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Archive for the ‘Neurogenesis’ Category

Radiation treatment is a crucial tool for treating brain tumors, but it has the unfortunate side effect of promoting cognitive decline. One of the pathways that this is believed to occur is through decreased neurogenesis in the dentate gyrus of the hippocampus.

Manda et al recently investigated the support for this hypothesis using a mouse model of irradiation. Mice in the irradiation group had about 50 +/- 5 immature cells in the dentate gyrus as opposed to about 200 +/- 30 in the control group, a statistically significant decrease. The irradiation group also had about 5 +/- 1 proliferating cells in the dentate gyrus as opposed to about 17 +/- 2 in the control group, another statistically significantly decrease.

The researchers also proposed a treatment for the damage due to irradiation: pretreatement with melatonin. Melatonin is good as crossing the blood-brain barrier because it is naturally found in the brain, and it is proficient at scavenging free-radicals and reducing thus reducing oxidative stress.

Compared to the non-melatonin irradiattion treatment groups (noted above), the melatonin groups had on average 35% more immature cells and 25% more proliferating cells. Also, the melatonin had no statistically significant effect in non-irradiation treatment groups, suggesting that the reason for this difference was due to free-radical scavenging and reduced oxidative stress.

If it is true that decreased neurogenesis is responsible for the cognitive behavioral decline following brain irradiation, then that provides additional evidence for the importance of neurogenesis to cognitive function. This study also has obvious possible implications to the treatment of brain tumors in neurology.

Reference

Manda K, Ueno M, Anzai K. 2009 Cranial irradiation-induced inhibition of neurogenesis in hippocampal dentate gyrus of adult mice: attenuation by melatonin pretreatment. Journal of Pineal Research 48: 71-78. doi: 10.1111/j.1600-079X.2008.00632.x.

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The spinal cord is a crucial component of the CNS and efforts to recovery from injuries to it mirror the kind of efforts that will be undertaken to combat injury to the brain.

Tyselling-Mattiace et al. recently analyzed the effects of peptide amphiphiline (PA) molecules that self-assemble into cylindrincal nanofibers incorporated into isoleucine-lysine-valine-alanine-valine (IKVAV), a neuroactive pentapeptide epitope, on recovery from a model of spinal cord injury in mice.The IKVAV allows the peptide amphiphiline to spontaneously assemble into nanofibers in vivo, meaning that it can be inserted as a liquid near the injury and become a tissue inside the body once it contacts cations.

This incredible technology allows for some pretty amazing results. The IKVAV PA and the control groups (glucose, sham injection, or nonbioactive PA) had liquid inserted 24 hours following the SCI injury. The IKVAV PA is present 2 weeks following injury but appears to be mostly degraded by 4 weeks.

Nine weeks later, the mice in each group were tested by the BBB locomotor scale, and the IKVAV PA group scored significantly higher than each of the other groups, which had no difference between one another. It was deemed that these numbers represented a much better recovery for the group with IKVAV PA liquid injected.

The explanation behind this recovery is a combination of many factors, including decreased aptosis, increased numbers of oligodendrocytes (these first two are clearly concurrent), decreased astroglosis (scarring), and regeneration of both motor and sensory axons.

For this last factor, mice injected with IKVAV PA had 35% of labeled corticospinal motor fibers grow through the lesion and entered the spinal cord, while no labeled fibers in the control groups were detected even 25% of the way through the lesion. This is strong evidence that the matrix of peptide amphilphile promotes the regeneration of motor axons following injury. The results were similar for the sensory axons.

The authors speculate on the mechanisms for some of this behavior, and believe that the axon regeneration may simply be a byproduct of the decreased aptosis and astroglosis, since the material has degraded before many of these changes become evident. Whatever the explanation, these self-assembling cylindrical nanofibers are a fascinating new way of conducting treatment after injury.

Reference

Tyselling-Mattiace VM, Sahni V, Niece KL, Birch D, Czeisler C, Fehlings MG, Stupp SI, Kessler JA. 2008 Self-assembling nanofibers inhibit glial scar formation and promote axon elongation after spinal cord injury. The Journal of Neuroscience 28: 3814-3823.  doi:10.1523/JNEUROSCI.0143-08.2008.

