behavior etiketine sahip kayıtlar gösteriliyor. Tüm kayıtları göster
behavior etiketine sahip kayıtlar gösteriliyor. Tüm kayıtları göster

Running and neurogenesis; the plastic brain

A new paper online in the Journal of Physiology ("Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained," Nokia et al.), and described here by the NYT, reports that running is good for the brain.  At least the rat brain.

From the paper (emphasis mine):
Adult hippocampal neurogenesis (AHN) is a continuous process through which cells proliferate in the subgranular zone of the dentate gyrus, mature into granule cells, and ultimately become incorporated into hippocampal neuronal networks. In rodents, adult-born hippocampal neurons seem crucial for a variety of adaptive behaviors such as learning, pattern separation, and responses to stress. Aerobic exercise, e.g. running, increases AHN and improves cognitive performance in both male and female adult rodents. The increase in AHN in response to running is reported to be in part due to an increase in the number of surviving neuronal precursor cells (type 2) rather than to the shortening of the cell cycle. There are also studies indicating that running increases the survival and incorporation of newly divided hippocampal cells, born days before commencing training, to increase net neurogenesis. [See the paper for citations for reported findings, which I've removed here for length.]
It has already been well-established that aerobic exercise is associated with an increase in adult hipocampal neurogenesis, the number of neurons in the hippocampus, the region of the brain associated with producing long-term memory among other functions.  But, Nokia et al. wondered if it was only aerobic exercise, or whether other kinds of exercise have the same effect.

So they compared the number of neuronal cells of mice subjected to high-intensity interval training, resistance training and distance running.  They found no increase in the rats who did resistance training compared to sedentary rats, and a smaller than expected increase in rats that did the interval training.  It was only in the brains of the rats who did aerobic exercise that neurogenesis was significantly increased.  The authors hypothesize that this is because running stimulates the production of  brain-derived neurotrophic factor and insulin-like growth factor, which are associated with neurogenesis. The more aerobic exercise the animal does, the more of these the animal produces, and thus the more neurons.

Currently the best advice for preventing dementia in old age is to maintain a social life, quit smoking, and exercise.  And, if this rat study can be applied to humans, this should at least qualify that as aerobic exercise; running or biking, say.  As with all such lifestyle advice, this surely won't work for everyone, but the evidence is increasingly in its favor, at least on a population basis.

But there are deeper implications of this work, I think.  If exercise changes the architecture of the brain in ways that can affect learning, even in adults, and, as has been repeatedly demonstrated, stimulating children by reading to them, using lots of words, playing music to them, and so on, or the reverse, growing up in poverty,  or with disease, or amid famine all can affect brain architecture and thus cognitive ability for better or for worse, why do so many continue to privilege genes and genes alone -- or even more, a single gene -- for the creation of intelligence?



Source: "Effects on brain development leading to cognitive impairment:  A worldwide epidemic," Olness,
Journal of Developmental & Behavioral Pediatrics:
April 2003 - Volume 24 - Issue 2 - pp 120-130

It seems that the brain responds to experience at all ages, but it's possible that there's a 'sensitive period' for cognition.  As just one example, the cognitive abilities of children reared in institutions in Bucharest were compared to that of children never placed in an institution to those whose lives began there but who moved to foster care before age two.  Those who were reared entirely in institutions had much lower cognitive ability than the other two groups; the cognitive abilities of those who were moved to foster care before age two significantly improved.  The authors of this study suggest that there may be a sensitive period for developing cognitive ability, just as there is one for learning language, and many other aspects of brain function.

Of course, as with any trait, genes play a crucial role in the development of the brain.  But they don't do it alone.  E.g., a 2010 paper in Child Development describes the genetic underpinnings of the developing brain, but its plasticity as well.
The foundations of brain architecture are established early in life through a continuous series of dynamic interactions between genetic influences and environmental conditions and experiences (Friederici, 2006; Grossman, 2003; Hensch, 2005; Horn, 2004; Katz & Shatz, 1996; Majdan & Shatz, 2006; Singer, 1995). There is increasing evidence that environmental factors play a crucial role in coordinating the timing and pattern of gene expression, which in turn determines initial brain architecture. Because specific experiences potentiate or inhibit neural connectivity at key developmental stages, these time points are referred to as sensitive periods (Hess, 1973; Knudsen, 2004). Each one of our perceptual, cognitive, and emotional capabilities is built upon the scaffolding provided by early life experiences. Examples can be found in both the visual and auditory systems, where the foundation for later cognitive architecture is laid down during sensitive periods for basic neural circuitry.  
Genetic determinists might acknowledge the plasticity of the brain but then say that how the brain responds to experience is what's genetically determined, and thus that there are children who just aren't genetically equipped to be the next Einstein, or even to learn calculus.  We know this is true at least at one extreme of the distribution of intelligence, because there are many alleles known to be associated with low cognitive ability.  These usually cause syndromic conditions, however, so aren't related only to how quickly synapses are crossed, or memories made, or whatever it is that underlies -- or defines -- intelligence.  As with many other trait distributions, what happens at the extremes doesn't necessarily represent what's going on in the middle, so I think the jury is still out as to the overriding importance of single or even a small number of alleles in the development of normal or above normal intelligence (again, whatever that is -- for the moment, let's call it the ability to score well on IQ tests).  And indeed no genes with large effects on intelligence have yet been identified, despite decades of looking.  That has so far included comparison of the tails of the distribution among individuals without a clear-cut pathology.

