in tandem with a more stimulating environment, and it’s been assumed that the improvement in cognitive function has resulted from the neurogenesis. However, a new study has produced the startling finding that if neurogenesis is prevented, an enriched environment still produces improved spatial memory skills and less anxiety in mice. This doesn't mean adult neurogenesis plays no role, but it does indicate that neurogenesis is not the whole story.

[601] Meshi D, Drew MR, Saxe M, Ansorge MS, David D, Santarelli L, Malapani C, Moore H, Hen R. Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nat Neurosci [Internet]. 2006 ;9(6):729 - 731. Available from: http://dx.doi.org/10.1038/nn1696

http://sciencenow.sciencemag.org/cgi/content/full/2006/503/1?etoc

Losing sleep inhibits neurogenesis

A new sleep study using rats restricted rather than deprived them of sleep, to mimic more closely the normal human experience. The study found that the sleep-restricted rats had a harder time remembering a path through a maze compared to their rested counterparts. The sleep-restricted rats showed reduced survival rate of new hippocampus cells — learning spatial tasks increases the production of new cells in the hippocampus. This study shows that sleep plays a part in helping those new brain cells survive. However, the sleep-restricted rats that were forced to use visual and odor cues to remember their way through the maze did better on the task than their rested counterparts, implying that some types of learning don’t require sleep.

[994] Hairston IS, Little MTM, Scanlon MD, Barakat MT, Palmer TD, Sapolsky RM, Heller CH. Sleep Restriction Suppresses Neurogenesis Induced by Hippocampus-Dependent Learning. J Neurophysiol [Internet]. 2005 ;94(6):4224 - 4233. Available from: http://jn.physiology.org/cgi/content/abstract/94/6/4224

http://www.eurekalert.org/pub_releases/2006-01/aps-lsu010506.php

Fitness counteracts cognitive decline from hormone-replacement therapy

A study of 54 postmenopausal women (aged 58 to 80) suggests that being physically fit offsets cognitive declines attributed to long-term hormone-replacement therapy. It was found that gray matter in four regions (left and right prefrontal cortex, left parahippocampal gyrus and left subgenual cortex) was progressively reduced with longer hormone treatment, with the decline beginning after more than 10 years of treatment. Therapy shorter than 10 years was associated with increased tissue volume. Higher fitness scores were also associated with greater tissue volume. Those undergoing long-term hormone therapy had more modest declines in tissue loss if their fitness level was high. Higher fitness levels were also associated with greater prefrontal white matter regions and in the genu of the corpus callosum. The findings need to be replicated with a larger sample, but are in line with animal studies finding that estrogen and exercise have similar effects: both stimulate brain-derived neurotrophic factor.

[375] Erickson KI, Colcombe SJ, Elavsky S, McAuley E, Korol DL, Scalf PE, Kramer AF. Interactive effects of fitness and hormone treatment on brain health in postmenopausal women. Neurobiology of Aging [Internet]. 2007 ;28(2):179 - 185. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16406152

http://www.eurekalert.org/pub_releases/2006-01/uoia-fcc012406.php

Immune function important for cognition

New research overturns previous beliefs that immune cells play no part in — and may indeed constitute a danger to — the brain. Following on from an earlier study that suggested that T cells — immune cells that recognize brain proteins — have the potential to fight off neurodegenerative conditions such as Alzheimer’s, researchers have found that neurogenesis in adult rats kept in stimulating environments requires these immune cells. A further study found that mice with these T cells performed better at some tasks than mice lacking the cells. The researchers suggest that age-related cognitive decline may be related to this, as aging is associated with a decrease in immune system function, suggesting that boosting the immune system may also benefit cognitive function in older adults.

[435] Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci [Internet]. 2006 ;9(2):268 - 275. Available from: http://dx.doi.org/10.1038/nn1629

http://www.eurekalert.org/pub_releases/2006-01/acft-wis011106.php

How new neurons are integrated in the adult brain

Now that we accept that new neurons can indeed be created in adult brains, the question becomes: how are these new neurons integrated into existing networks? Mouse experiments have now found that a 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. It’s hoped the discovery will help efforts to increase neuron regeneration in the brain or to make transplanted stem cells form connections more efficiently.

[237] Ge S, Goh ELK, Sailor KA, Kitabatake Y, Ming G-li, Song H. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature [Internet]. 2006 ;439(7076):589 - 593. Available from: http://dx.doi.org/10.1038/nature04404

http://www.eurekalert.org/pub_releases/2005-12/jhmi-nnt122205.php

Neuron growth in adult brain

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 remodeling 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. The finding also offers new hope that one day it may be possible to grow new cells to replace ones damaged by disease or spinal cord injury.