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Some of the factors that are known to affect the extent of neurogenesis in the subgranular zone of the hippocampus are exercise (enhances), exposure to enriched environment (ie, more ways for rats to be active in their cages; enhances), and seizures. Seizures are perhaps the most interesting of the three, because the way that they impact the rate of neurogenesis depends on the type. Acute or persistent seizures induce new neurons to migrate to different regions of the CA3 network, while spontaneous motor seizures in temporal lobe epilepsy reduce neurogenesis altogether.

In their recent paper, Kuruba et al review the literature on the subject and suggest a number of mechanisms for these observations. For the acute seizure migration, one possibility is that the secreted migration cue reelin is expressed less after seizures and that without this cue new neurons do not know which path to follow and end up in unintended locations. There is in vitro evidence that blocking reelin expression causes anomalies in dentate gyrus cell migration, which provides evidence for this hypothesis.

It is possible that the altered migration in hippocampal migration is partly responsible for why single-shot seizures often develop into chronic epilepsy. As evidence for this, the authors discuss some animal models in which blocking abnormal neurogenesis was beneficial reducing cognitive deficiencies following seizure. It is interesting to contrast the effect of neurogenesis on recovery from seizures to the effect of neurogenesis on recovery from stroke, where neurogenesis is believed to be instrumental in a normal recovery.

Reference

Kuruba R, Hattiangady B, Shetty AK. 2009 Hippocampal neurogenesis and neural stem cells in temporal lobe epilepsy. Epilepsy & Behavior 14: 65-73. PubMed link.

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There are definitive physiological changes that occur during the recovery from a stroke. However, is the recovery from cerebral ischemia more a function of brain plasticity or the contribution of newly born cells?

To attempt to answer this question, Raber et al. form an experimental design where they disrupt neurogenesis and see whether it has a negative impact on recovery from cerebral ischemia. From previous work, it was found that there is a dose-related depression of neurogenesis after subjects are treated with whole-brain x-irradiation. In order to see whether this depression of neurogenesis in the dentate gyrus has a negative effect on recovery from stroke, they treated gerbils with x-ray radiation and then subjected the gerbils to five minutes of bilateral common carotid artery occlusion (BCCAO). BCCAO shuts off blood supply to the brain and simulates the effects of cerebral ischemic trauma, so based on the recovery the researchers hoped to find an answer to their question. They also used 5-bromo-2-deoxyuridine-5-monophosphate (BrdU) to analyze the phenotype and survival ratio of newborn cells. This is a very common method to investigate the proliferation of newly inserted cells that relies on a substitution of the thymide nucleotide so that all newly replicated cells can be identified.

The team separated the gerbils into four groups: controls, x-ray irradiation only, BCCAO only, and x-ray irradiation followed by BCCAO. The key group difference that they were looking for was a functional difference in learning performance between the gerbils subjected to just BCCAO and gerbils subjected to x-ray irradiation followed by BCCAO, because this would determine whether neurogenesis is responsible for some of the recovery following cerebral ischemia.

What they found were strong results on the functional side. The gerbil group subjected to x-ray irradiation and then BCCAO performed dramatically worse on a water maze test, which simulates a learning exercise, with p<.01. However, when they used the results from the BrdU test to analyze the number of neurons in the subgranular zone of the dentate gyrus, they found no statistically significant difference in the number of new neurons in the four treatment groups. Since neurogenesis in this region is supposed to be the mechanism for the difference in learning, this discrepancy poses some tough questions. There are, however, a few ways to address the discrepancy:

1) Cells from other regions besides the dentate gyrus might be involved in functional outcomes, since ischemia affects other regions as well.

2) New neuron cells (from adult neurogenesis) may have contributed from regions other than the dentate subgranular zone. This is a fairly radical suggestion, but one that may deserve consideration.

3) Although the new neuron cells in the dentate gyrus may have been negligible in number, they may have been crucial in their connections to other neurons. It is difficult to tell what role individual neurons could play in the functional whole (that may be the understatement of the year), but it is possible that these new granule cells played crucial roles in coordinating the timing of action potentials of other neurons.

Their paper is concise and informative, and it has some good data showing that neurogenesis is a key mechanism behind the recovery from cerebral ischemic trauama.

Reference

Raber J, et al. 2004 Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits. Annals of Neurology 55: 381-389. doi: 10.1002/ana.10853.

