New Brain Cells, Anyone?
What does exercise and experience do for the brain? Improving maternal care, the brain networks of impulsive behaviour and the rewards of sharing experiences with friends! Plus turning hair into nerve cells to help beat Alzheimer's and we find out what keeps a Nobel Laureate up all night.
In this episode
01:16 - Exercise and Interaction for the Brain?
Exercise and Interaction for the Brain?
with Professor Fred Gage, Salk Institute, California
Hannah - Can we stimulate new nerve cells to form in our brains, or are we stuck with the number of brain cells that we are born with? We discuss this and the implications with Professor Fred Gage from the Salk Institute, California.
Sound Bite Fred - Many of us believe that the brain is the seat of our awareness or consciousness of knowledge of who we are and the site of all our memories. And if it's changing, and new cells are dividing, how do we have any constancy? How do we have any sense of cells that's retained throughout life?
Hannah - People have estimated that we have about 100 billion nerve cells in our brains with 100 trillion supporting cells and connections. Traditionally, people thought that this number was for life.
But since the 1960s, there has been a growing body of evidence that new nerve cells are born in particular regions of the brain throughout your life, including in the dentate gyrus of the hippocampus - a key brain region important for learning and memory.
This natural birth of new cells in your brain is called neurogenesis and it's in a constant state of flux as Professor Fred Gage from the Salk Institute, California explains...
Fred - Neurogenesis is not a stable phenomenon. It's affected by all kinds of things like learning and exercise, and just how much you stimulate yourself. New, and exciting experiences will increase neurogenesis whereas sedation, high stress levels, and ageing can affect it in a negative way and decrease it. So, everybody is different and it's regulated by experience.
It would be hard to get vast numbers in regular individuals, so it's better controlled in experimental animals where you can control the environment a little better. It turns out that if you take a normal healthy animal and shift them into what we call an enriched environment filled with interesting objects that they can explore, the can move around and burrow, nest. And you leave them in there for 1 month and then you count the number of newly born brain cells. You'll find that there is a dramatic increase in that core of animals compared to genetically identical, gender same, same age, everything exactly the same.
In fact, when you count the total number of neurons in this area, in a mouse, it's about 300,000 neurons. If you put them in a chamber that's a rich environment for a month, you can count 350, 000 cells. So there's a 15% increase or 50,000 new neurons are added to the dentate by virtue of being an enriched environment.
Hannah - That's incredible! And this increase in neurogenesis, this birth of new brain cells when in an enriched environment, this is taking place in adult rodents?
Fred - These were in adult animals. If you take that same paradigm and you used aged animals where you get a decline in neurogenesis, a dramatic decline by an order of magnitude, the enriched environment will increase neurogenesis.
There's another feature of this and the enriched chambers had running wheels in them and you couldn't really determine whether or not the increase was because of the running wheels, the exercise, or was it because of the enriched environment. So, subsequent experiments were conducted, isolating out just the enrichment from exercise. That turns out that these two experiences have different effects. Normally, when neurogenesis occurs, it takes about a month to 2 months for the cells to fully mature into neurons. And in that process, under, let's say, standard conditions, a fair number of the cells don't make it. Say, 50% or so don't make it. Only about 50% of the cells that are born early on actually survive. But if you put them into the enriched environment, now, nearly 80% of the cells survive. So the increase in neurogenesis that is seen is a result of the survival effect rather than anything else. However, if you just put them into a cage with a running wheel where they have exercise, they voluntarily do this of course, and they actually will work to get a chance to run in the running wheel, that doesn't have much of a survival effect, but it increases the stimulation and the proliferation of the cells. So, the increase in neurogenesis that one sees from exercise appears to be - because of proliferation - whereas the increase from enrichment is for survival.
Hannah - And if this translates to humans. I mean, that's an incredible finding isn't it? If we exercise more and also stimulate ourselves more then we will have new nerve cells being born at a higher rate, and surviving as well?
Fred - That's right. There are a couple of studies that have looked at this. One is using what's called functional magnetic resonance imaging, which measures basically metabolism and blood flow. And taking humans that have had exercise over a period of 8 weeks were imaged repeatedly, every, I think about every 3 weeks as they exercising. And what was determined was that those subjects that were exercising regularly showed a long term increase in blood glucose utilisation, just in this dentate gyrus where new neurons are being formed. And then it was done both in humans and in mice. In the mice, they could also see this imaging increase in the dentate gyrus. But if you block neurogenesis from coming, you didn't get that increase in the fMRI signal. At least it's correlated both between what's happening in mouse, running or exercise let's say in humans.
