Brain-altering early-life inflammation
Compared with “summer babies”, individuals born in the winter months have a higher risk of a range of different diseases, including neurological and neuropsychiatric conditions. Why though, we don’t know. A tempting theory - but one that’s very hard to test - is that the higher rates of infection that prevail in winter might be to blame. Now, as she explains to Chris Smith, Oregon University’s Adrianne Huxtable has come up with a way to explore how inflammation in early life affects the way at least one part of the nervous system develops and operates…
Adrianne - So what we're showing in this paper is that one bout of sickness early on in life can lead to permanent changes in how the neural circuitry that controls breathing functions into adulthood. We know that early life inflammation is really common, but what we don't know is what lasting effect that might have on this important neural circuitry that controls breathing.
Chris - What's the neural circuitry that you're referring to?
Adrianne - The neural circuitry I'm referring to is housed within the medulla, and the drive for breathing begins here and is then transmitted to relevant respiratory-related motor neuron pools, which innervate the muscles that control your breathing. And we're specifically looking at how these motor neurons that are housed in the spinal cord are influenced by early-life inflammation.
Chris - So if you look at an individual that's been subject to some early life inflammation, or some kind of infection, how does their respiratory effort, or their pattern of respiration, change in line with that past infection or inflammation?
Adrianne - What we're seeing is that it's not necessarily the baseline breathing that's changed. What's changed is the ability of this system to learn, and then respond to subsequent challenges to breathing. So here we're seeing that the system fails to learn properly, so it does not exhibit any plasticity, which could undermine the system in response to disease, or injury, or other challenges to respiratory control.
Chris - How did you do the experiments?
Adrianne - We did the experiments in a rodent model, since most people don't like their central nervous system poked and prodded. Four days after the rats are born we give them an inflammatory challenge; so it's mimicking aspects of a bacterial type infection. Once they're adults, we can then stimulate the respiratory system with changes in oxygen, changes in carbon dioxide, and see how the respiratory system responds. The main stimuli that we're using is repetitive episodes of low oxygen to induce one form of learning within the system. And what we find, is that that one inflammatory stimulus during the neonatal period undermined the ability of the system to learn in adulthood.
Chris - So what should happen in response to that bout of low oxygen exposure in a healthy non-inflamed individual first?
Adrianne - In a healthy, non-inflamed individual, you should see this lasting increase in respiratory motor output. And we don't see that increase if we treated the animals at postnatal day four with an inflammatory challenge.
Chris - Is there anything you can do to reverse this, to try and put them back to the situation that they should be in?
Adrianne - Interestingly, we can reverse it by applying sort of a general anti-inflammatory - sort of analogous to an Advil or a Tylenol. We use ketoprofen in the rodents, and we can reverse one form of learning, but not the other. So we think that there are different pathways to this learning and plasticity, and that they seem to be impaired differently in response to early-life inflammation.
Chris - Where do you think then, based on these observations, that the seat of the problem is? What is being hit during this critical postnatal period, during that bout of inflammation, which leads to this respiratory learning deficit down the road?
Adrianne - I would love to know the answer to that right now. We don't know yet. But we do think that it is related to how different cell types in the central nervous system communicate with each other.
Chris - Presumably it's not the nerve cells themselves? Because the fact that you've got messages being conveyed out of the central nervous system and to the muscles that drive respiration - these animals are aren't stopping breathing, so they must have intact nerve pathways, so that can't be it. So is it something upstream of that?
Adrianne - Yeah, exactly. We don't think it's the neurons themselves that are impaired, and we think it's likely to involve other cell types in the CNS known as glia. We are specifically targeting whether there are changes in microglia, the resident immune cells of the central nervous system, and astrocytes. Astrocytes were largely thought to be support cells within the CNS, but we now know that they can play pretty active roles in how the cells communicate with each other within the CNS.
Chris - And not just for respiratory issues as well, because it strikes me that if one looks at sort of public health data, individuals who are born in the winter characteristically are at risk for a whole raft of conditions compared with people who are not born in the winter. I'm thinking things like schizophrenia. Could it be, then, that actually the phenomenon you've discovered here could be broader than just changes to the way the respiratory networks work; and in fact, you could be finding what underpins why some people are at higher risk when they're born in winter?
Adrianne - Yes, exactly. And things like Sudden Infant Death Syndrome also go up during the winter months. So there may be more here than we know just yet, but it really suggests that there are these really important windows for development of respiratory control; but also more broadly, as you mentioned, neuropsychiatric disorders are also associated with early-life inflammation. There's been a lot of excellent work done recently looking at these different regions of the brain, and trying to understand how different regions are susceptible to early life inflammation. So I think this is a pretty exciting new area of research that might lead us to better understand both some of this acute mortality that you see in infants, as well as some development of things like obstructive sleep apnoea in adults and other disorders as well.