Adult Neurogenesis – A Pointed Review(slatestarcodex.com)
slatestarcodex.com
Adult Neurogenesis – A Pointed Review
http://slatestarcodex.com/2018/04/04/adult-neurogenesis-a-pointed-review/
40 comments
A response to the Cell article from the team from the article that did not find neurogenesis.
""" In an email statement, that group, which works out of developmental neuroscientist Arturo Alvarez-Buylla’s lab, said that while they found the new study’s evidence of declining blood vessel growth in the adult hippocampus interesting, they are not convinced that Boldrini and her colleagues found conclusive evidence of adult neurogenesis.
"Based on the representative images they present, the cells they call new neurons in the adult hippocampus are very different in shape and appearance from what would be considered a young neuron in other species, or what we have observed in humans in young children," they wrote. """
Much more at the original article. TL;DR: They think this probably doesn't meaningfully change things from their own findings.
http://www.latimes.com/science/sciencenow/la-sci-sn-new-brai...
""" In an email statement, that group, which works out of developmental neuroscientist Arturo Alvarez-Buylla’s lab, said that while they found the new study’s evidence of declining blood vessel growth in the adult hippocampus interesting, they are not convinced that Boldrini and her colleagues found conclusive evidence of adult neurogenesis.
"Based on the representative images they present, the cells they call new neurons in the adult hippocampus are very different in shape and appearance from what would be considered a young neuron in other species, or what we have observed in humans in young children," they wrote. """
Much more at the original article. TL;DR: They think this probably doesn't meaningfully change things from their own findings.
http://www.latimes.com/science/sciencenow/la-sci-sn-new-brai...
They're confusing something else with neurogenesis.
Probably. But to clarify you think something besides immature GNs in the granular zone expresses DCX and PSA-NCAM but not NeuN?
I have my idea; I just want to hear yours.
I have my idea; I just want to hear yours.
In the cortex at least there have been reports of DCX+ NCAM+ cells that are arrested in an immature state, meaning they are not necessarily newly generated, just stuck in "standby" mode.
Why don't you go for it? I'd like to hear.
glial cells moonlighting, by expressing the molecular marker signature of young neurons.
And in terms of papers like Spalding et al., 2013 which "assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear-bomb-test-derived 14C in genomic DNA"?
https://www.sciencedirect.com/science/article/pii/S009286741...
The original study https://www.nature.com/articles/nature25975 that prompted the SSC article has an interesting discussion of this result in their supplement:
"A study using 14C birthdating on sorted NeuN+ nuclei suggested that hundreds of new neurons are generated per day in the adult human hippocampus, with little decline with age. The results obtained from this method differ from the data presented here and other histology studies that show a sharp decline in markers of newly formed neurons during early postnatal development. Birthdating with 14C relies on the isolation of neuronal nuclei using NeuN antibodies, but subpopulations of oligodendrocytes and microglia can also express NeuN. 14C could also possibly become incorporated into DNA through methylation or DNA repair independent of cell division, processes that have been shown to occur at higher rates in the hippocampus. The proposed addition of new neurons to the adult caudate nucleus using this method is not supported by other work in the human or BrdU labeling in adult macaques. The 14C method is an innovative approach to perform birthdating in postmortem human samples, but it has not been validated in animal studies."
"A study using 14C birthdating on sorted NeuN+ nuclei suggested that hundreds of new neurons are generated per day in the adult human hippocampus, with little decline with age. The results obtained from this method differ from the data presented here and other histology studies that show a sharp decline in markers of newly formed neurons during early postnatal development. Birthdating with 14C relies on the isolation of neuronal nuclei using NeuN antibodies, but subpopulations of oligodendrocytes and microglia can also express NeuN. 14C could also possibly become incorporated into DNA through methylation or DNA repair independent of cell division, processes that have been shown to occur at higher rates in the hippocampus. The proposed addition of new neurons to the adult caudate nucleus using this method is not supported by other work in the human or BrdU labeling in adult macaques. The 14C method is an innovative approach to perform birthdating in postmortem human samples, but it has not been validated in animal studies."
This is a critical comment that should be upvoted widely. The reason that this is such a difficult challenge is that the rate of adult hippocampal neurogenesis, even in rodents where everyone believes it happens, is on the order of between 1 neuron per minute and 1 neuron per hour. In a brain of 100 billion neurons, that's hard to detect.
The original SlateStarCodex post addresses this. He argues that a microscopic amount of neurogenesis that is too small to be responsible for the effects everyone cares about (depression, brain plasticity, etc.) should be rounded to zero.
It is entirely possible that the base-rate of neurogenesis in adult humans is very low, but in response to new stimuli (a new exercise regimen, for example) responds by generating neurons..Perhaps I am missing the information in one of the supplemental pages, but I do not see info on history of exercise or anti-depressant use in the Nature paper.
