Adult Neurogenesis – A Pointed Review

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[I am not a neuroscientist and apologize in advance for any errors in this article.]

Hey, let’s review the literature on adult neurogenesis! This’ll be really fun, promise.

Gage’s Neurogenesis In The Adult Brain, published in the Journal Of Neuroscience and cited 834 times, begins:

A milestone is marked in our understanding of the brain with the recent acceptance, contrary to early dogma, that the adult nervous system can generate new neurons. One could wonder how this dogma originally came about, particularly because all organisms have some cells that continue to divide, adding to the size of the organism and repairing damage. All mammals have replicating cells in many organs and in some cases, notably the blood, skin, and gut, stem cells have been shown to exist throughout life, contributing to rapid cell replacement. Furthermore, insects, fish, and amphibia can replicate neural cells throughout life. An exception to this rule of self-repair and continued growth was thought to be the mammalian brain and spinal cord. In fact, because we knew that microglia, astrocytes, and oligodendrocytes all normally divide in the adult and respond to injury by dividing, it was only neurons that were considered to be refractory to replication. Now we know that this long accepted limitation is not completely true

Subsequent investigation has found adult neurogenesis in all sorts of brain regions. Wikipedia notes that “In humans, new neurons are continually born throughout adulthood in two regions of the brain: the subgranular zone and the striatum”, but adds that “some authors (particularly Elizabeth Gould) have suggested that adult neurogenesis may also occur in regions within the brain not generally associated with neurogenesis including the neocortex”, and there’s also some research pointing to the cerebellum.

Some research has looked at the exact mechanism by which neurogenesis takes place; for example, in a paper in Nature cited 1581 times, Song et al determine that astroglia have an important role in promoting neurogenesis from FGF-2-dependent stem cells. Other research has tried to determine the rate; for example, Cameron et al (1609 citations) find that there is “a substantial pool of immature granule neurons” that may generate as many as 250,000 new cells per month. Still other research looks at the chemical regulators – a study by Lie et al, cited 1312 times, finds that Wnt3 signaling is involved.

(which is making you more nervous – the fact that I keep emphasizing how many citations these studies have, or the fact that one of the principal investigators is named “Lie”?)

But the most exciting research has been the work identifying the many important roles that neurogenesis plays in the adult brain – roles vital in understanding learning, memory, and disease.

Snyder et al (775 citations) finds “a new role for adult neurogenesis in the formation and/or consolidation of long-term, hippocampus-dependent, spatial memories.” Dupret et al go further and find that “spatial relational memory requires hippcampal adult neurogenesis”. Aimone et al (633 citations) find “a possible role” for adult neurogenesis in explaining the “temporal clusters of long-term episodic memories seen in some human psychological studies”. And Jessberger et al (506 citations) finds a role in object recognition memory as well.

In terms of learning, one of the major studies was Gould et al in Nature Neuroscience (2207 citations) finding that Learning Enhances Adult Neurogenesis In The Hippocampal Formation. Lledo et al (1288 citations) find that neurogenesis plays a part in explaining the brain’s amazing plasticity, and is “highly modulated, revealing a plastic mechanism by which the brain’s performance can be optimized for a given environment”. Clemenson et al (17 citations) find that “from mice to humans”, enviromental enrichment improves neurogenesis, and this “may one day lead us to a way to enrich our own lives and enhance performance on hippocampal behaviors”.

But I’ve always been most interested in the link with depression. In 2000, Jacobs et al published Adult Brain Neurogenesis And Psychiatry: A Novel Theory Of Depression (961 citations). It’s important enough that I want to quote the whole abstract:

Neurogenesis (the birth of new neurons) continues postnatally and into adulthood in the brains of many animal species, including humans. This is particularly prominent in the dentate gyrus of the hippocampal formation. One of the factors that potently suppresses adult neurogenesis is stress, probably due to increased glucocorticoid release. Complementing this, we have recently found that increasing brain levels of serotonin enhance the basal rate of dentate gyrus neurogenesis. These and other data have led us to propose the following theory regarding clinical depression. Stress-induced decreases in dentate gyrus neurogenesis are an important causal factor in precipitating episodes of depression. Reciprocally, therapeutic interventions for depression that increase serotonergic neurotransmission act at least in part by augmenting dentate gyrus neurogenesis and thereby promoting recovery from depression. Thus, we hypothesize that the waning and waxing of neurogenesis in the hippocampal formation are important causal factors, respectively, in the precipitation of, and recovery from, episodes of clinical depression.