Lee, W.C.A., Huang, H., Feng, G., Sanes, J.R., Brown, E.N. et al. 2006. Dynamic remodeling of dendritic arbors in GABAergic interneurons of adult visual cortex. PLoS Biol 4(2): e29.

Full text available at http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040042

http://www.eurekalert.org/pub_releases/2005-12/miot-mrf122205.php
http://www.eurekalert.org/pub_releases/2005-12/plos-anw122205.php

More light on adult neurogenesis; implications for dementia and brain injuries

New research has demonstrated that adult mice produce multi-purpose, or progenitor, cells in the hippocampus, and indicates that the stem cells ultimately responsible for adult hippocampal neurogenesis actually reside outside the hippocampus, producing progenitor cells that migrate into the neurogenic zones and proliferate to produce new neurons and glia. The finding may help in the development of repair mechanisms for people suffering from dementia and acquired brain injury.

[977] Bull ND, Bartlett PF. The Adult Mouse Hippocampal Progenitor Is Neurogenic But Not a Stem Cell. J. Neurosci. [Internet]. 2005 ;25(47):10815 - 10821. Available from: http://www.jneurosci.org/cgi/content/abstract/25/47/10815

http://www.eurekalert.org/pub_releases/2005-11/ra-nrt112305.php

Wnt signaling vital for adult neurogenesis

Neurogenesis (the birth of new neurons) only occurs in adult brains in two areas: the lateral ventricle, and the dentate gyrus (in the hippocampus). New neurons are spawned from the division of stem cells — but how do they decide whether to remain a stem cell, turn into a neuron, or a support cell (an astrocyte or oligodendrocyte)? A new study has pinpointed the protein that provides a vital chemical signal that helps this decision in the hippocampus. When Wnt3 proteins were blocked in the brains of adult mice, neurogenesis decreased dramatically; when additional Wnt3 was introduced, neurogenesis increased. Wnt3 molecules are secreted by astrocytes.

[537] Dearie AR, Gage FH, Lie D-C, Colamarino SA, Song H-J, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature [Internet]. 2005 ;437(7063):1370 - 1375. Available from: http://dx.doi.org/10.1038/nature04108

http://www.eurekalert.org/pub_releases/2005-10/si-wsc102405.php

Why premature brains improve over time

A new study explains why premature babies often develop better than expected. A mouse study has found that infants born prematurely and with hypoxia (inadequate oxygen to the blood) are able to recover some cells, volume and weight in the brain after oxygen supply is restored, by a process of neurogenesis.

[1402] Fagel DM, Ganat Y, Silbereis J, Ebbitt T, Stewart W, Zhang H, Ment LR, Vaccarino FM. Cortical neurogenesis enhanced by chronic perinatal hypoxia. Experimental Neurology [Internet]. 2006 ;199(1):77 - 91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15916762

http://www.eurekalert.org/pub_releases/2005-06/yu-gsh062705.php

One gene links neurogenesis with neurodegenerative diseases such as Alzheimer's

It used to be thought that the neurons we were born with (or created soon after birth) were all that we could ever have. Then it was discovered that certain neurons in specific brain regions, could be created in an adult brain (neurogenesis). A recent study has investigated the question of what’s different about these neurons, and to the researchers’ surprise, has discovered that replaceable neurons differed from unreplaceable neurons by having persistently low levels of a particular gene known as UCHL1. Intriguingly, UCHL1, expressed as a protein in high quantities throughout the brain, has also been identified as being deficient in degenerative diseases such as Alzheimer's and Parkinson's. Further research revealed that behavior that increases the chance of new neurons surviving is also associated with increases in the level of UCHL1 in replaceable neurons. The findings suggest that rising levels of UCHL1 may be associated with a reduced risk of neuronal death.

[336] Lombardino AJ, Li X-C, Hertel M, Nottebohm F. Replaceable neurons and neurodegenerative disease share depressed UCHL1 levels. Proceedings of the National Academy of Sciences of the United States of America [Internet]. 2005 ;102(22):8036 - 8041. Available from: http://www.pnas.org/content/102/22/8036.abstract

http://www.eurekalert.org/pub_releases/2005-05/ru-ogl052005.php

Social status influences brain structure

A rat study has found that dominant rats have more new nerve cells in the hippocampus than their subordinates, suggesting that social hierarchies can influence brain structure. Seven colonies of 6 rats (4 male and 2 female) established their pecking order within three days, and were tested two weeks later. The dominant males had some 30% more neurons in their dentate gyrus than both the subordinate rats and controls. The increase seems to be because the new cells constantly being born in this area of the brain (most of which usually die within a week) were surviving longer. Hippocampal neurons have already been shown to be responsive to negative factors such as stress, and positive factors such as exercise and environmental enrichment. The increase in neurons was maintained when the rats were removed from the social setting.