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Clearly humans care a lot about neurogenesis not just because understanding whether it happens in humans would be a stepping stone to building a robust model of how cognition happens, but also because intuitively it has to do with whether we can enhance our own mental abilities in our lifetime-- one of the most fervent desires of many, I'm sure.
We've already had to write off things like growth mindset as a way to increase our fluid intelligence, it seems. It is dismaying that, based on this study, we'll have to write off things like exercise as well which we now realize only work in rats. What's left that could plausibly help? Perhaps just: building better work and study habits and simply spending more time on mental tasks. At least we're pretty sure those aren't illusory.
We've already had to write off things like growth mindset as a way to increase our fluid intelligence, it seems. It is dismaying that, based on this study, we'll have to write off things like exercise as well which we now realize only work in rats. What's left that could plausibly help? Perhaps just: building better work and study habits and simply spending more time on mental tasks. At least we're pretty sure those aren't illusory.
Whether adult human neurogenesis happens doesn't indicate whether exercise (or growth mindset, or diet, or whatever else) isn't effective; there are plenty of other modes of neuroplasticity that could be modulated by such things. Similar to how the article noted that, despite claims that antidepressants worked via promoting neurogenesis, they still work even in the face of evidence against neurogenesis happening at all.
Even if human neurogenesis turns out to be a complete fable, the implications for actual humans trying to boost their intelligence is minimal. IQ correlates with brain size only modestly, and typical variations in brain size are (I haven't done the math, but I feel fairly confident) an order of magnitude greater than what anyone has claimed adult neurogenesis could produce; simply adding more neurons wasn't going to get you where you wanted to go, regardless. But that's not the only game in town- there are many ways the brain changes itself.
(As it happens, thousands of hopeful nootropic-poppers and brain-trainers haven't been terribly successful at boosting their IQ yet. But it remains a possibility.)
Even if human neurogenesis turns out to be a complete fable, the implications for actual humans trying to boost their intelligence is minimal. IQ correlates with brain size only modestly, and typical variations in brain size are (I haven't done the math, but I feel fairly confident) an order of magnitude greater than what anyone has claimed adult neurogenesis could produce; simply adding more neurons wasn't going to get you where you wanted to go, regardless. But that's not the only game in town- there are many ways the brain changes itself.
(As it happens, thousands of hopeful nootropic-poppers and brain-trainers haven't been terribly successful at boosting their IQ yet. But it remains a possibility.)
They are not illusory, but I think people run into problems finding a structure or deeper meaning that cements those good habits into their daily life. They just become more “to do” items on our daily growing list of shit to do.
What is illusory, is that something outside of human perception will “fix” a perception problem. Something like repetitive exertion, like exercising... that is not a solution if there is a core perception problem in that person’s lens. As long as a “fix” or “solution” is being sought, it will always be temporary unless it opens up something in the person that allows them to see the original issue. But most often that stuff is used like a multivitamin, and people forget the significance of the fragile foundations they’re laying down as stuff to make the “rest of their life” possible. And they just move their attention to something else, something like watching Netflix instead of thinking about why they have such a hard time getting up to exercise in the first place.
It’s a spiritual problem.
What is illusory, is that something outside of human perception will “fix” a perception problem. Something like repetitive exertion, like exercising... that is not a solution if there is a core perception problem in that person’s lens. As long as a “fix” or “solution” is being sought, it will always be temporary unless it opens up something in the person that allows them to see the original issue. But most often that stuff is used like a multivitamin, and people forget the significance of the fragile foundations they’re laying down as stuff to make the “rest of their life” possible. And they just move their attention to something else, something like watching Netflix instead of thinking about why they have such a hard time getting up to exercise in the first place.
It’s a spiritual problem.
It's a fascination problem. Everything falls into place when what genuinely deeply interests you coincides with your work, with the source of your motivation to work, and with the source of your mental fitness to do the work. When I think of long-lived scientists, mathematicians, composers, artists who produce brilliant work into old age, these are people who never lose fascination for what they do.
Agreed. Something significant is getting missed somewhere in the pipeline. But still, all of those brilliant people found something inside themselves to drive them. None are/were dependent on society beyond the knowledge that got them to the point where they broke away from the herd and pushed us further, and that's what makes them special.
And yet I think most of them miss something significant as well. It's pretty painful to read Feynman's thoughts on poetry, for example, but following his natural curiosity led him to a place that satisfied all/most of his psychological needs.
And yet I think most of them miss something significant as well. It's pretty painful to read Feynman's thoughts on poetry, for example, but following his natural curiosity led him to a place that satisfied all/most of his psychological needs.
