Neuron Regeneration

[Psychedelics_r_best]

I was in my Bilogy course today and the teacher meantioned how nerve cells and neurons are inable to perform mitosis, resulting in any damage caused the rbain by injury or drug use being permanent. I have the tendency to believe this is not true given the information presented in this study:http://www.eurekalert.org/pub_releases/2004-11/uonc-nbc110504.php

Has anyone any imput on this?

I have been under the impression that the brain can recover from damage through the proliferation of neurons and their connections.

Another pressing question is whether DMT stimulates dendrite growth in neurons. I am under the impression it does, but I can't find the original source from which I learned this.

 

[Matt the Raver]

The answer is yes and no.
Most brain cells (by brain cells I mean neurons) can't reproduce. However, neurons in the hippocampus (an important area for short term memory) ARE capable of mitosis.
There is a connection between hippocampal volume and depression.

But it's important to point out that hippocampal mitosis is an exception to the rule.

It's also important to point out that while mitosis might not happen, neurons are still capable of forming new connections.

As for DMT, encouraging neural growth, I'm not sure. But there are hormones such as Nerve Growth Factor (NGF) and Brain Derived Neurotrophic Factor (BDNF) which do. Therefore any drug which increases NGF or BDNF would encourage neural growth.

 

[ayjay]

Also - damage to particular neurons might be permanent, but damage to brain function can reduce due to plasticity of connections. On the flipside - most stuff I have come across about increasing brain function looks at mental exercises (improving & maintaining connections) - playing chess, music etc - or using CBT for anxiety

 

[5-HT2]

Neurons can't reproduce, period, no exceptions. Once a neural stem cell adopts a neuronal fate, it is no longer capable of mitosis. However, some regions of the brain, of which the best-documented are the dentate gyrus of the hippocampus and the subventricular zone, have populations of neural progenitors that can differentiate into neurons or glia.

 

[raybeez]

Neurons can't reproduce, period, no exceptions. Once a neural stem cell adopts a neuronal fate, it is no longer capable of mitosis. However, some regions of the brain, of which the best-documented are the dentate gyrus of the hippocampus and the subventricular zone, have populations of neural progenitors that can differentiate into neurons or glia.

^^^^

I believe the neuron progenitor stem cells can also migrate to other regions of the brain, and THEN differentiate, thus providing a source of new neurons. This happens in response to a number of cues, such as hormones like prolactin.

 

[Psychedelics_r_best]

I read somewhere though that stimulation to certain parts of the brain can cause the cells to proliferate. I suppose what is meant, then, is that the connections of dendrites and axons grow in frequency.

When your brain is maturing though, from infancy, do neurons mulitply, or are they set from birth and simply mulitply in their connections with each other?


"For decades, neuroscientists believed the number of new cells, or neurons, in the adult brain was fixed early in life. Adaptive processes such as learning, memory and mood were thought tied to changes in synapses, connections between neurons.

More recently, studies have shown that the adult human brain is capable of producing new brain cells throughout life, a neurogenesis resulting in formation of hundreds of thousands of new neurons each month. "Prior to our work, everyone merely assumed that glia, the supporting cells of the brain, regenerated or that existing brain cells altered their connections," said Nixon. "We have shown a burst in new cell birth that may be part of the brain's recovery after the cessation of alcohol."

^What of this then? Doesnt it clearly say "the adult human brain is capable of producing new brain cells throughout life, a neurogenesis resulting in formation of hundreds of thousands of new neurons each month."

 

[mad_scientist]

From my uni notes (back in 2003 so bit out of date now):

Neural stem cells undergo neurogenesis, mainly in the olfactory bulb and dentate gyrus, and migrate to the rest of the brain where they differentiate into neurons and glia. This process is involved in learning in the hippocampus.

It is unclear however (in 2003 at least) whether neural stem cells in adult humans are able to migrate elsewhere in the brain to repair damage etc. or if they have other functions.

Neurogenesis is influenced by the nerve growth factors NGF, BDNF and GDNF. Levels of these are affected by drugs and environment; environmental enrichment, calorie restriction, cannabinoids, SSRIs and 5HT2A agonists increase neurogenesis, while chronic stress, old age, opiates and amphetamines decrease neurogenesis.

 

[ayjay]

The OP was questioning the suggestion that brain damage from injury or drug use is permanent. Damage to individual neurons is permanent - but damage to brain function is not the same thing.

