Stephen Noctor, Neuro-immune Interactions and Control Cell Production in the Prenatal Brain

Stephen Noctor, Neuro-immune Interactions and Control Cell Production in the Prenatal Brain


Hi, I’m Steve Noctor. I’m in the Department of Psychiatry and Behavioral Sciences here at the UC Davis Med School, and today I’m goingto talk about neuroimmune interactions that control cell production in the prenatal brain. Now, I’m going to talk about two aspects of work that’s going on in my lab. One is the
role of microglial cells during normal development of the brain, and secondly, the implications that this has for the etiology of neurodevelopmental disorders. Now, in my laboratory we study development of the cerebral cortex, and on the right hand side here you can see a cross-section of an adult human brain and this is the cerebral cortex. It’s this outer bumpy surface of the brain that you’re probably familiar with. What I study is not the adult functioning of the
brain, but how it arrives at that stage during fetal development. Now, one of the major questions in my field is, how is cortical expansion achieved? How do you go from a teeny little structure at three weeks of gestation to this very large complex structure? There’s a lot of focus in the field on mechanisms that promote growth. How do you make the brain bigger? But, there also has to be a flip side to that question. What are the mechanisms that restrain growth? You want the brain to be big enough, but not too big, and what we’ve hit upon in my laboratory is that microglial cells may play a role in restraining growth of the brain so that it
doesn’t get too large. Now, what you’re looking at here is a video from Albert’s Cell Biology, and what it shows is an immune cell, a neutrophil, in a dish chasing after a bacteria. So, that
little black dot right there is a bacterial cell and it’s being chased by the neutrophil, and the immune cells are highly responsive and they don’t stop, and what you’ll see is
that it corners the bacteria, it phagocytizes it, eating it, and then moves on to its next
target. Now, these immune cells are in the adult brain. They make up about 5% of the cells in the adult brain. They’re also found in the fetal brain, but until very recently very little
was known about microglial function in the prenatal brain. So, to address these questions, what are the functions of microglial cells in the in the fetal brain? We looked at the
distribution first of microglial cells in the monkey brain. So, monkeys, the macaque monkey, has a gestation of a hundred sixty-five days and the neurons for the cerebral cortex are generated in the second trimester, roughly from gestation day 50 until gestation day
100, and what you’re looking at here are cross-sections of the fetal macaque brain at day 50, when neurogenesis is starting, and the images are labeled in blue and green. Blue labels all of the cells in the fetal brain and green labels the immune cells in the microglia, and you can see that at 50 there are very few of these cells. You can see these little green dots here. Those are the fetal immune cells , the microglia. Two weeks later, at gestation day 65, again you can see that there’s a very sparse population of these green cells. I’m highlighting a few of them here with the arrow. And finally, at gestation day 80, what you see is that the microglial cells begin to colonize the brain very densely. They don’t do it all
over the brain, but they do it in a very specific location, and in fact what they do is they
colonize proliferative zones where cells are being generated for the fetal brain, and then at day 100, you can see again that there are many of the cells, and they’re highlighted
with the red circles there. Now, these are proliferating zones where neural stem cells or neural precursor cells reside. We looked in the fetal human brain and we saw the same pattern. So early in development there’s very few of those green microglial cells. Here is gestation week 17, and by gestation week 20, they begin colonizing the proliferative zones. So we wanted to know what was going on there, why are these microglial cells colonizing the proliferative zones? To do that, we obtain sections of the fetal macaque brain, and we triple stain them and quadruple stain them for various markers, including microglia. So, the microglial cells are highlighted here in green, they’re labeled in green, and then there are two types of neural stem cells, indicated in blue and red. Those are primary and secondary neural precursor cells, and what we saw is that the microglia are colonizing the same regions where you have the neural stem cells that are making the neurons for the developing brain. We wanted to look at that in greater detail, and what we found in the stained section is that the microglial cells, indicated here
in green, so this is an individual microglial cell, what we saw was that they would reach
out and touch the neural stem cell. So, here’s a neural stem cell labeled with a red dye,
and the microglial cell is reaching out and touching it, and then we saw other images where the microglial cells appear to be wrapping their arms around them, and here’s a go-getter who’s going after two of these neural stem cells. You can see that the microglia is targeting two of them, and then they phagocytize them. They actually eat these neural precursor cells. This is another example here where the microglial cell has entirely enveloped the neural stem cell. After enveloping them, then they digest them. So, we found microglial cells, again indicated here in green, that were digesting those former neural stem cells. You can see that little
red dot in the microglial cell, and those dots would become much smaller, and in independent experiments we showed that this only takes about two hours. So, they will phagocytize the neural stem cell, eat it and digest it in about two hours time. So, the thing to remember is the microglia
are immune cells. This isn’t the fetal brain, and again, this is in the normally developing brain. This is not a diseased brain. This is what’s happening in normal development, and since they are immune cells, one of the questions we asked ourselves was, are these microglia competent to respond to immune challenges? One of the ways to look at that is to use
this model that investigates maternal immune activation. So, when a woman is pregnant, she can get an infection, and this can be a bacterial or viral infection, and that activates her
immune system. So, her immune system generates a response which involves the production of many cytokines, including pro-inflammatory cytokines like interleukin 6 or IL-6 and IL-beta, and those are indicated with these little green dots here. The pro-inflammatory cytokines will course throughout the mother’s body, but they also cross the placenta and get into
the fetal compartments, and you can see they actually end up in the fetal brain. We wanted to find out what impact that might have, and in rodent models of maternal immune activation, we gave the pregnant rats an infection and then looked at the fetal brain, and what we saw is that there was a significant decrease in the number of neural stem cells in the
developing fetal brain, so there is about a 20% decrease, and the implications for this we believe are fairly strong for neurodevelopmental disorders. So, for example, schizophrenia is a neurodevelopmental disorder and there’s growing evidence that influenza exposure during the first trimester of pregnancy increases greatly the mother’s chance of having a
child who has schizophrenia. So, to highlight our key findings, what we find is that in the normally developing brain, microglial cells regulate the number of precursor cells through phagocytosis, and I put an asterisk there because this is probably just the tip of the iceberg. This
is a new discovery, and undoubtedly the microglia are doing many other things in addition, and furthermore, the implication is that maternal immune response can impact fetal brain development by activating those fetal immune cells and this could contribute to the development of psychiatric diseases. Now, this project has been funded by departmental awards within the Department of Psychiatry. I have received the Tupin award, faculty development awards, and this project has been funded by the NIH. I’ve also received a lot of very helpful departmental mentoring from David Amaral and Cam Carter, so I would like to thank them very much for that assistance.

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