Huh? Growth mindset has been validated. For small interventions, the effect is not large, but it IS replicable. If even just a couple of 25 minute pep talks show a statistically measurable effect (even if it is small), then that is important when scaled up.
http://marginalrevolution.com/marginalrevolution/2018/03/gro...
http://marginalrevolution.com/marginalrevolution/2018/03/gro...
Here's[0] what the literature on growth mindset interventions looks like, taken from the Sisk et al. meta analysis.
[0] https://image.ibb.co/kn4ePx/image.png
[0] https://image.ibb.co/kn4ePx/image.png
So... looks like it's a small but replicable effect.
Constant exposure to novelty. The brain is an adaptive organ and subjecting it to repetition and normalcy actively prevents any adaptation from taking place. Living in the same place, doing the same thing, experiencing the same things, being with the same people, never having intense new experiences provide markedly fewer novel stimuli which are what fundamentally drive all brain development.
The desire to sit still in the same room for decades on end, experiencing nothing interesting or pleasurable or intense, is a desire for a brain that stops its functioning.
The desire to sit still in the same room for decades on end, experiencing nothing interesting or pleasurable or intense, is a desire for a brain that stops its functioning.
I recommend practicing memory palace techniques if you really want a brain work out. Storing sets of information, retrieving them, and replacing them is intensely exhausting. You know you're getting a brain work out. I try and memorize one deck of cards every day at a minimum. After a bit of practice, you'll have laser focus. Not so sure about whether this promotes neurogenesis though. Does anybody have any resources on this?
I don’t, but please tell us more about the spillover effects based on your subjective experience. This sounds like something I would try but I’d like to hear more.
Prime factoring of license plate numbers before the car exits or otherwise gets out of view. Good way to exercise brain... and get in a wreck. (You'll grow to hate those occasional plates from states with 5 digit numbers.)
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Fun article. Best line: "if we want to believe something, it will accrete a protective layer of positive studies whether it’s true or not."
I've wondered for a long time if stem cell therapy could, for example, cure my amblyopia — though it hardly seems worth the cancer risk. This very surprising news is a data point in favor of that kind of thing.
It's also a kind of data point that we really need to improve science a lot in order to be able to advance as a civilization.
(Amblyopia is due to anomalous neural development caused by, more or less, early childhood early sensory deprivation from one eye. The result is a lifelong lack of visual competence in that eye — it may focus perfectly, as mine does, but recognition is poor, apparently because perception of Gabors at certain spatial frequencies is very poor. I say "more or less" because the eye is still providing sensory input, but because it's pointing in the wrong direction, that input isn't useful.)
It's also a kind of data point that we really need to improve science a lot in order to be able to advance as a civilization.
(Amblyopia is due to anomalous neural development caused by, more or less, early childhood early sensory deprivation from one eye. The result is a lifelong lack of visual competence in that eye — it may focus perfectly, as mine does, but recognition is poor, apparently because perception of Gabors at certain spatial frequencies is very poor. I say "more or less" because the eye is still providing sensory input, but because it's pointing in the wrong direction, that input isn't useful.)
This may sound weird but: try lsd (1p-lsd - a legal analog - in my case). I have amblyopia too (although milder, refractive). It comes with a total lack of stereoscopic vision. 300ug (100ug wasn't enough) of 1p-lsd turned it on for about a week, getting progressively weaker each day. While on 1p-lsd the vision in my weaker eye was way, way better than normally, very close to the dominant eye! Unfortunately it got worse immediately after and remained only slightly better for days.
It's not a cure (who knows though - brains are weird) but the temporary experience of true 3d was well worth it. Depth suddenly became an _equivalent_ dimension to width and height - it's impossible to describe. I suddenly understood why I always sucked at ball sports and for the first time in my life became mildly afraid of heights - not an irrational phobia, but as normal people do (normally I have absolutely zero automatic fear of heights which is perhaps why I enjoy free climbing).
If you decide to try it, do it on an empty stomach and drink only water, have some place to lie down. The come up for heavy doses sucks because body thinks that it ate something poisonous - nausea, urge to vomit, sweating. It passes after about 1.5h. Mentally 300ug is way below that required to lose contact with the reality so no danger here.
Decided to use a throwaway to not have an admission of drug use on my current account.
It's not a cure (who knows though - brains are weird) but the temporary experience of true 3d was well worth it. Depth suddenly became an _equivalent_ dimension to width and height - it's impossible to describe. I suddenly understood why I always sucked at ball sports and for the first time in my life became mildly afraid of heights - not an irrational phobia, but as normal people do (normally I have absolutely zero automatic fear of heights which is perhaps why I enjoy free climbing).