Just as well!

 

[Matt the Raver]

5HT2: Thank you for clarifying that. I kinda forgot the diiference between mitosis and differentiation (quite an important one)!

Alot of research concerning neurogenesis seems to focus around the hippocampus.

The idea that hippocampal activity is an important factor in depression is associated with this. Previously, I thought that this was an effect of changes in serotonin rather than a direct cause.

http://biopsychiatry.com/neurogenesis.htm

http://biopsychiatry.com/neurogenesis.html

Oh yeah.....and it's official! Weed (Well, CB1 agonists at least) can be good for you!!!!
http://biopsychiatry.com/cannabinoids-neogenesis.htm

5HT2A agonists increase neurogenesis.

I'm very surprised that 5HT2A promotes neurogenesis. Have you got a reference on that?

 

[Matt the Raver]

The OP was questioning the suggestion that brain damage from injury or drug use is permanent. Damage to individual neurons is permanent - but damage to brain function is not the same thing.

Just as well!

I think it's a bit greyer than that. A good example is stroke patients, where the extent of damage will dictate the degree of recovery possible.

But the number of synapses is probably more important than the number of neurons.

 

[Psychedelics_r_best]

Neurogenesis is influenced by the nerve growth factors NGF, BDNF and GDNF. Levels of these are affected by drugs and environment; environmental enrichment, calorie restriction, cannabinoids, SSRIs and 5HT2A agonists increase neurogenesis, while chronic stress, old age, opiates and amphetamines decrease neurogenesis.

Do you have sources for all this information? I have read studies that have said cannibanoids can cause alterations in the neural connections of the hippocampus, causing change in learning and memory fucntion. Most of the traditional psychedelics, LSD, Psilocybin, DMT and related tryptamines are, of course, 5HT2A agonists. Are you claiming these all stimulate neurogenesis?

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10986361&query_hl=2&itool=pubmed_docsum

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1666926&dopt=Abstract

 

[Matt the Raver]

I'm VERY sceptical about 5HT2A promoting neurogenesis. Mainly because it couples predominantly to Gq.

The more you study cell biology, the more 'big themes' start to appear.
Generally speaking a physiological response can be described as one which either proinflammatory, or pro-growth.

This is important, for either using energy to encourage cell growth, or to remove damaged tissue and fight infection.

It just so happens that cellular responses mediated by Gq tend to be pro inflammatory and Gi tends to be pro-growth.

That's why I'm not surprised that CB1 would cause neurogenesis, but I would if 5HT2A did!

 

[Psychedelics_r_best]

I understand that most indole psychedelic 5HT2A agonists such as Psilocybin and DMT are known to exhibit no neurotoxicity, but of course that does not equate to retardation of neurogenesis. I am not familiar with what Gq and Gi are, but I suppose they are enzymes that mediate cellular responses. Does anyone else have any input on this? I certainly would like to think that 5HT2A agonists increase neurogenesis though.

Does anyone have any knowledge as to the nature of CB1 agonists in correspondance to their neurotoxicity or hippocampal alteration? I would be skeptical if all that could be claimed was that they promote neurogenesis.

I still remember reading somewhere that DMT increased levels of NGF in your brain, but I cant remember where.



Additionally, there is all this hype about MDMA neurotoxicity, and so much time spent into its consideration. Do we have extensive knowledge regarding the effects of other drugs on the brain? I understand that most indole psychedelics are completely without neurotoxicity, while phenethylamines and amphetamines cause oxidative stress. In comparison to MDMA, shouldn't most amphetamines and phenethylamines cause similar neurotoxic effects? What accounts for the notorious neurtoxic properties of methamphetamine? From what I understand, cannabis temporarily effects function in the hippocampus, but does not produce neurotoxic effects unless used habitually for at least 7 years. Dissosciatives and Depressants can cause Excitotoxicity. And opiates are often minorly neurotoxic.

Does anyone have any information on Olneys Legions? I could read all those bad news, no bad news, blah blah, neuropharmacology indexes at erowid, but right now Im too lazy.

 

[Matt the Raver]

Firstly, doesn't DMT also work as a 5HT1A agonist? If so this might explain any increases in NGF, because 5HT1A activates Gi, which then increases NGF.

So while DMT might be activating 5HT2A, it's also activating 5HT1A.

