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Archive for the ‘Neurogenesis’ Category

Which cell types are targeted by neurogenesis in the olfactory bulb? To answer this question (among others), Bardi et al. used a optogenetic mouse model selective for adult-born olfactory cells to test various cell types for post-synaptic responsiveness following light stimulation.

So if the (randomly chosen) cells in the olfactory bulb slices respond to light, as measured via patch-clamping, that means that they must receive input from an adult-born cell. They found that 86% (65/76) of tested cells projecting to cortical regions had such functional connections, whereas only 21% (9/42) of tested local neurons did. Although the proportion is biased towards neurons with longer-range axons, it is clear that adult-born neurons have a diverse set of synaptic targets.

In one of their slices they labelled responsive cells with biocytin/streptavidin and visualized them with confocal microscopy. Different colors correspond to different postsynaptic cell types, as you can see below.

cell types: mitral = red, tufted = purple, juxtaglomerular = blue, granule = green, and short axon = dark gray; scale bar = 100 μm; doi: 10.1523/ JNEUROSCI.4543-10.2010

Since all of the adult-born olfactory neurons communicate with inhibitory GABAergic signals, their role would be more limited if they only targeted cells projecting to cortical regions. This study highlights another level of complexity, showing that these neurons could in certain cases act to inhibit inhibitory interneurons, thus adding to excitatory signals leaving the olfactory bulb from particular axons. Layers upon layers.

Reference

Bardy C, et al. 2010 How, when, and where new inhibitory neurons release neurotransmitters in the adult olfactory bulb. J Neuro, PubMed, doi: 10.1523/​JNEUROSCI.4543-10.2010.

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Granulocyte-colony stimulating factor (GCSF) is a recently discovered neurotrophic factor that counteracts apoptosis, boosts synaptic plasticity, and, perhaps through the same mechanism, increases neurogenesis. Diederich et al (here) have an interesting study showing that the beneficial cognitive effects of training on a radial maze for 11 days and receiving daily 20 µg/kg injections of G-CSF can have synergistic effects on newborn cell survival in the dentate gyrus of rats:

confocal microscopy of immunohistochemically stained cells; doi/10.1371/journal.pone.0005303.g003

The authors note in their discussion that,

A ‘use it or lose it’ principle is thought to underlie the survival of hippocampal neurons. The finding of the present study suggests that the combination of hippocampus-dependent learning and G-CSF treatment may facilitate the integration of adult-born neurons into existing neural networks and therefore insure their survival.

It is interesting to note that neurotrophins and cognitive training can have synergistic effects. In so far as rodent models are useful, this shows how important lifestyle variables like diet and education-like activities can be, because they can feed forward upon each other to at least some extent.

What is the mechanism for the synergy? That remains an open question…

Reference

Diederich K, Schäbitz W-R, Kuhnert K, Hellström N, Sachser N, et al. (2009) Synergetic Effects of Granulocyte-Colony Stimulating Factor and Cognitive Training on Spatial Learning and Survival of Newborn Hippocampal Neurons. PLoS ONE 4(4): e5303. doi:10.1371/journal.pone.0005303

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Jason Snyder has compiled a very interesting list of 224 studies that have attempted to correlate neurogenesis with behavior while controlling for outside variables. Check out the full list here. Taking the author’s assertions at face value, it appears that 14/47 (29.8%) studies that correlated neurogenesis with depression / anxiety found a significant association, 0/12 studies that correlated neurogenesis with locomotion found a significant association, and  37/71 (52.1%) of studies that correlated neurogenesis with memory found a significant association, in some cases via reduced hippocampal dependence. So based on his cursory lit review the most consistent correlation between adult neurogenesis and behavior in adults can be found in differences in memory.

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Yu et al recently reported their use of twin-spot mosaic analysis with repressible cell markers to track the development of clusters of neurons in Drosophila. This is an exciting avenue of research because development is so tightly linked to cell phenotype, and classifying all brain cell types is a major goal of neuroscience. Aside from reporting that their technique “worked,” some of the interesting findings of the paper were that, 1) Neurons of the same lineage (i.e., same progenitors) exist as clusters in the central brain and ventral nerve cord, and 2) There is a unit production of one, two, or a small cluster of mature neurons that arise from any given neuroblast. Determination is huge in the developing brain.

Reference

Yu HH, et al. 2009 Twin-spot MARCM to reveal the developmental origin and identity of neurons. Nature Neuroscience 12: 947-953.

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Neurogenesis induces anxiety?