Hannah - Once these new nerve cells have been born, they also have to survive and they also have to form a fairly functional circuit with the existing neurons as well.
Fred - That's right and I think that's sometimes overlooked because it's so remarkable that these cells are being born alone, but it takes a good 2 months from the time that the cell divides initially from the stem cell to give rise to what we call the neural progenitor cell. To the time that they send out their processes, receive 5,000 connections from their inputs, and then send their axon out to make contact with the target cells, it takes about 2 months to do that and this is a very prescribed pathway where they need to go through certain stages of maturation and it's crucial that the cells are allowed to go through these stages and not rushed through this, in order to make a fully functional cell.
Hannah - And as well as kind of decreasing our stress levels, exercising a bit more, and engaging more with our environment, are there other ways that we can promote neurogenesis or that drugs that we can take?
Fred - You know, this is a very, very hot area of investigation right now where biotech companies and pharmaceutical companies are in the process of developing drugs. I know that there are companies that have drugs at various stages of development for increasing neurogenesis.
Hannah - That was Professor Fred Gage from the Salk Institute, speaking about how exercise and new experiences stimulate the birth of new brain cells.
08:34 - A Researchers Pick of Neuroscience News
A Researchers Pick of Neuroscience News
It's time to take a look at the top stories from this month. I'm joined by Emily Jordan, a PhD student at the Department of Experimental Psychology, Cambridge.
Emily - So, the first paper is very exciting - some scientists at the University of Virginia actually found a way to improve maternal behaviour in mice. Dr. Danielle Stolzenberg could improve behaviour in mouse moms. So, mice usually do have a behaviour after they give birth called retrieval where they carry their pups back to the nest.
Stolzenberg and colleagues wanted to see if they could induce these behaviour in virgin mice who actually hadn't given birth. So they put a chemical in the drinking water of these mice that would increase histone acetylation and this is the process that increases gene transcription in the brain. The scientists found that the previously non-maternal mice then readily retrieved pups like a good mouse mom would, and then the researchers looked in the brain, in regions that are important for maternal behaviour, and they found that certain genes that are crucial for maternal care were actually upregulated in these mice that had never even given birth.
Hannah - So, they had promoted maternal care in these virgin mice. What are implications of these research? I mean, in what way does it help our understanding of pregnancy perhaps or post-birth care?
Emily - Usually, moms undergo vast array of hormonal changes and if you haven't gone through pregnancy and birth, you as an individual wouldn't have those hormonal changes, but you can still provide maternal care. So this experiment really looks at particular brain regions and genes that could be affected by experience, such as just being around infants that would also provide the same brain changes that would induce maternal care.
Hannah - And then moving on to the second paper...
Emily - So, the second paper looks at adolescent impulsivity and the brain networks behind impulsivity. It was conducted by a large consortium of researchers who imaged about 2,000 adolescent people, looking at their impulsive behaviour. The study was headed up by Dr. Robert Whelan and Professor Hugh Garavan at the University of Vermont.
What they found was that when they screened a large population of impulsive adolescents, a lot of the impulsive individuals performed exactly the same on a common task of impulsivity. They then wanted to look in the brain to see if there were the same brain networks that work or different brain networks in people who had ADHD (attention deficit hyperactivity disorder) and also, people who had begun initiating drug use at a young age. Because we already know that impulsivity is a common factor in both ADHD and in drug addiction and that stop signal task performance can predict both of these behaviours. It wasn't known however if the brain mechanisms behind both of these disorders were the same and these researchers actually found that there were two different networks at work.
Hannah - Is this going to be helpful as a diagnostic tool or is it really more getting to grips with an understanding of what's happening in the brain, so the brain correlate for these different behaviours?
Emily - It's really about understanding the underlying mechanisms behind both addiction and ADHD because the behavioural predictors of both of those disorders are quite similar. All of those people seem to be more impulsive than normal controls and actually, knowing that there are two different patterns of brain activity that could explain these impulsive behaviours might provide novel targets for both drug addiction and ADHD.
Hannah - And moving on to your final paper...