So, of course there are genes involved in how quickly people think, or make connections between ideas, or memorize, or invent things, or remember -- how people learn.  But it's not either mainly genes or environment.  It's both, interacting, and molding the reactive brain.  There is enough evidence now to show that the brain is a hungry organ, soaking up and responding to experience at all times, throughout life.  Whether or not we believe that society should be investing in optimizing the environment of every child to maximize their potential is a social and political decision, not a scientific one.

Somatic mutation and neurological traits. Part I. Background and Epilepsy

Epilepsies are disorders of cascades of uncontrolled neural firings.  Local or large parts of the brain can be involved in seizures, and the affected person's functioning is seriously impaired until the wave or storm of 'undisciplined' synapse firing has passed....until the next episode.  Epilepsy can be triggered by different stimuli in different people, and can affect specific parts of the brain, either quite localized or on just one side, or more general and bilateral. Epilepsies also  have variable onset triggers and ages in different people.

Waves of unconstrained neural firing seem to be related to signal transfers between connections between neurons (synapses) in the brain.  Since signal molecules are basically genetic (that is, not dietary or due to exogenous chemicals), one would expect epilepsy to be basically 'genetic' in its basic causal physiology.  Indeed, some epilepsies have long been known to result from mutations in single genes, occur in Mendelian fashion in families, involve neural signaling molecules, and some of these genes are known to cause epileptic symptoms when mutated in laboratory mice.  But most epilepsies are sporadic, not obviously familial, and have resisted attempts to map the responsible genes.

This was the general picture in around 2004, when I was asked to give a presentation to a meeting at NIH, of people working on epilepsy, to discuss what I saw as the general genetic causal landscape at the time.  This was early in the age of GWAS and other genomewide approaches.

I don't remember the details, but in my presentation I gave a general picture and issues in genetic mapping, and relevant evolutionary genetics.  But I also wanted to make a contribution beyond just a review, and I had thought about the genetics, physiology, and epidemiological patterns of the epilepsies.  I suggested what I thought would be relevant, based on previous work I had done over the years on the genetics of cancer and aging.  Basically, I hypothesized that many epilepsies might, like many cancers, be due not to inherited mutations but to somatic mutations--that is, mutations in relevant genes that occurred in neural cells during embryonic development or later in life, rather than being inherited from parents.

I found considerable interest in this idea, which I thought (and still think) could be a positive, potentially innovative way to understand the biology and epidemiology of epilepsies.  Some interest was shown, and a leading epilepsy neurobiologist offered to work on a paper about this idea and how one might test for it.  But for whatever reason, he lost interest before any paper could be published.  Partly perhaps, that was because of the difficulty of testing the idea, which would have required identifying the specific misfiring neurons in epilepsy victims and, when they died, sequencing those areas looking for mutations not found in neighboring normal neurons.

After my potential collaborator had more important things to do (or, probably, more important people to please) and dropped the idea of doing a collaborative review paper, I published my ideas in Trends in Genetics in 2005 (paywalled; if you're interested, email me for a pdf).  With some helpful discussion with a then-junior colleague, Dan Burgess (now working at Roche, I believe), we thought about ways in which, depending on embryonic or postnatal age, somatic mutation in neural cells or their precursors, could generate epileptic effects.  The idea is shown in this figure, drawn in collaboration with Dan, and taken from the paper.

Possible Epileptogenic somatic mutation scenarios.  From Weiss, TiGs, 2005; drawn with Dan Burgess
There are at least two main ways this might happen.  First, a somatic mutation arising early in embryonic development in a cell that was the precursor of neurons, could set up that descendant lineage  or clade of cells (and their respective part of the brain) to be vulnerable to uncontrolled firing, that is, to epilepsy.

Alternatively, a single later-occurring mutation might make the affected neuron too ready to fire under some conditions, and that could entrain firing in the often thousands of other neurons with which it synapses, and their neurons in turn  In a sense, such an episode could 'burn in' the synaptic connection in this set of neurons, all genetically normal except for the mutant triggering cell, making the set vulnerable to later episodes triggered by the original offending cell.  The location in the brain of the 'parent' aberrant cell(s) and its or their synaptic network would determine the side and part(s) of the brain that were affected by the seizures.