This theory got a boost from studies like Duman et al (522 citations), which found that antidepressant drugs like SSRIs upregulated neurogenesis – could this be their mechanism of action? And Ernst et al (327 citations) find that “there is evidence to support the hypothesis that exercise alleviates MDD and that several mechanisms exist that could mediate this effect through adult neurogenesis” – ie the antidepressant effects of exercise seem to work this way too. Electroconvulsive therapy, the most effective known treatment for depression? Works by promoting adult neurogenesis, at least according to Schloesser et al.

Is there anything that doesn’t have important neurogenesis-related effects? It would seem there is not. Sex, for example, “promotes adult neurogenesis in the hippocampus, despite an initial elevation in stress hormones” according to Leuner et al (124 citations). Drug addiction is modulated by neurogenesis. We need rock n’ roll to complete the triad, so here’s Music Faciliates The Neurogenesis, Regeneration, and Repair of Neurons.

A study in Nature Neuroscience that garnered over 3000 citations found that running increased neurogenesis. The popular science press was quick to notice. A slew of exercise-neurogenesis studies spawned articles like Psychology Today’s More Proof That Aerobic Exercise Can Make Your Brain Bigger. Dr. Perlmutter (“Empowering Neurologist!”) has a video about how you can Grow New Brain Cells Through Exercise. After this the pop sci world might have gotten a little carried away, until neurogenesis controls everything and is controlled by everything in turn. Slimland (of course there’s a site called Slimland) has a How To Grow New Brain Cells And Stimulate Neurogenesis page, suggesting you can “set yourself free and start flying” by removing toxins, eating a ketogenic diet, and meditating. Naturalstacks.com boasts 11 Proven Ways To Generate More Brain Cells, Improve Memory, And Boost Mood, which advises…really? Do you really want to know what it advises? Come on.

Also, growth mindset. Of course growth mindset. Carol Dweck’s Mindsetworks helpfully provides an infographic for teachers, urging them to tell their students that each time they set a goal or become motivated to learn a new skill, “a new neuron is formed through a process called neurogeneis” [sic].

So it’s no surprise that researchers in the area are calling adult neurogenesis “one of the most exciting and rapidly evolving areas of research in the field of neuroscience”.

II.

Fun fact: there’s no such thing as adult neurogenesis in humans.

At least, this is the conclusion of Sorrells et al, who have a new and impressive study in Nature. They look at “59 post-mortem and post-operative slices of the human hippocampus” and find “that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans.” Also, the subgranular zone, the supposed part of the brain where neurogenesis begins, isn’t even a real structure.

I am not a neuroscientist and am unqualified to evaluate it. But the Neuroskeptic blog, which I tend to trust in issues like this, thinks it’s legit and has been saying this for years. Ed Yong from The Atlantic has a really excellent review of the finding that interviews a lot of the major players on both sides and which I highly recommend. Both of these reinforce my feeling that the current study makes a really strong case.

I was kind of floored when I saw this, in a way that I hope I was able to replicate in you by preceding this with the literature review above. How do you get so many highly-cited papers speaking so confidently about every little sub-sub-detail of a phenomenon, if the phenomenon never existed in the first place?

As far as I can tell, this was entirely innocent, well-intentioned, and understandable. It happened like this:

Adult neurogenesis was discovered in rats. This was so surprising, and such a violation of established doctrine, that it quickly became one of the most-investigated areas in neuroscience. Hundreds of studies were done on rats to nail down every little detail of the process.

The work was extended to many other mammals, to the point where it seemed inevitable that it must be true of humans as well. This was difficult to test because the relevant studies involve dissecting brains, and there aren’t that many human brain specimens available with the necessary level of preservation. After a lot of work, a few people got a couple of brains, did some very complicated and contamination-prone tests, and found evidence of adult neurogenesis. This encouraged everyone to assume that the things they had discovered about rat neurogenesis were probably true in humans as well, even though they could never prove them directly because of the difficulty of human experimentation. Later some other researchers tried to replicate the complicated and contamination-prone tests and couldn’t find adult neurogenesis in humans, but everyone assumed they had just messed up some aspect of the complicated testing process.