Emily - So, the third paper I found this month looks at social network modulation of reward-related signals. It was published in the Journal of Neuroscience and the work was carried out by a grad student called Dominic Fareri. The researchers asked participants to play a guessing game with a teammate who was either a friend, a stranger or a computer. And during the game, the scientists measured physiological excitement and also, activity in reward areas of the brain. They found that when participants got a correct answer in the guessing game, and were working with a close friend, they showed a greater BOLD response (blood-oxygen-level-dependent level, basically showing how much oxygen is going to different parts of the brain, thereby indicating how active that region is) in the ventral striatum which is an important reward-related area in the brain. And the participants also showed increase skin conductance, indicating physiological excitement. People who had worked with a closer friend reported that their experience had been more positive and rewarding.
Hannah - So, that was showing the scientific data supporting the idea that sharing experiences with close friends makes experiences more rewarding and more enjoyable.
Thanks to Emily Jordan, PhD student at the Department of Experimental Psychology, Cambridge University for her top neuroscience stories of the month.
15:44 - From Hair cells to Nerve cells
From Hair cells to Nerve cells
with Dr Rick Livesey, Cambridge University
We'll be hearing about a new technique, hot from the laboratory, which may revolutionise the way that we study the nervous system...
Cambridge scientists have created functional networks of nerve cells in a glass petri dish, just by using a small sample of your hair. They created a network of neurons of an important brain region called the cerebral cortex which is involved in memory, attention, perceptual awareness, language and consciousness.
This allows us to study an individual human's brain cells and circuits in a dish. The findings were published in Nature Neuroscience and with us to discuss the study is Group Leader Rick Livesey from Cambridge University.
Rick - So, what we did was we took skin cells from ordinary people, turned them backwards into stem cells and that's a technology that's been around for about five years now. And then what we did was we basically replayed brain development. So, turn those stem cells into the part of the brain's cerebral cortex which is the bit that makes up about three quarters of the human brain. It's the bit of the brain that makes humans human. And that essentially allowed us to watch human cortical development happen over three or four months in the lab, which is as long as it takes in a real human.
Hannah - And these skin cells that you got from your volunteers, how much skin did you get and where did you get it from?
Rick - So, these are actually skin cells of a fibroblast, so you get them from little skin biopsies, a couple of millimetres across. So that's the current way doing it. The way that's becoming quite popular now is to actually take them from the bottom of a hair. So, a lot of labs now are working on ways to just pull a hair from someone's head and that would give you enough cells that then you can turn back into stem cells.
Hannah - Can you talk a little bit about how exactly you transform this skin cells around the hair follicle into a stem cell and transform it into a cerebral cortex cell?
Rick - Sure. So, in normal development when a mouse or a human, or anything, is being born, you go through a stage where you start off from one cell as everybody does, and then you go through a phase where in your little ball of cells, and in that, there are what are called embryonic stem cells and those are cells that can make any cell in your body.
This technology that was worked out about five years ago by a guy called Yamanaka in Japan. He showed that you could take an adult cell like a skin cell or a muscle cell and by introducing a couple of genes, you could eventually back those up so that they became very much like those embryonic stem cells. So, you're like rewinding development back, so that they're like a very early primordial stem cell.
So, where we step in this, we then said, "Well, can we find ways to turn those stem cells into what is another type of stem cell?" But they're called a neural stem cell, but they're the stem cell that specifically make the cerebral cortex, and that was the magic thing that takes about two weeks. And then, once you get those neural stem cells, they then, over a long period, turn out these neurons over time and then the neurons spontaneously wire up to another and start talking to another. They were in the dish, so they make neural networks. So after about three months, you got these networks of nerve cells that are, what we call ('firing away') that's being electrically active within the dish.
Hannah - And you can measure the electrical activity, record the electrical activity of this neural circuit, and make sure that it is actually functional?
Rick - Yes, exactly which is the ultimate proof that they really are what you want them to be.
Hannah - So, there's some mention of the fact that this might be useful for Alzheimer's research and looking at developing new drugs for Alzheimer's. Can you touch on that a little bit and describe exactly why developmental cerebral cortical cells in a dish might be useful for trying to treat Alzheimer's?
Rick - One of the big problems in Alzheimer's disease research is that other animals don't get the disease. So, to make a mouse get Alzheimer's, you've potentially got to put human forms of three or four different genes in and then they get something that looks like Alzheimer's, but it's not quite the real thing.
So, there's a lot of interest in trying to recreate Alzheimer's disease in the lab and to do that, what you need is you need to make the part, the nerve cells, that normally get the disease and then you need some way of giving them the disease. So, we've kind of solved the first part which is Alzheimer's disease is the disease of the cerebral cortex. For the second part, so how would we then get the disease process?