[372] Kozorovitskiy Y, Gould E. Dominance Hierarchy Influences Adult Neurogenesis in the Dentate Gyrus. J. Neurosci. [Internet]. 2004 ;24(30):6755 - 6759. Available from: http://www.jneurosci.org/cgi/content/abstract/24/30/6755

http://www.nature.com/news/2004/040802/full/040802-18.html

Learning involves the death of neurons too

When we think about learning at the neural level, it is always the birth of new neurons and new synaptic connections that is thought of. Now it appears that death is involved too. A recent rat study has found that while new cells are being generated in the hippocampus, other cells are dying off. The study distinguished two phases of learning during a water maze task: the first phase, when the rat learns to navigate the maze; and the second phase, when the learned behavior is refined. During the second phase, it appears, new cells are born in the dentate gyrus, while some of the cells that were born during the first phase, disappear. If true, this could be "a trimming mechanism that suppresses neurons that have not established learning-related synaptic connections."

[724] Dobrossy MD, Drapeau E, Aurousseau C, Le Moal M, Piazza PV, Abrous DN. Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date. Mol Psychiatry [Internet]. 0 ;8(12):974 - 982. Available from: http://dx.doi.org/10.1038/sj.mp.4001419

http://www.eurekalert.org/pub_releases/2003-11/mp-cdp112103.php

FGF-2 implicated in adult neurogenesis

The whole question of neurogenesis (the making of new neurons) in the adult brain has been much debated – does neurogenesis happen? how does it happen? how much does it happen? Well, recent research has appeared to answer the first question – yes, neurogenesis does happen in the adult brain – and now a new study provides some clarification about the mechanism. Experiments with a special strain of laboratory-bred mice indicate that fibroblast growth factor-2 (FGF-2) is at least partly responsible for regulating the replacement of neurons, and suggest that supplementation with FGF-2 might be a beneficial strategy for those suffering traumatic brain injury, by both enhancing neurogenesis and reducing neurodegeneration.

[887] Moskowitz MA, Yoshimura S, Teramoto T, Whalen MJ, Irizarry MC, Takagi Y, Qiu J, Harada J, Waeber C, Breakefield XO. FGF-2 regulates neurogenesis and degeneration in the dentate gyrus after traumatic brain injury in mice. Journal of Clinical Investigation [Internet]. 2003 ;112(8):1202 - 1210. Available from: http://www.jci.org/articles/view/16618?search%5Babstract_text%5D=&search%5Barticle_text%5D=&search%5Bauthors_text%5D=&search%5Bfpage%5D=1202&search%5Bissue%5D=&search%5Btitle_text%5D=&search%5Bvolume%5D=112

http://www.biomedcentral.com/news/20031016/03

Too much exercise may be bad for the brain

Mice bred for 30 generations to display increased voluntary wheel running behavior – an "exercise addiction" – showed much higher amounts of BDNF (brain-derived neurotrophic factor – a chemical involved in protecting and producing neurons in the hippocampus) than normal, sedentary mice. In a related study, it was found that the mice also grow more neurons there as well. However, while BDNF and neurogenesis are good for learning and memory, this doesn’t necessarily mean an exercise addict learns at a faster rate. The “running addict” mice in fact performed much worse than normal mice when attempting to navigate around a maze. It could be that too much BDNF and neuron production may be a bad thing, or it may be that the hyperactive wheel running exercise actually kills or damages neurons in the hippocampus, and the high BDNF production is simply trying to minimize this damage. At the moment, all we can say with surety is that exercise greatly activates the hippocampus.