And to complicate matters, everyone in the new study has been very careful to say they can’t prove with certainty that zero adult neurogenesis occurs – just that the levels are so low and hard to detect that they can’t possibly matter. Looking back on some past studies, it seems that “so low and hard to detect that they can’t possibly matter” was actually within their confidence intervals. So it may be that some team found some extremely tiny and irrelevant population of immature neurons in the brain, gave a confidence level that included that number, and then everyone just assumed we were talking about levels similar to the ones we saw in rats.

With real scientists taking not-entirely-sufficient care to distinguish rat from human results, the popular press felt licensed to totally ignore the distinction (did you even notice which of the studies in Part I were done on which species? Don’t worry, nobody else did either).

Meanwhile, synaptogenesis – the growth of new synapses from existing nerve cells – was getting linked to depression and all kinds of other things in a lot of interesting studies. When people started talking about neurogenesis’ role in depression, psychiatrists like me who have trouble keeping words ending with -genesis separate just sort of nodded and said “Oh, yeah, I heard about that” and didn’t give it the sort of scrutiny it deserved.

(I wonder if this is young-earth creationists’ problem too)

So it’s not like any one person made a spectacular mistake anywhere along the lines. Most of the studies done were in rats, and 100% correct. A few studies were done in humans, and may have gotten the wrong answer in a very difficult domain, while also hedging their bets and admitting they were trying something hard. It was only on a structural, field-wide level that all of this came together into people just assuming that adult human neurogenesis had to happen and be important.

…or at least, that’s the optimistic take on it. But I can’t help thinking – antidepressants work in humans, which suggests that the people who found neurogenesis was necessary for antidepressant effects must have just been plain wrong. And if exercise has antidepressant effects in humans, then the claim that those effects are neurogenesis-mediated must be wrong too. And, uh, humans form spatial and temporal memories, so unless we do this by a totally different mechanism than the ones rats use, people must have been wrong when they said neurogenesis was involved in that. ECT? Works in humans. Brain plasticity? Happens in humans. So maybe it would be better to say that the original claim that adult neurogenesis happens in humans seems innocent and understandable – but if the new study is true, that suggests that a lot of the followup claims must have been imaginary. Anything that focuses on a process that happens in humans and says “neurogenesis causes this” must not only be wrong to extend the results to humans, but must be under strong suspicion of being wrong even about rats, unless rat brains and human brains accomplish the same basic tasks through totally different mechanisms (eg antidepressants work on rats but for different reasons than in humans).

We know many scientific studies are false. But we usually find this out one-at-a-time. This – again, assuming the new study is true, which it might not be – is a massacre. It offers an unusually good chance for reflection.

And looking over the brutal aftermath, I’m struck by how prosocial a lot of the felled studies are. Neurogenesis shows you should exercise more! Neurogenesis shows antidepressants work! Neurogenesis shows we need more enriched environments! Neurogenesis proves growth mindset! I’m in favor of exercise and antidepressants and enriched environments, but this emphasizes how if we want to believe something, it will accrete a protective layer of positive studies whether it’s true or not.

I’m also struck by how many of the offending studies begin by repeating how dogmatic past neuroscientists were for not recognizing the existence of adult neurogenesis sooner. Remember Gage’s review above:

A milestone is marked in our understanding of the brain with the recent acceptance, contrary to early dogma, that the adult nervous system can generate new neurons. One could wonder how this dogma originally came about…

Or from Neurogenesis In Adult CNS: From Denial To Opportunities And Challenges For Therapy:

The discovery of neurogenesis and neural stem cells (NSC) in the adult CNS has overturned a long‐standing and deep‐routed “dogma” in neuroscience, established at the beginning of the 20th century. This dogma lasted for almost 90 years and died hard when NSC were finally isolated from the adult mouse brain. The scepticism in accepting adult neurogenesis has now turned into a rush to find applications to alleviate or cure the devastating diseases that affect the CNS.