If you decide to try it, do it on an empty stomach and drink only water, have some place to lie down. The come up for heavy doses sucks because body thinks that it ate something poisonous - nausea, urge to vomit, sweating. It passes after about 1.5h. Mentally 300ug is way below that required to lose contact with the reality so no danger here.
Decided to use a throwaway to not have an admission of drug use on my current account.
This is more speculative than anything: have you tried eye-patching the good eye to force your brain into being trained to use the bad one? Specifically for a long period of time (months).
Yes, I did that 12 hours a day for five years in my early childhood, starting at 2 years old. Before that, I couldn't see out of my left eye at all.
I wonder if you would have better results if you did it 100% of the time. I wonder if training was hindered simply because other neural pathways would still "win" after the 12 hours each day. But all of this speculation is centered around neural growth and formation - I have no idea what could have happened because of lack of use during development (ie. atrophy, etc).
Neural progenitor transfer works in mice - http://science.sciencemag.org/content/327/5969/1145
While this comes to the right conclusion I think it mistraces a lot of the issues.
For example: a fair amount of the depression and neurogenesis studies (and indeed neurogenesis manipulation studies) suffered from the same issue: it's really hard to make a population of cells die without generally poisioning the remaining cells. Most of the initial studies relied on things like radiation, ie radiate a rat and it starts acting depressed. There is now increasing evidence that radiation kills off a bunch of synapses and causes some wicked disregualtion across the system so that turned out to be wrong. Conversely BDNF enhances neurogenesis but it also enhances synaptic learning so even positive manipulations had this issue but in reverse. Newer timed genetic manipulation studies were more precise but the depression-neurogenesis link has been slowly losing steam in light of these studies.
But the BIG issue boils down to this: there was never strong evidence for the importance of neurogenesis. The dentate gyrus is a tiny region of the brain with neurons that act in unusual ways. In humans it's an even tinier region. While it is probably required, at least as a pass through, to learn new memories, it's surprising how much weight people were placing on neurogenesis in this tiny tiny structure. Given, networks can make small zones have big effects, but the weight of evidence should have always been on people pushing the area to prove the dentate was this massively important structure. This has not been conclusively done (studies have linked it to some specific subtypes of learning but those have limited it as much as they have found an important role for it). This is a structural issue in science broadly, there is an incentive to push forward with the next big finding but no incentive to go back and confirm the gulf of assumptions that a literature is resting on.
The good news is, human brains could always change, synaptic plasticity is present throughout life and has been shown by many good studies to occur throughout adulthood. We don't need new cells in a tiny part of the brain to learn new things, networks rewire and while that rewiring isn't something as dramatic as new cells, small effects can lead to big outcomes in dynamic systems. People obviously make new habits, learn new skills, and make new memories throughout life. The onus should have always been on science to show why it occurs, not to lend credibility that it occurs.
But the BIG issue boils down to this: there was never strong evidence for the importance of neurogenesis. The dentate gyrus is a tiny region of the brain with neurons that act in unusual ways. In humans it's an even tinier region. While it is probably required, at least as a pass through, to learn new memories, it's surprising how much weight people were placing on neurogenesis in this tiny tiny structure. Given, networks can make small zones have big effects, but the weight of evidence should have always been on people pushing the area to prove the dentate was this massively important structure. This has not been conclusively done (studies have linked it to some specific subtypes of learning but those have limited it as much as they have found an important role for it). This is a structural issue in science broadly, there is an incentive to push forward with the next big finding but no incentive to go back and confirm the gulf of assumptions that a literature is resting on.
The good news is, human brains could always change, synaptic plasticity is present throughout life and has been shown by many good studies to occur throughout adulthood. We don't need new cells in a tiny part of the brain to learn new things, networks rewire and while that rewiring isn't something as dramatic as new cells, small effects can lead to big outcomes in dynamic systems. People obviously make new habits, learn new skills, and make new memories throughout life. The onus should have always been on science to show why it occurs, not to lend credibility that it occurs.
A recent study[0] seems to provide meaningful evidence that while adult neurogenesis occurs in rats, rabbits and some other species, as mentioned in the research referred to by the OP, it does not actually occur in humans. I'm not claiming to know the truth on this, but I thought this research should be part of the discussion.
[0] https://www.theatlantic.com/science/archive/2018/03/do-adult...
[0] https://www.theatlantic.com/science/archive/2018/03/do-adult...
Oh wow, thank you so much for filling me in. I didn't read the whole thing because it was quoting a lot of animal studies, which I knew were questionable in light of the adult human research, and I was aware of no reason to expect the turnaround in part 2! :) You were very kind about it. Sorry for wasting everyone's time!
You didn't read the second half of the article.
:) Its kind of the point of the whole article, FYI.
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http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(18)30...
It usually flips every month.