[747] Johnson RA, Rhodes JS, Jeffrey SL, Garland T, Mitchell GS. Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running. Neuroscience [Internet]. 2003 ;121(1):1 - 7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12946694

[504] Rhodes JS, van Praag H, Jeffrey S, Girard I, Mitchell GS, Garland, Theodore J, Gage FH. Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running. Behavioral Neuroscience [Internet]. 2003 ;117(5):1006 - 1016. Available from: http://psycnet.apa.org/journals/bne/117/5/1006/

http://www.eurekalert.org/pub_releases/2003-09/ohs-cn092603.php

Rat studies provide more evidence on why aging can impair memory

Among aging rats, those that have difficulty navigating water mazes have no more signs of neuron damage or cell death in the hippocampus, a brain region important in memory, than do rats that navigate with little difficulty. Nor does the extent of neurogenesis (birth of new cells in an adult brain) seem to predict poorer performance. Although the researchers have found no differences in a variety of markers for postsynaptic signals between elderly rats with cognitive impairment and those without, decreases in a presynaptic signal are correlated with worse cognitive impairment. That suggests that neurons in the impaired rat brains may not be sending signals correctly.

Gallagher, M. 2002. Markers for memory decline. Paper presented at the Society for Neuroscience annual meeting in Orlando, Florida, 5 November

New neurons in adult brains are functional

Following studies indicating that new neurons are generated in the adult mammalian hippocampus, this study demonstrates that these newly generated cells do mature into functional neurons.

[590] van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature [Internet]. 2002 ;415(6875):1030 - 1034. Available from: http://dx.doi.org/10.1038/4151030a

Living in large groups could give you a better memory

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. Does this have relevance for humans? We don't know yet, but it has been observed that social animals such as elephants tend to have better memories than loners.

[774] Lipkind D, Nottebohm F, Rado R, Barnea A. Social change affects the survival of new neurons in the forebrain of adult songbirds. Behavioural Brain Research [Internet]. 2002 ;133(1):31 - 43. Available from: http://www.sciencedirect.com/science/article/B6SYP-44HXHXB-2/2/b08159d165c2f37ddc4145359a1f2fbd

http://www.eurekalert.org/pub_releases/2002-02/ns-lil022002.php

http://www.newscientist.com/article/mg17323312.700-the-brainy-bunch.html

New study contradicts earlier finding of new brain cell growth in the adult primate neocortex

A very exciting finding a couple of years ago, was that adult monkeys were found to be able to create new neurons in the neocortex, the most recently evolved part of the brain. However a new study, using the most sophisticated cell analysis techniques available to analyze thousands of cells in the neocortex, has found that those neurons that appear to be new are in fact two separate cells, usually one “old” neuron and one newly created cell of a different type, such as a glial cell — although new neurons were indeed found in the hippocampus and the olfactory bulb (both older parts of the brain).

[208] Kornack DR, Rakic P. Cell Proliferation Without Neurogenesis in Adult Primate Neocortex. Science [Internet]. 2001 ;294(5549):2127 - 2130. Available from: http://www.sciencemag.org/cgi/content/abstract/294/5549/2127

http://www.eurekalert.org/pub_releases/2001-12/uorm-std120601.php

BDNF

BDNF is involved in protecting and producing neurons in the hippocampus. higher levels of BDNF are associated with higher levels of neurogenesis. Neurotrophins are molecules that function in the survival, growth and migration of neurons

Nerve-cell transplants help brain-damaged rats recover lost ability to learn

After destroying neurons in the subiculum of 48 adult rats, some were given hippocampal cells taken from newborn transgenic mice. On spatial memory tests two months later, the rats given cell transplants performed as well as rats which had not had their subiculums damaged; however, those without transplants had significantly impaired performance. The new cells were found to have mainly settled in the dentate gyrus, where they appeared to promote the secretion of two types of growth factors, namely BDNF and basic fibroblast growth factor (bFGF).

Rekha, J. et al. 2009. Transplantation of hippocampal cell lines restore spatial learning in rats with ventral subicular lesions. Behavioral Neuroscience, 123(6), 1197-1217.

http://www.eurekalert.org/pub_releases/2009-12/apa-nth120909.php

Exercise may counteract bad effect of high-fat diet on memory

An animal study has investigated the interaction of diet and exercise on synaptic plasticity (an important factor in learning performance). A diet high in fat reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, and impaired performance on spatial learning tasks, but both of these consequences were prevented in those animals with access to voluntary wheel-running. Exercise appeared to interact with the same molecular systems disrupted by the high-fat diet.

[883] Molteni R, Wu A, Vaynman S, Ying Z, Barnard RJ, Gómez-Pinilla F. Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor. Neuroscience [Internet]. 2004 ;123(2):429 - 440. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14698750

Too much exercise may be bad for the brain

Mice bred for 30 generations to display increased voluntary wheel running behavior – an "exercise addiction" – showed much higher amounts of BDNF (brain-derived neurotrophic factor – a chemical involved in protecting and producing neurons in the hippocampus) than normal, sedentary mice. In a related study, it was found that the mice also grow more neurons there as well. However, while BDNF and neurogenesis are good for learning and memory, this doesn’t necessarily mean an exercise addict learns at a faster rate. The “running addict” mice in fact performed much worse than normal mice when attempting to navigate around a maze. It could be that too much BDNF and neuron production may be a bad thing, or it may be that the hyperactive wheel running exercise actually kills or damages neurons in the hippocampus, and the high BDNF production is simply trying to minimize this damage. At the moment, all we can say with surety is that exercise greatly activates the hippocampus.