Furthermore, 5HT2A is supposed to increase arachidonic acid (AA) levels. This is pretty important because AA in a very potent inflammatory mediator.

The upshot off all of this is: How selective is the drug you're talking about? The less selective the drug, the more complex the response.

On the cannabinoid thing, here's a pretty good looking review.

http://www.ncbi.nlm.nih.gov/entrez/..._uids=16375685&query_hl=2&itool=pubmed_docsum

The effects of MDMA are pretty complex, but MDMA mediated neurotoxicity is more to do with the physiological changes it causes, rather than any toxicity of MDMA itself.

I try and describe it like this:

'Jumping out of a plane doesn't kill you, hitting the ground does.'

Likewise, taking MDMA doesn't cause brain damage, but the breakdown products produced as a result of excessive serotonin catabolism does.

MDMA doesn't necessarily cause brain damage, as long as the breakdown products are dealt with properly.

This fits in with another 'big theme' in cellular biology: Oxidative stress

Using oxygen to release energy from food (aerobic respiration) is far more efficient than other methods (anaerobic respiration). The downside is that using oxygen produces highly toxic by-products called free radicals.

This is also why antioxidants are important, as they work by 'mopping up' radicals.

What MDMA does is cause an unregulated increase in 5HT, activating 5HT2A, desensitising 5HT2C and causing dopamine release.

The problem comes when the 5HT is reabsorbed and broken down. Basically there's too much to breakdown, you get loads of free radicals being produced, which causes cellular damage.

Any attempt at neuroprotection involves either reducing reuptake or getting rid of radicals.

To my knowledge, methamphetamine does the same thing, but at dopamine transporter rather than the serotonin transporter, but the concept is very similar.

As for Olney's lesions, I've read the wikipedia entry on it and it stikes me as odd, because I thought NMDA antagoninsts were supposed to be neuroprotective and had been considered for preventing damage caused by excititoxicity caused during stroke.

http://en.wikipedia.org/wiki/Olney's_lesions

 

[Matt the Raver]

I am not familiar with what Gq and Gi are, but I suppose they are enzymes that mediate cellular responses.

Gq and Gi are examples of a couple of what are called 'G proteins' (short for Guanosine Tri-Phsophate binding proteins).

G proteins bind to the intracellular surface to a very large number receptors. These are termed 'G-protein binding receptors' (GPCRs).

Dopamine, Noradrenaline (Norepinephrine), Opioid and all serotinin receptors except for 5HT3 are GPCRs.

G proteins are a first step in a number of subcellular pathways. With different G proteins activating different pathways.

For example:

Gi inhibits protein kinase A

Gq promotes phospho lipase C, protein kinase C and calcium ion influx.

It's very important to understand what pathways any given receptor activates. As different pathways can interact. Sometimes enhancing each other, sometimes inhibiting each other.

 

[Psychedelics_r_best]

Ah yes, I know what G-protein pathways are. Arent G-protein pathways largely those to which hormones bind to produce a response after the signal has been transduced through the various kinases and whatnot?

How do these transductions of signals transmit into slowing of neurogenesis?

I was only mainly aware of, when a neurotransmitter or drug binds, of the electrical signal released to produce the effect, as well as any local neurotoxic action. So secondarily, the binding of drugs or neurotansmitters also triggers a transduction pathway that can inhibit or promote neurogenesis, based on which of these proteins, Gi and Gq, are activated?

 

[mad_scientist]

I'm very surprised that 5HT2A promotes neurogenesis. Have you got a reference on that?

5HT2A agonists were just one of the drug classes listed as inducing neurogenesis in my uni notes;

"Serotonin may enhance neurogenesis via the 5HT2A receptor, whose activation selectively increases BDNF expression in the dentate gyrus"

J. Neurosci 1997; (17):2785-2795

But like i said those notes were from a few years ago and may now be out of date, as you point out many of the 5HT2A agonist hallucinogens also activate 5HT1A receptors to some extent; it may be that this has a neurogenesis-promoting effect while the 5HT2A activation has no effect either way.

The evidence is much stronger for SSRIs promoting neurogenesis, and they would be increasing serotonin levels generally and hence activating all of the 5HT receptors more than baseline. And if i remember correctly some of the SSRIs are also 5HT1A agonists in their own right (i know fluoxetine is, not sure about the others)

Neurogenesis in adult humans is a very important area of research due to the potential in treating Alzheimers, Parkinsons etc so there will have been a huge amount of new work done in the area since i left uni.