We went to people who have got a very high risk of developing the condition and in that situation, we went to people with Down syndrome. So a lot of people have heard about Down syndrome. It's the commonest cause of learning disability still worldwide, but what a lot of people aren't aware of is that people with Down syndrome have a very high risk of developing dementia or Alzheimer's.
So, we followed up the people you mentioned with another paper this week where we then took skin cells from people with Down syndrome to turn them into cortical neurons. And what we found that on a very accelerate time scale again of the order of months, they then developed the Alzheimer's disease, so the features that you'd expect to see in this living being, but now, in the dish.
Hannah - And what kind of features are you seeing in this dish?
Rick - So classically, what you get if you'd talk to a neurologist about what you see in an Alzheimer brain, there's that two kind of classic things you see. They're what are called plaques and tangles. Plaques are sort of lumps of protein that form outside the nerve cells and those are very early features, and they're made up of a specific little bit of protein. And then later on, you start getting a protein in the neurons which is then called Tau, and it gets abnormally modified, and it moves and accumulates in the parts of a neuron. Essentially, that's what we see in the dish. We start off with these plaques and then we start seeing this protein was growing and accumulating, and actually then we see the final end stages, the neurons start dying.
Hannah - And when you compare this to cells that you've taken from a healthy volunteer, you wouldn't be seeing these?
Rick - You see none of these from healthy volunteers' cells. And the reason it's important for us is it opens up to things that lets you study these progression real-time, on a regional timescale, so this is a disease which takes decades in a human as it were. So we can test and now, we can test ideas about how do you start, how do you get the plaques, and then if you don't let the plaques form, well you get the latest stage of the disease, work and intervene in theory.
The other obvious big use is used for testing drugs which is the other thing we're doing. So, with Alzheimer's disease, there were no drugs which modified the disease process at all. So it's a condition which people have this idea that Alzheimer's disease is sort of like an extreme form of normal ageing, that people have some memory loss if they get older, and Alzheimer's is just like a nastier version. And that's a misconception. It's a disease which typically, if you get from diagnosis to death is an average of about seven years, and that's, if you think about some of the nastier cancers that typically you think about if someone said you got a disease which from diagnosis would kill you within seven years, that's clearly not a normal process.
So, it's a disease that kills. In the UK alone, there is over 800,000 people with the condition, six million in Europe alone, and the the numbers are rising. So, it's really important that obviously, we would say that there's more and more research. But also, as a public health problem, it's increasing every year.
Hannah - And also, I'm presuming that your new technology for developing the cerebral cortex cells in vitro may have applications and implications for schizophrenia research and autism research as well, so with the disorders where the cerebral cortex is also implicated.
Rick - Exactly, so that's the idea. Again, what those condition share is that - you're right, the disease of cerebral cortex, but there are also diseases for which we don't really have animal models that we can study the disease. So, there's a lot of interest and again, starting from inherited forms of the disease where you can you create a model in the dish and then start moving on to the more common sort of sporadic form.
Hannah - That's Rick Livesey from Cambridge University, describing how he's been converting skin from the scalp to functional cerebral cortex networks, and creating a new way to look at Alzheimer's.
23:26 - Where do you get stem cells from?
Where do you get stem cells from?
Hannah - Sticking with the theme of the birth of brain cells, I visited the Gurdon Institute in Cambridge to quiz Professor Andrea Brand with questions from listeners about the use of stem cells (the cells which give rise to the new nerve cells in the brain). And the first question was from Emily Caesar via Facebook asking, "Where do you get stem cells from?"
So, there is the new technology of creating stem cells and neural stem cells are created throughout life in the hippocampus brain region of rats and humans. But how else can we get stem cells?
Andrea - There are stem cells in different animals and in different places in different animals. So, for example in my lab, we work on stem cells in the fruit fly (Drosophila melanogaster) and in particular, we work on stem cells that are found in the brain. And in this case of course, we don't have to invade a patient or use an embryo. We can just take fruit fly embryos or fruit fly adults, and isolate stem cells from them and study what it is that makes the stem cells special.
24:24 - What directs a stem cell's fate?
What directs a stem cell's fate?
We put this question to Andrea Brand, from the Gurdon Institute, in Cambridge...