For somatic mutation to have detectable effect at the organismal level, there must be some sort of phenotype amplification, such that even a single or few aberrantly firing cells, that might on their own not be particularly noticeable would entrain enough other cells to cause a seizure. Cancers are now extensively studied for somatic mutation, because of their exuberant growth and histological characteristics.  One transformed cell leads to a large number of descendant cells--a tumor.

As noted above, aberrantly behaved neurons even if not individually detectable could, in principle at least, entrain so many other otherwise normal cells in a synaptic network, as to amplify the effect to make it noticeable to the person as a whole and to clinicians.  Thus in a variant of the precedent of cancer, one mutant transformed neural cell early in the embryo may be unnoticeable in itself, but after millions of cell divisions it can lead to a clone of misfiring cells.

With this sort of thing in mind, one can naturally also ask about a potential role for somatic mutation, arising in developing neural cells after fertilization in the embryo's later life, in other aspects of brain function--even including traits like intelligence, behavior, learning ability, memory, and personality, or other pathologies such as schizophrenia?  Behaviors and especially behavior genetics are highly contentious areas.  Some would like these traits and abilities to be due entirely to environments, while others are fervid in their belief that you are what you inherited in your genome--what you are is inborn.  That was the view, of course, of the eugenics movement and it's still around today in the belief system of many.

We've posted on this general topic before.  The argument for inherency has always been assumed to be about germ-line genotypes, that is, inheritance from parent to offspring. But could similar effects arise by somatic mutation--or, rather, if they can be inherited how could they not in some instances be due to somatic mutation?

Testing for somatic mutation in regard to brain function, even specific traits like epilepsy, has been prohibitively difficult, because specific somatic mutations would need to be identified systematically in specific brain areas or subsets of neurons.  Detecting and characterizing somatic mutation in traits like epilepsy will be challenging and may not quickly lead to therapy, but it could at least illuminate etiology and mechanisms.

At least, the idea that I laid out (and others may have as well, though not that I know of), hasn't been tested.  But that may be changing, as we'll discuss tomorrow.

[Since first being posted, this has been edited, twice, for clarity and to correct inapt phrasing]

Oh Koko!

We'll be sharing much more, in the coming months, about why Anne and I are a wee bit obsessed with Koko the gorilla. She's one of the stars of a project we've got going--a project that will likely diminish our chances of ever meeting the lovely and extraordinary creature.

It's because we've been stalking Koko that Anne and I were perplexed, but not surprised, by this recent piece in The Atlantic:



Click here for the article.

Our eyebrows arched just reading the headline.

It leads a reader to anticipate a conversation with Koko the gorilla, but instead it is mostly an interview with Koko's main human, Penny Patterson. So, I guess the headline is describing what that interview is about--a conversation about conversing. There's no other way to make sense of it. Yet, it's still problematic because gorillas don't converse. Not even Koko.

The piece begins with an anecdote about Koko describing herself with the "queen" sign. Morin, the article's author, follows it with this quote of explanation from Patterson:
Koko understands that she’s special because of all the attention she's had from professors, and caregivers, and the media.
And this is where, to my mind, any interviewer actually fascinated with Koko's mind asks: This is amazing...how could Koko understand that she receives more human attention than most other gorillas on the planet? And how does she make the connection between this concept, this existence of hers, and that of a queen? When you taught her "queen," what was the definition? 

Unfortunately, this isn't the direction the piece goes. That nugget was a foray into her backstory about her sign language training and her home in California.  And just because the written product of Morin's interview doesn't dive into questions like those italicized up there, it doesn't mean it didn't. But if he did go there, why on earth didn't that gold make it into the piece?

More to the point, why have I never read an interview about Koko that asks penetrating questions about the stories that Koko's humans tell about her mind? Is that nuts and bolts stuff merely uninteresting fodder for readers or is it off-limits to writers who are permitted access? There's an answer at the end of this blog post.

But first, I have more, seemingly infinite, questions... How does Koko's language ability, and let's add Kanzi's too, compare to a highly-trained border collie like Chaser?



Is it categorically different, indicating an actually different kind of cognition?
You might be thinking about this video of Kanzi and saying, yes, yes it's different:



But how is it different? Kanzi is just pairing up two things, which is not really all that different from Chaser getting one toy at a time. It might appear to be more extraordinary than it is because in pairing the two objects for which Kanzi knows the English words, he behaves with them in ways they're meant to be behaved with by people.

That was a sentence worthy of a tinier brain than mine.