From Adult Human Neurogenesis: From Microscopy To Magnetic Resonance Imaging:

The discovery of adult neurogenesis crushed the century-old dogma that no new neurons are formed in the mammalian brain after birth. However, this finding and its acceptance by the scientific community did not happen without hurdles. At the beginning of the last century, based on detailed observations of the brain anatomy reported by Santiago Ramon y Cajal and others, it was established that the human nervous system develops in utero (Colucci-D’Amato et al., 2006). In adult brains, it was thought, no more neurons could be generated, as the brain is grossly incapable of regenerating after damage (for a more detailed historical report see Watts et al., 2005; Whitman and Greer, 2009). This dogma was deeply entrenched in the Neuroscience community, and Altman’s (1962) discovery of newborn cells in well-defined areas of the adult rodent brain was largely ignored.

I’m bolding the word “dogma” because for some reason every article in this field uses it like a verbal tic. Washington University’s “Neuroscience For Kids” page feels compelled to use the word even though they don’t expect their readers to understand it:

The dogma (a set of beliefs or ideas that is commonly accepted to be true) that nerve cells in the adult brain, once damaged or dead, do not replace themselves is being challenged. Research indicates that at least one part of the brain in adults maintains its ability to make nerve cells.

I think Patient Zero in this use-of-the-word-dogma epidemic might be Neurogenesis In The Adult Brain: Death Of A Dogma, (880 citations) whose abstract says:

For over 100 years a central assumption in the field of neuroscience has been that new neurons are not added to the adult mammalian brain. This perspective examines the origins of this dogma, its perseverance in the face of contradictory evidence, and its final collapse. The acceptance of adult neurogenesis may be part of a contemporary paradigm shift in our view of the plasticity and stability of the adult brain.

The dogma-concern isn’t totally wrong. Previous neuroscientists thought there wasn’t neurogenesis in rats, and there is. That was a legitimate mistake and one worth examining. But is it possible that the reaction to that mistake – a field-wide obsession with talking about how dogmatic you had to be to miss the obvious evidence of mammalian neurogenesis, and a desire never to repeat that mistake – contributed to the less-than-stellar effort to make sure neurogenesis was happening in humans? Heuristics work until they don’t. Those who fail to learn from history are doomed to repeat it, but those who learn too much from history are doomed to make the exact opposite mistake and accuse anyone who urges restraint of “failing to learn from history” and “dogmatism”. From the Virtues of Rationality:

The Way is a precise Art. Do not walk to the truth, but dance. On each and every step of that dance your foot comes down in exactly the right spot. Each piece of evidence shifts your beliefs by exactly the right amount, neither more nor less.

Or maybe I’m just grasping for straws. But I feel like I have to grasp for something. I have nowhere near as much expertise as the actual neuroscientists writing about this result (and there are many). I’m sure I’ve made some inexcusable mistakes somewhere in the process of writing this. The reason I feel compelled to dabble in this subject anyway is that I don’t feel like anyone else is conveying the level of absolute terror we should be feeling right now. As far as I can tell, this is the most virulent outbreak of the replication crisis thus far. And it didn’t happen in a field like social psychology which everyone already knows is kind of iffy. It happened in neuroscience, with dramatic knock-on effects on medicine, psychology, and psychiatry.

I feel like every couple of months we get a result that could best be summed up as “no matter how bad you thought things were, they’re actually worse”. And then things turn out to be even worse than that. We can’t just become 100% certain things are arbitrarily bad – that would be making the same mistake as the neuroscientists who were overly eager to reject the no-neurogenesis dogma. But that means we always have to be ready for disappointment.

From the Neuroskeptic article:

So what does this all mean? Sorrells et al. conclude by speculating, provocatively, that our lack of adult hippocampal neurogenesis may actually be part of what makes us human:

“Interestingly, a lack of neurogenesis in the hippocampus has been suggested for aquatic mammals (dolphins, porpoises and whales), species known for their large brains, longevity and complex behaviour.”

This hypothesis seems pretty wild to me. But it’s no wilder than some of the other theories that have long surrounded adult neurogenesis

Our total inability to ever change or get better in any way is what separates us from the animals. Inspiring!