Andrea - So, this is a question that many, many people are interested in and many different labs are trying to answer. It depends very much on what type of cell you want to get the stem cell to generate. Each cell in the body expresses a particular subset of genes that tell it how to behave, what to look like, and if it’s a neuron, what type of neuron to be, what signals to send out, what signals to receive. And so, one area of investigation that’s very exciting at the moment is trying to discover all the different genes that are on or off in a particular type of cell. And if you have this knowledge, then you can try to turn on the appropriate genes to make a stem cell to make a particular type of neuron or a muscle cell, or really any type of cell that you want.
25:21 - Are there stem cell therapies for the brain?
Are there stem cell therapies for the brain?
We put this question to Andrea Brand, from the Gurdon Institute in Cambridge...
Andrea - Well, this is really something that we would all like to see happen in the not too distant future, but it’s still early days and there are some studies going on at the moment on using stem cells, transplanting stem cells into the brains of stroke patients.
But as I say, it’s still very, very early days, so I wouldn’t say that there's been successful treatments yet. However, there are some very encouraging work going on in repairing defects in the eye, and I think that will probably be the first place where stem cells really come into their own, perhaps in restoring photoreceptors or restoring sight. So, I think that’s probably where the first advances will be seen.
In terms of transplantation into the brain, the other possibility which may be a little bit further in the future, there are stem cells in the adult brain of healthy individuals. And these stem cells where these cells that give rise to the neurons in the brain in the first place. And so, if we could somehow prompt those cells to generate new neurons, then you could imagine this might be a way of repairing the nervous system after damage or neurodegenerative disease. And that’s why it’s important to understand what makes a stem cell a stem cell, and what one has to do to get that stem cell to produce particular cell types.
26:56 - Could stem cells cause cancer?
Could stem cells cause cancer?
We put this question to Andrea Brand, from the Cambridge Gurdon Institute...
Andrea - Well, a few years ago, the cancer stem cell hypothesis was proposed which suggested that many tumours might actually arise from stem cells and I think that there's still some debate about that.
But there is more evidence that either stem cells, or the cells they give rise to, can, under particular conditions give rise to cancer.
And again, coming back to the fruit fly, there was some very nice work done by Cayetano Gonzalez’s lab in Barcelona where he showed that if you mutate certain genes in stem cells, they do start to overgrow and can form tumours. In fact, if you take those tumours, you can transplant them from one animal to the next and they continue to grow and metastasise. And so, this is quite a nice model for looking at cancer that are generated from stem cells, and what are the signals that prevent stem cells and their becoming tumorigenic. And this is something that we, amongst others are working on to try to understand what goes wrong in the stem cell or its daughters that give rise to tumours.
Hannah - So, we may be able to use stem cells to actually find a new way of treating cancer?
Andrea - Well, that’s a hope. Some of the basic research that’s going on in various different model systems like in fruit flies or in mouse for example, once we get at the basic biology seem to be well conserved.
28:48 - What Keeps a Nobel Laureate Up All Night?
What Keeps a Nobel Laureate Up All Night?
with Professor Sir John Gurdon, Cambridge University
We close with the enigma of integration, with Professor Sir John Gurdon from Cambridge University.
John - It is possible to take a tiny piece of skin from an animal or human and to grow that into functional cells such as heart. This has been done in some elegant work by Bern and others. A series of steps are involved, but the end result is, that you can see thousands of cells beating in unison in the laboratory, all under culture conditions (that means usually cultured in a flask or on a substrate). These cells then behave just like you might hope for a heart so that they are beating in unison and as I say, several thousand of them. However, when these cells are transplanted to a recipient, they do not integrate properly into the recipient's own heart. They go on behaving independently and are therefore not readily useful to a patient.
The nervous system work is comparable. It has been possible to inject some brain cells into a Parkinson's patient and the patient shows some benefit of these implanted cells for a few months. However, in a particular case, such a patient eventually died some 17 years later and they found that the implanted cells was still alive or their progeny were, were over this long period of time, but had actually made no useful contribution to relief of the Parkinson's condition.
Having got cells which seem to work very effectively in culture in the laboratory, there is still some problem in getting such cells to integrate functionally into a recipient. It seems to me that this is one of the future challenges of this field.
It's really rather remarkable to me that one can go from a tiny piece of skin to functional heart or functional brain cells in the laboratory, and yet, that final step of getting them to actually integrate and continue their useful function in the patient does still have to be solved.
Hannah - That was Professor John Gurdon from Cambridge University presenting his fascinating facts on the progression with birth of brain cells or neural stem cell biology and what we have yet to learn in order to successfully integrate new cells into the brain and body.