Hopefully the treatments they come up with will be equally useful for repairing the brain damage in all those meth heads out there - apparantly with enough methamphetamine use you can kill just as many dopamine neurons as in severe Parkinsons disease, but its a different area of the brain thats affected so the damage is not so obvious...

 

[mad_scientist]

As for Olney's lesions, I've read the wikipedia entry on it and it stikes me as odd, because I thought NMDA antagoninsts were supposed to be neuroprotective and had been considered for preventing damage caused by excititoxicity caused during stroke.

The NMDA receptor is a regulatory site on a calcium channel which is both ligand and voltage dependent. The details went a bit over my head but as i understand it, if calcium levels inside the neuron go too high then it dies from necrosis, while if calcium levels drop too low then the neuron dies from apoptosis.

In serious head injury, stroke etc, the trauma/hypoxia releases large amounts of free calcium which leads to a wave of necrotic death of neurons. This can be blocked with NMDA antagonists as they stop the neurons from taking up the excess calcium, and so in this context they are neuroprotective.

In Alzheimers, Parkinsons etc, the cell death is more predominantly from apoptosis, and so full NMDA antagonists don't help, but a "partial antagonist" (can't remember the proper name for it sorry) like memantine can help prevent the neurons dying by flattening NMDA activity to a low but constant level and hence calcium levels inside the neuron don't go too high or too low.

Olneys lesions are induced by apoptosis following huge doses of full NMDA antagonists like ketamine or PCP, the neurons die because calcium influx is totally blocked. However the mg/kg doses used to produce these lesions in animals far exceed the doses of ketamine or PCP that humans would use recreationally, so its hard to say how neurotoxic these drugs are in practice. I would suspect they do some damage as people seem to get pretty brainfried after using large amounts of ketamine or PCP for a long time, but whether this is permenent damage is hard to say.

 

[Matt the Raver]

5HT2A agonists were just one of the drug classes listed as inducing neurogenesis in my uni notes;

"Serotonin may enhance neurogenesis via the 5HT2A receptor, whose activation selectively increases BDNF expression in the dentate gyrus"

J. Neurosci 1997; (17):2785-2795

But like i said those notes were from a few years ago and may now be out of date, as you point out many of the 5HT2A agonist hallucinogens also activate 5HT1A receptors to some extent; it may be that this has a neurogenesis-promoting effect while the 5HT2A activation has no effect either way.

I've had a look at the paper. It's a study on using in-situ hybridisation. This is a technique which identifies changes in gene expression. The rationale being that more expression = more activity.

In this case, look at changes in BDNF expression caused by 5HT1A and 5HT2A.
It's results show an that 5HT1A doesn't do anything and that 5HT2A increases BDNF expression in the parietal cortex and decreases it in the dentate gyrus (part of the hipocampus).

The moral of this story is:

WHAT is a receptor doing?

WHERE is it doing it?

Because you can only understand drug effects if you can answer both of these questions.

The explaination given by the paper is that 5HT2A is expressed by glutamatergic neurones in the cortex and GABAergic neurones in the dentate gyrus, this would increase cortical activity and decrease DG activity.

So: More neural activity = More BDNF = Synaptic strengthening and (maybe) neurogenesis.

This would seem to apply so long as neurotransmitter release or neural activity doesn't go too high, because that would cause oxidative stress and cause neural damage rather than neural growth.

 

[tobala]

Hopefully the treatments they come up with will be equally useful for repairing the brain damage in all those meth heads out there - apparantly with enough methamphetamine use you can kill just as many dopamine neurons as in severe Parkinsons disease, but its a different area of the brain thats affected so the damage is not so obvious...

But are the dopamine neurons really dead? I thought that reducing dopamine release through neuroadaptation was the brain's way of compensating for the excess dopamine loitering around the synaptic gap after, for example, the chronic use of cocaine.

When cocaine use stops, there are the obvious withdrawal symptoms resulting from a dopamine deficit, but the brain eventually realizes that it's got to start pumping more out again and the neurons involved adapt to these new conditions by increasing their dopamine output to (theoretically) original levels.

I believe there are therapies on the horizon, some of which may involve ibogaine, that attempt to "trick" the brain into thinking that there were never dopamine surpluses in the first place, so it senses the dopamine deficit and reverse-neuroadaptation takes place much faster.