Voluntary wheel running in rodents is correlated with an upregulation of adult neurogenesis, as well as activation of the HPA axis. However, the findings on the effects of voluntary exercise on anxiety have been ambiguous, with some tests indicating no change, some indicating a decrease, and some indicating an increase, the latter of which may be contra to the presupposition that neurogenesis unilaterally decreases depression.

Fuss et al allowed mice 3 weeks of free access to a running wheel and measured the amount of usage during that time. When subjected to an open field test, running mice showed a decrease in distance moved and velocity of movement compared to controls, and they showed increased anxiety-like behavior in other tests like the O-maxe and dark-light box as well. Although cell differentiation in the hippocampus was significantly higher in the brains of running mice as opposed to controls (as measured by doublecortin), the overall number of cells in the dentate gyrus had no significant difference. Thus the authors suggest that instead of simply targeting increased neurogenesis in all anxiety cases it may be prudent to simply attempt to return it to basal levels.

Reference

Fuss et al. 2009 Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis.

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Tashiro et al (2007) describe how mice exposed to an “enriched environment”, meaning larger cages with tunnels and running wheels, can have higher levels of neurogenesis than those without that exposure. That finding in itself is not new, but their team found that mice exposed to the enriched environment for just one week showed an increase in the number of newly differentiated neurons in the dentate gyrus.

They also looked for evidence of a “critical period” by placing the mice in the enriched cages either 1, 2, 3, or 4 weeks after the injection of BrdU, which stains differentiating neurons. The 1, 2, and 3 week enriched mice all had significantly more new neurons than control mice, but those enriched in the second week had the most new cells: the control had 12.5 +/- 0.6 cells per 106µm3; group 1 had ~ 22 +/2, group 2 had 27.9 +/- 3.7, and group 3 had ~18 +/-1 cells. The researchers determined that the majority of these new cells were the result of increased survival of differentiated neurons instead of increased proliferation. The density of the BrdU positive cells in group 2 was also significantly higher than that of any other. The authors suggest that the circuits formed at different times after neuron proliferation could correspond to specific experiences, which would allow for a time encoding of new memories.

Leuner et al describe a different pathway through which adult neurogenesis can increase: conditioned responses in a hippocampal-dependent stimulus learning tasks. Although the number of BrdU-labeled cells did not vary based on whether the mice were exposed to paired on unpaired stimuli, there was a significant and positive correlation between the number of conditioned responses the mice performed and the number of BrdU-labeled cells, r=0.65, p=0.03. The amount of new neurons dropped off slightly in number between 1 days to 30 days but there was no significant additional decline to 60 days, indicating that the increased neurogenesis is not transient.

The authors attempt to fit their data into the existing neurogenesis as increased learning paradigm, with some success. It is pretty clear that the better the animal learns (as measured by conditioned responses), the more the number of newly-born cells exist in the dentate gyrus, and based on the Tashiro’s evidence that is probably due to increased survival of neurons. Elucidating the role of neurogenesis in learning and memory is a theoretically important step for both enhancing normal human learning processes and understanding how and where the process fails.

References

Leuner B, Mendolia-Loffredo S, Kozorovitskiy Y, Samburg D, Gould E, Shors TJ. 2004 Learning enchances the survival of new neurons beyond the time when the hippocampus is required for memory. Journal of Neuroscience 24:7477-7481. doi:10.1523/JNEUROSCI.0204-04.2004.

Tashiro A, Makino H, Gage FH. 2007 Experience-specific functional modification of the dentate gyrus through adult neurogenesis: A critical period during an immature stage. Journal of Neuroscience 27:3252-3259. doi:10.1523/JNEUROSCI.4941-06.2007.

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MIT’s Technology Review reports:

By injecting stem cells directly into the brain, scientists have successfully reversed neural birth defects in mice whose mothers were given heroin during pregnancy. Even though most of the transplanted cells did not survive, they induced the brain’s own cells to carry out extensive repairs.

… [T]hey are consistent with an emerging consensus of how adult stem cells perform their many functions through so-called bystander or chaperone effects. Beyond simply generating replacements for damaged cells, stem cells seem to produce signals that spur other cells to carry out normal organ maintenance and initiate damage control.

Interesting stuff, with obvious biomedical applications. As the article discusses, it is somewhat of a paradigm shift to think that instead of cellular replacement all that is needed to solve certain problems is an injection of stem cells. This research lends indirect support to the importance of neurogenesis to many neurological functions.

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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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