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.

Rhodes, J.S., van Praag, H., Jeffrey, S., Girard, I., Mitchell, G.S., Garland, T. Jr., & Gage, F.H. 2003. Exercise Increases Hippocampal Neurogenesis to High Levels but Does Not Improve Spatial Learning in Mice Bredfor Increased Voluntary Wheel Running. Behavioral Neuroscience, 117 (5), 1006–1016.

http://www.eurekalert.org/pub_releases/2003-09/ohs-cn092603.php

Meal skipping protects the nerve cells of mice

Further to the study reported in January, a new mouse study suggests fasting every other day may protect brain neurons as well as or better than either vigorous exercise or caloric restriction. The mice were allowed to eat as much as they wanted on non-fasting days, and did not, overall, eat fewer calories than the control group. Their nerve cells however, proved to be more resistant to neurotoxin injury or death than nerve cells of both the calorie-restricted mice or the control group. Previous research has found that meal-skipping diets can stimulate brain cells in mice to produce a protein called brain-derived neurotrophic factor (BDNF) that promotes the survival and growth of nerve cells. The researchers are now investigating the effects of meal-skipping on the cardiovascular system in laboratory rats.

[1429] Anson MR, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A, Ingram DK, Lane MA, Mattson MP. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proceedings of the National Academy of Sciences of the United States of America [Internet]. 2003 ;100(10):6216 - 6220. Available from: http://www.pnas.org/content/100/10/6216.abstract

http://www.eurekalert.org/pub_releases/2003-04/nioa-msh042403.php

Gene linked to poor episodic memory

Brain derived neurotrophic factor (BDNF) plays a key role in neuron growth and survival and, it now appears, memory. We inherit two copies of the BDNF gene - one from each parent - in either of two versions. Slightly more than a third inherit at least one copy of a version nicknamed "met," which the researchers have now linked to poorer memory. Those who inherit the “met” gene appear significantly worse at remembering events that have happened to them, probably as a result of the gene’s effect on hippocampal function. Most notably, those who had two copies of the “met” gene scored only 40% on a test of episodic (event) memory, while those who had two copies of the other version scored 70%. Other types of memory did not appear to be affected. It is speculated that having the “met” gene might also increase the risk of disorders such as Alzheimer’s and Parkinsons.

[1039] Dean M, Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D. The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function. Cell [Internet]. 2003 ;112(2):257 - 269. Available from: http://www.cell.com/abstract/S0092-8674(03)00035-7

http://www.eurekalert.org/pub_releases/2003-01/niom-hga012203.php
http://news.bbc.co.uk/1/hi/health/2687267.stm

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A little stress can make brains sharper

While it’s well-established that chronic stress has all sorts of harmful effects, including on memory and cognition, the judgment on brief bouts of acute stress has been more equivocal. There is a certain amount of evidence that brief amounts of stress can be stimulating rather than harmful, and perhaps even necessary if we are to reach our full potential.

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Why learning gets harder as we get older

February, 2013

A mouse study shows that weakening unwanted or out-of-date connections is as important as making new connections, and that neurological changes as we age reduces our ability to weaken old connections.

A new study adds more support to the idea that the increasing difficulty in learning new information and skills that most of us experience as we age is not down to any difficulty in acquiring new information, but rests on the interference from all the old information.

Memory is about strengthening some connections and weakening others. A vital player in this process of synaptic plasticity is the NMDA receptor in the hippocampus. This glutamate receptor has two subunits (NR2A and NR2B), whose ratio changes as the brain develops. Children have higher ratios of NR2B, which lengthens the time neurons talk to each other, enabling them to make stronger connections, thus optimizing learning. After puberty, the ratio shifts, so there is more NR2A.

Of course, there are many other changes in the aging brain, so it’s been difficult to disentangle the effects of this changing ratio from other changes. This new study genetically modified mice to have more NR2A and less NR2B (reflecting the ratio typical of older humans), thus avoiding the other confounds.

