Microbes and sociability
According to the saying, “You are what you eat”. And to endorse that, it’s looking increasingly likely that your microbiome might even affect how you behave in social situations. Mice uncolonised by bacteria, reared in so-called “germ-free” environments, and born to mothers who were themselves microbe-free tend to socialise a lot less than mice born normally. And in the brains of these microbially-deficient mice, neurones in the amygdala, which coordinates fear and other emotional responses, express very different patterns of gene expression, suggesting that the microbes in the intestines can influence how the brain handles information. Chris Smith hears how from University College Cork's Roman Stilling...
Roman - We were looking at the reasons that germ-free mice, so mice that are devoid of any microbiome, have social behaviour alterations - they are socially impaired. What we find in a classical paradigm that is called the "three chamber social interaction test" where you have one chamber with another mouse that the test mouse can interact with, or on the other side of the arena there's another chamber that has just an object like a ball or an egg cup or something like that. And we know that we usually see, when we just test normal mice that they interact a lot with their partner and less with the unsocial object. But with the germ free animals they interact less with their social partners.
Chris - So what was the additional set of questions you were able to ask of these mice when you did this?
Roman - In a previous study, we compared the gene expression in a specific brain region that we know is involved in social behavior to control mice. And we found that in the amygdala, this specific brain region, there were several genes differentially regulated that are associated with neuronal activity. Based on this finding, we wanted to see what is actually happening in a dynamic situation, so when they actually encounter a social interaction, what is then happening to this amygdala?
Chris - So how did you measure what the genes are doing in that part of the brain at the time that the animals are having their social relationship compared to when they're not?
Roman - What we need to take into account is that the gene expression is always a bit delayed. So we do this task just the normal way, put the right into an areana and let them explore. And then we wait one hour afterwards, take out the brain, and then we look specifically for the brain region we were interested in. We extract the new made RNA, then we send this for RNA sequencing, which is a method to look at the whole transcript home, so all RNAs that are in the cells that we analyzed at once with the next generation sequencing technology.
Chris - So what do you find then?
Roman - In a normal mouse when iT experiences an novel situation specific genes are switched on and and off. What we find now in the germ-free elements is that we also see these pathways and we also find something completely novel and unexpected. Genes that are in themselves regulating gene expression by modifying the chemicals that are produced during gene expression - the RNAs. And these RNAs, when they are they are produced by the cell to make new proteins then they need to be cut in to the right message, right, and this is why they're called messenger RNAs. And this RNA processing pathway that was heavily upregulated in our study.
Chris - Interesting. So the way that the RNA is being handled in the cell is changing. How is that being affected?
Roman - We don't know exactly how this is happening. But we see that the genes that are coding for factors that do the cutting, these genes themselves are turned on and off to a much higher degree than in control animals.
Chris - And are these changes in gene expression profile and splicing profiles reflected in a structural or connectivity difference in the amygdala so if you look at a sort of microscopic level can you see any differences?
Roman - We have done this in another study and actually did find more sinuses and more complex dendritictry in the germ-free animals, which somehow fits our narrative.
Chris - So how do you think that the message is transmitted between the microbiome, which is broadly in the intestine, and the developing nervous system?
Roman - To be honest we don't really know. But I think what we need to focus on in the future is the immune system. We know that the immune cells of the brain, the microglia, they are also impaired in their function in germ-free animals. That I think is certainly a way that we need to look closer at to study the interaction of the bacteria in the gut with the function of the brain.