What I'm trying to say, poorly, with my human language "abilities," is that grabbing two things, like a soap pumper and a ball, and behaving routinely with one of them (like pumping the soap, which is what one does with a soap pumper) doesn't necessarily require as much human-like comprehension of what Sue's saying as a we might assume--that is, without thinking it through more deeply, or perhaps without trying to think like a dog or like a bonobo, or like a toddler.

Or like a gorilla--a gorilla who's arguably not a gorilla, given she's not socialized like one and given how her humans have admitted that they've intentionally raised her as a human and consider her one:



As they've raised Koko, they've narrated her mind as if it works like ours.This is evident right from the beginning of the interview portion of Morin's article. Patterson is explaining how Koko generalized the sign for "food", saying:
She would perch on this high spot where she could watch people come and go and she would sign “food” to them. It might mean “Give me the treat you’ve got,” or it might mean “I want my toothbrush,” or even just, “Engage with me.” She understood that signs had power. That particular sign got her food, so she wondered, “What else can I do with it?
She did? She wondered? And it was about how to use a sign in different settings to get what she wants? It's not just simply that it's something she could produce and did, in various circumstances? I think describing such processes as "wondering" would be giving humans too much conscious credit most of the time. But it's how we talk about minds. It's how we narrate one another's behaviors, and that of our pets, and that of whatever Koko is.

Often this is lumped into "anthropomorphism" and it's not all bad, but one could argue that it's to be avoided like the plague. If the goal is to understand how an animal thinks, then anthropomorphism risks being more of an obstacle than a helpful metaphor.

Whether the Koko project is scientifically rigorous, I have absolutely no idea. But Patterson's fantasy description of wild gorilla communication rings more of science fiction:
The free-living gorillas might talk about simple things like “Where are we going to get our next meal?” but here [at the research facility] there is so much more to talk about.
Death is one of those things. Here's Patterson's evidence that Koko understands things about death:
The caregiver showed Koko a skeleton and asked, “Is this alive or dead?” Koko signed, “Dead, draped.” “Draped” means “covered up.” 
Again, this is where my dream interviewer asks, What is the connection between "dead" and "draped"? It's even harder to understand the connection between a skeleton and draped. Can you help us understand the logic of her language? 

But we're not given that in this piece.  Morin does follow with "How would Koko know about death?" but it's not demanding a response that gets at the crucial connection between her mind and her signs.

We need to know whether what Patterson says about Koko's mind is true or not and no one seems to be able to  help us learn this. As the piece continues, my desperation for such a person escalates.

Patterson describes how Koko was making a sign that her brother made just before jumping off a rock. It took Koko's people a while to understand what she was trying to say because they hadn't seen her brother do this, but once they saw a film, it was apparent that the sign...
...means “take off” in the sense of “jump off.” Koko wanted us to take off our lab coats.
How does Koko's mind connect "jump off" a rock with "take off" your lab coats? If Morin asked this, he neither published it nor the answer. If Morin asked this question, then he is hoarding the gold all to himself.

The rest of Morin's piece is fascinating, and in parts it's heart-warming, especially if you have a soft spot for gorillas and for people who have those soft spots too. But there's still no conversation with a gorilla, or a conversation about a conversation either.

Read far enough into the article and you'll see what happened to Morin as he prepared to meet Koko:
Patterson cautioned me earlier to refrain from asking Koko questions. I was to let the gorilla take the lead. “She has that royal air about her,” the researcher explained, “and she doesn't entertain questions. Just like you wouldn’t question the queen—Koko is the same way. She’ll disengage.”
So, no conversation is going to be had with an ape, conveniently, because that totally capable ape wouldn't like it if he tried. Hm.

But there would be some lovely and touching moments through the enclosure's fence.

After recounting those, Morin reflects on what I've been discussing:
There was no way to know how much of her behavior was intentional and how much was my own or Patterson’s projection. Allegations of selective interpretation have accompanied ape-language research from the beginning. Still, it was impossible to be there interacting with her, and not feel that I was in the presence of another self-conscious being.
I don't see anything wrong with describing her as self-conscious while also doubting that her mind works like ours.  I live with a one-year old. And even before I had this baby, before I lived with an alien mind, I didn't see anything wrong with this thinking. Morin's final thoughts compare Koko's mind to an alien's, but his piece paints that alien as just another Hollywood humanoid.

When you share the link to Morin's The Atlantic piece on Facebook, the headline in the feed reads: "What gorillas can teach us about being human"

Well, what can they?

I think it's obvious from the article, and from others like it, that Koko is teaching us about our limitations. She's teaching us that we wouldn't care as much about gorillas without her fairytales; that we wouldn't care as much about these truly magnificent animals if they weren't furry humans. And that would be less depressing if we were any good at caring about actual humans.

Rare Disease Day and the promises of personalized medicine

O ur daughter Ellen wrote the post that I republish below 3 years ago, and we've reposted it in commemoration of Rare Disease Day, Febru...