To the researchers’ surprise, the mice were found to be still good at making strong connections (‘long-term potentiation’ - LTP), but instead had an impaired ability to weaken existing connections (‘long-term depression’ - LTD). This produces too much noise (bear in mind that each neuron averages 3,000 potential points of contact (i.e., synapses), and you will see the importance of turning down the noise!).

Interestingly, LTD responses were only abolished within a particular frequency range (3-5 Hz), and didn’t affect 1Hz-induced LTD (or 100Hz-induced LTP). Moreover, while the mice showed impaired long-term learning, their short-term memory was unaffected. The researchers suggest that these particular LTD responses are critical for ‘post-learning information sculpting’, which they suggest is a step (hitherto unknown) in the consolidation process. This step, they postulate, involves modifying the new information to fit in with existing networks of knowledge.

Previous work by these researchers has found that mice genetically modified to have an excess of NR2B became ‘super-learners’. Until now, the emphasis in learning and memory has always been on long-term potentiation, and the role (if any) of long-term depression has been much less clear. These results point to the importance of both these processes in sculpting learning and memory.

The findings also seem to fit in with the idea that a major cause of age-related cognitive decline is the failure to inhibit unwanted information, and confirm the importance of keeping your mind actively engaged and learning, because this ratio is also affected by experience.

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Exercise may be best way to protect against brain shrinkage

November, 2012

A large study of older adults shows that physical exercise is associated with less brain atrophy and fewer white matter lesions. A small study shows that frail seniors benefit equally from exercise.

A study using data from the Lothian Birth Cohort (people born in Scotland in 1936) has analyzed brain scans of 638 participants when they were 73 years old. Comparing this data with participants’ earlier reports of their exercise and leisure activities at age 70, it was found that those who reported higher levels of regular physical activity showed significantly less brain atrophy than those who did minimal exercise. Participation in social and mentally stimulating activities, on the other hand, wasn’t associated with differences in brain atrophy.

Regular physical exercise was also associated with fewer white matter lesions. While leisure activity was also associated with healthier white matter, this was not significant after factors such as age, social class, and health status were taken into account.

Unfortunately, this study is reported in a journal to which I don’t have access. I would love to have more details about the leisure activities data and the brain scans. However, although the failure to find a positive effect of stimulating activities is disappointing, it’s worth noting another recent study, that produced two relevant findings. First, men with high levels of cognitive activity showed a significant reduction in white matter lesions, while women did not. Women with high levels of cognitive activity, on the other hand, showed less overall brain atrophy — but men did not.

Secondly, both genders showed less atrophy in a particular region of the prefrontal cortex, but there was no effect on the hippocampus — the natural place to look for effects (and the region where physical exercise is known to have positive effects).

In other words, the positive effects of cognitive activity on the brain might be quite different from the positive effects of physical exercise.

The findings do, of course, add to the now-compelling evidence for the benefits of regular physical activity in fighting cognitive decline.

It’s good news, then, that a small study has found that even frail seniors can derive significant benefits from exercise.

The study involved 83 older adults (61-89), some of whom were considered frail. Forty-three took part in group exercises (3 times a week for 12 weeks), while 40 were wait-listed controls. Participants were assessed for physical capacity, quality of life and cognitive health a week before the program began, and at the end.

Those who took part in the exercise program significantly improved their physical capacity, cognitive performance, and quality of life. These benefits were equivalent among frail and non-frail participants.

Frailty is associated with a higher risk of falls, hospitalizations, cognitive decline and psychological distress, and, of course, increases with age. In the U.S, it’s estimated that 7% of seniors aged 65 to 74, 18% of those aged 75 to 84, and 37% of seniors over the age of 85 are frail.

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How green tea helps fight cognitive decline & dementia

November, 2012

A mouse study adds to evidence that green tea may help protect against age-related cognitive impairment, by showing how one of its components improves neurogenesis.

Green tea is thought to have wide-ranging health benefits, especially in the prevention of cardiovascular disease, inflammatory diseases, and diabetes. These are all implicated in the development of age-related cognitive impairment, so it’s no surprise that regular drinking of green tea has been suggested as one way to help protect against age-related cognitive decline and dementia. A new mouse study adds to that evidence by showing how a particular compound in green tea promotes neurogenesis.

The chemical EGCG, (epigallocatechin-3 gallate) is a known anti-oxidant, but this study shows that it also has a specific benefit in increasing the production of neural progenitor cells. Like stem cells, these progenitor cells can become different types of cell.

Mice treated with EGCG displayed better object recognition and spatial memory than control mice, and this improved performance was associated with the number of progenitor cells in the dentate gyrus and increased activity in the sonic hedgehog signaling pathway (confirming the importance of this pathway in adult neurogenesis in the hippocampus).