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How can we rebuild the brain when it has been affected by disease or age? There are two possible ways to develop new brain cells:

1) Cells relocated or generated from within the individual. The advantage of this strategy is that it is less invasive, you don’t have to deal with immunological problems of compatibility, and it is parsimonious with the body’s existing framework. These cells are called endogenous.

2) Cells from an outside source (such as a donor) and transplanted into the individual. the advantage here is that larger numbers can be obtained, different sources can be used (embryonic and adult stems cells, or even one day some sort of synthesis), and the state of the cell before differentiation can be optimized outside of the brain. These cells are called exogenous.

How can we stimulate more neurogenesis within the brain?

There is evidence that many factors which contribute to neurogenesis in vitro also contribute to neurogenesis in vivo, including epidermal growth factor and basic fibroblast growth factor-2. The process is regulated physiologically by glucocorticoids, sex hormones, growth factors, excitatory neurotransmission, learning, and stress. It can be stimulated by certain drugs, such as lithium, antidepressants (that may be why they work), antipsychotics, NMDA antagonists, phosphodiesterase inhibitors, and anti-inflammatories.

Injury is also one of the main contributors to neurogenesis in the adult brain, and there are a number of potentially useful applications based on this process. In stroke-induced neurogenesis, the new cells were found in areas not directly affected by injuries themselves, which means that there must be a mechanism to couple neurogensis with injury across the brain. Also, an injury to one half of the brain produced neurogenesis on both sides of the brain, implying that there may be some central part of the brain regulating neurogenesis that is blind to the actual location but still able to recognize which functions are impaired.

If we could tap into this endogenous system to repair regions that have not yet been damaged (or regions that have been damaged by disease but not injury), we could exploit our body’s own system to help repair ourselves. There is no such thing as a free lunch, but the most detrimental effect of such action might be for the brain to simply consume more energy. This may have been a limiting factor in the Paleolithic era in which human ancestors evolved, but we have plenty of food and nutrients to go around in most areas of the industrialized world.

One of the most important questions is how well these neurons integrate into the existing framework of the brain. Some studies have been done to touch upon this question, but it is still a relatively open question and without its affirmative answer all of this work may be for naught. Of course, it doesn’t make much sense for the body to waste energy on neurogenesis if it doesn’t accomplish anything.

But even if the natural amount of neurogenesis is unable to procure an effect, it is possible that a supraphysiological level could be reached from growth factors, drugs, or some combination that would provide us with methods for using adult neurogenesis clinically.

Reference

Greenburg DA, Jin K 2007 Regenerating the brain. International Review of Neurobiology 77: 1-22. doi: 10.1016/S0074-7742(06)77001-5.

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One of the conundrums about modern psychotherapy is that while we know SSRIs work to alleviate symptoms of unipolar depression, nobody is sure exactly why. That is to say, we know that the drugs inhibit the reuptake of serotonin, but what does that neurotransmitter have to do with depression?

The neurogenesis hypothesis is one proposed way to explain how depression functions in the brain. Most of the neurogenesis in humans takes place in the dentate gyrus of the hippocampus (although there is some olfactory neurogenesis as well). There are two parts to the hypothesis:

1) That there is a causal relationship between neurogenesis and depression. This largely relies on correlative and indirect evidence, such as the link between stress and neurogenesis, and the link between stress and depression. However, in order to show a causal relationship, then depression would have to lead to a decreases in neurogenesis, which is not the case in rodents (see Vollmayr et al., 2003). So the first part of the hypothesis has been (mostly) placed aside for the time being.

2) That anti-depressants may work via the stimulus of neurogenesis. This remains a viable idea (Santarelli et al., 2003), although the evidence supplied is primarily in non-humans.

All of this leads to yesterday, when the MIT Tech Review reported that a drug specifically stimulating neurogenesis was going to clinical trials. It will be interesting to see how effective the drug is. And if part 2 of the neurogenesis hypothesis holds true, then it is indeed possible that patients who don’t respond to SSRIs may respond to a drug that stimulates hippocampal neurogenesis directly.

Again, we shall see.

Link to article in the MIT Technology Review.

Reference

L. Santarelli, M. Saxe, C. Gross, A. Surget, F. Battaglia and S. Dulawa et al., Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants, Science 301 (2003), pp. 805–809.

B. Vollmayr, C. Simonis, S. Weber, P. Gass and F. Henn, Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness, Biological Psychiatry 54 (2003), pp. 1035–1040.

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