The findings add to evidence that green tea may help protect against cognitive impairment and dementia.

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Importance of Vitamin C during pregnancy

November, 2012

A guinea pig study demonstrates that low levels of vitamin C during pregnancy have long-lasting effects on the child's hippocampus.

Like us, guinea pigs can’t make vitamin C, but must obtain it from their diet. This makes them a good model for examining the effects of vitamin C deficiency.

In a recent study looking specifically at the effects of prenatal vitamin C deficiency, 80 pregnant guinea pigs were fed a diet that was either high or low in vitamin C. Subsequently, 157 of the newborn pups were randomly allocated to either a low or high vitamin C diet (after weaning), creating four conditions: high/high (controls); high/low (postnatal depletion); low/high (postnatal repletion); low/low (pre/postnatal deficiency). Only males experienced the high/low condition (postnatal depletion).

Only the postnatal depletion group showed any effect on body weight; no group showed an effect on brain weight.

Nevertheless, although the brain as a whole grew normally, those who had experienced a prenatal vitamin C deficiency showed a significantly smaller hippocampus (about 10-15% smaller). This reduction was not reversed by later repletion.

This reduction appeared to be related to a significant reduction in the migration of new neurons into the dentate gyrus. There was no difference in the creation or survival of new neurons in the hippocampus.

This finding suggests that marginal deficiency in vitamin C during pregnancy (a not uncommon occurrence) may have long-term effects on offspring.

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Learning another language boosts white matter

November, 2012

Foreign language learning increases the white matter in the language network and the bridge joining the hemispheres, perhaps helping explain why bilinguals have better executive control.

In my last report, I discussed a finding that intensive foreign language learning ‘grew’ the size of certain brain regions. This growth reflects gray matter increase. Another recent study looks at a different aspect: white matter.

In the study, monthly brain scans were taken of 27 college students, of whom 11 were taking an intensive nine-month Chinese language course. These brain scans were specifically aimed at tracking white matter changes in the students’ brains.

Significant changes were indeed observed in the brains of the language learners. To the researchers’ surprise, however, the biggest changes were observed in an area not previously considered part of the language network: the white matter tracts that cross the corpus callosum, the main bridge between the hemispheres. (I’m not quite sure why they were surprised, since a previous study had found that bilinguals showed higher white matter integrity in the corpus callosum.)

Significant changes were also observed within the left-hemisphere language network and in the right temporal lobe. The rate of increase in white matter was linear, showing a steady progression with each passing month.

The researchers suggest that plasticity in the adult brain may differ from that seen in children’s brains. While children’s brains change mainly through the pruning of unwanted connections and the death of unwanted cells, adult brains may rely mainly on neurogenesis and myelinogenesis.

The growth of new myelin is a process that is still largely mysterious, but it’s suggested that activity at the axons (the extensions of neurons that carry the electrical signals) might trigger increases in the size, density, or number of oligodendrocytes (the cells responsible for the myelin sheaths). This process is thought to be mediated by astrocytes, and in recent years we have begun to realize that astrocytes, long regarded as mere ‘support cells’, are in fact quite important for learning and memory. Just how important is something researchers are still working on.

The finding of changes between the frontal hemispheres and caudate nuclei is consistent with a previously-expressed idea that language learning requires the development of a network to control switching between languages.

Does the development of such a network enhance the task-switching facility in working memory? Previous research has found that bilinguals tend to have better executive control than monolinguals, and it has been suggested that the experience of managing two (or more) languages reorganizes certain brain networks, creating a more effective basis for executive control.

As in the previous study, the language studied was very different from the students’ native language, and they had no previous experience of it. The level of intensity was of course much less.

I do wonder if the fact that the language being studied was Mandarin Chinese limits the generality of these findings. Because of the pictorial nature of the written language, Chinese has been shown to involve a wider network of regions than European languages.

Nevertheless, the findings add to the evidence that adult brains retain the capacity to reorganize themselves, and add to growing evidence that we should be paying more attention to white matter changes.

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[3143] Schlegel AA, Rudelson JJ, Tse PU. White Matter Structure Changes as Adults Learn a Second Language. Journal of Cognitive Neuroscience [Internet]. 2012 ;24(8):1664 - 1670. Available from: http://dx.doi.org/10.1162/jocn_a_00240

Bialystok, E., Craik, F. I. M., & Luk, G. (2012). Bilingualism: consequences for mind and brain. Trends in Cognitive Sciences, 16(4), 240–250. doi:10.1016/j.tics.2012.03.001

Luk, G. et al. (2011) Lifelong bilingualism maintains white matter integrity in older adults. J. Neurosci. 31, 16808–16813

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Growing the brain with a new language

November, 2012

A new study adds to the growing evidence for the cognitive benefits of learning a new language, and hints at why some people might be better at this than others.

A small Swedish brain imaging study adds to the evidence for the cognitive benefits of learning a new language by investigating the brain changes in students undergoing a highly intensive language course.

The study involved an unusual group: conscripts in the Swedish Armed Forces Interpreter Academy. These young people, selected for their talent for languages, undergo an intensive course to allow them to learn a completely novel language (Egyptian Arabic, Russian or Dari) fluently within ten months. This requires them to acquire new vocabulary at a rate of 300-500 words every week.

Brain scans were taken of 14 right-handed volunteers from this group (6 women; 8 men), and 17 controls that were matched for age, years of education, intelligence, and emotional stability. The controls were medical and cognitive science students. The scans were taken before the start of the course/semester, and three months later.

The brain scans revealed that the language students showed significantly greater changes in several specific regions. These regions included three areas in the left hemisphere: the dorsal middle frontal gyrus, the inferior frontal gyrus, and the superior temporal gyrus. These regions all grew significantly. There was also some, more selective and smaller, growth in the middle frontal gyrus and inferior frontal gyrus in the right hemisphere. The hippocampus also grew significantly more for the interpreters compared to the controls, and this effect was greater in the right hippocampus.

Among the interpreters, language proficiency was related to increases in the right hippocampus and left superior temporal gyrus. Increases in the left middle frontal gyrus were related to teacher ratings of effort — those who put in the greatest effort (regardless of result) showed the greatest increase in this area.

In other words, both learning, and the effort put into learning, had different effects on brain development.

The main point, however, is that language learning in particular is having this effect. Bear in mind that the medical and cognitive science students are also presumably putting in similar levels of effort into their studies, and yet no such significant brain growth was observed.

Of course, there is no denying that the level of intensity with which the interpreters are acquiring a new language is extremely unusual, and it cannot be ruled out that it is this intensity, rather than the particular subject matter, that is crucial for this brain growth.

Neither can it be ruled out that the differences between the groups are rooted in the individuals selected for the interpreter group. The young people chosen for the intensive training at the interpreter academy were chosen on the basis of their talent for languages. Although brain scans showed no differences between the groups at baseline, we cannot rule out the possibility that such intensive training only benefited them because they possessed this potential for growth.

A final caveat is that the soldiers all underwent basic military training before beginning the course — three months of intense physical exercise. Physical exercise is, of course, usually very beneficial for the brain.

Nevertheless, we must give due weight to the fact that the brain scans of the two groups were comparable at baseline, and the changes discussed occurred specifically during this three-month learning period. Moreover, there is growing evidence that learning a new language is indeed ‘special’, if only because it involves such a complex network of processes and brain regions.

Given that people vary in their ‘talent’ for foreign language learning, and that learning a new language does tend to become harder as we get older, it is worth noting the link between growth of the hippocampus and superior temporal gyrus and language proficiency. The STG is involved in acoustic-phonetic processes, while the hippocampus is presumably vital for the encoding of new words into long-term memory.

Interestingly, previous research with children has suggested that the ability to learn new words is greatly affected by working memory span — specifically, by how much information they can hold in that part of working memory called phonological short-term memory. While this is less important for adults learning another language, it remains important for one particular category of new words: words that have no ready association to known words. Given the languages being studied by these Swedish interpreters, it seems likely that much if not all of their new vocabulary would fall into this category.

I wonder if the link with STG is more significant in this study, because the languages are so different from the students’ native language? I also wonder if, and to what extent, you might be able to improve your phonological short-term memory with this sort of intensive practice.

In this regard, it’s worth noting that a previous study found that language proficiency correlated with growth in the left inferior frontal gyrus in a group of English-speaking exchange students learning German in Switzerland. Is this difference because the training was less intensive? because the students had prior knowledge of German? because German and English are closely related in vocabulary? (I’m picking the last.)

The researchers point out that hippocampal plasticity might also be a critical factor in determining an individual’s facility for learning a new language. Such plasticity does, of course, tend to erode with age — but this can be largely counteracted if you keep your hippocampus limber (as it were).

All these are interesting speculations, but the main point is clear: the findings add to the growing evidence that bilingualism and foreign language learning have particular benefits for the brain, and for protecting against cognitive decline.

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