Environmental exposures and autism: roles for microbiota and microglia

Environmental factors such as air pollution and maternal stress are increasingly recognized as risk factors for autism in the human epidemiological literature. We set out to better understand the underlying biology of how such factors alter social behavior, using a mouse model.
Environmental exposures and autism: roles for microbiota and microglia
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Environmental exposures and autism

             Autism spectrum disorder (ASD) is a neurodevelopmental disorder primarily characterized by difficulties in social interaction, communication, and the presence of restricted or repetitive behaviors. A growing body of epidemiological evidence points towards environmental exposures as risk factors for ASD. In particular, exposure to air pollution during gestation increases ASD risk, as does maternal stress (MS) during pregnancy. These exposures are also highly inequitable, with low SES, minority communities bearing the greatest burden of both air pollution and stress. To interrogate the mechanisms by which these exposures converge biologically to alter the social brain and behavior we developed a model of combined prenatal exposure to diesel exhaust particles (DEP) and MS in mice and examined the impact on offspring development.

 

A role for the gut microbiome?

            At its core, ASD is defined by changes in social behavior. However, ASD is quite a multifactorial disorder that is increasingly recognized to be a “whole-body” rather than simply a “brain” disorder. In fact, more than 50% of individuals with ASD have co-morbid gastrointestinal issues and several studies in humans have observed changes in the composition of the gut microbiome in ASD patients. The gut microbiome refers to the collection of commensal microbes that reside within the gut lumen. These microbes serve many critical functions ranging from the digestion of insoluble fiber and generation of beneficial metabolites, to the education of the immune system during development, and the defense of the host against invading pathogenic bacteria. We hypothesized that prenatal DEP/MS exposure would shift the composition of the gut microbiome. 

 

The findings: Sex-specific effects of prenatal DEP/MS exposure on social behavior and microglia

            In our new paper published in Molecular Psychiatry, we found that DEP/MS exposure decreased social behavior in male but not female offspring. In line with this male-specific behavioral finding, we also observed male-specific shifts in the composition of the gut microbiome. Microglia, the resident immune cells of the brain, are sensitive to peripheral exposures such as pollutants and microbes and play a critical role in neural circuit organization. We found that DEP/MS exposure significantly altered the morphology and gene expression of microglia in the nucleus accumbens (NAc; a key social reward region). Once again, this effect was only present in male offspring. These findings were in line with previous work from our lab showing that DEP/MS alters microglial function in the prefrontal cortex in males but not females.

Excitingly, when we restored the gut microbiome to a control phenotype by cross-fostering DEP/MS male pups to a control mother on the day of birth, we found that this manipulation prevented both the changes in social behavior and in microglia. This work supports the idea that the gut microbiome might be an important target for therapeutic intervention in ASD. Moreover, it suggests that microglia are key to translating such changes into behavioral outcomes.

           

What’s dopamine got to do with it?

            The dopamine system is well-known to regulate social reward/motivation. Therefore, we were curious as to whether DEP/MS exposure might impact the dopamine system, consequently reducing social interaction. Indeed, we found reductions in both dopamine D1 and D2 receptor expression in the NAc, as well as lower dopaminergic fiber density, in male offspring. Moreover, chemogenetic activation of the dopamine system was sufficient to rescue social deficits following DEP/MS in males.

 

Recent work investigating the role of the gut microbiome in mouse models of ASD showed that supplementation with the bacterial species L. reuteri rescued social behavior deficits by modulating the activity of dopaminergic neurons. This raised the possibility that perhaps shifting the gut microbiome was rescuing social behavior via the dopamine system in our model. To our surprise, we observed no effect of our cross-fostering manipulation on dopamine endpoints in our study. But perhaps this is not so surprising, given several important differences between the previous work and ours. For example, DEP/MS exposure shifts the composition of the gut microbiome in different ways as compared to the previously studied exposures (maternal high fat diet and others) and we did not find changes in L. reuteri. Similarly, our bacterial modulation was not specific to L. reuteri as in the other studies. Our finding that microglia are strongly impacted by our cross-fostering manipulation suggested that our microbial modulation of social behavior may be due to differential microglial interactions with other neuronal populations instead.

 

A technical hurdle overcome, suggesting a new direction

            In our experiments we observed robust changes in the composition of the gut microbiome in male offspring following DEP/MS exposure. However, our findings also presented us with a puzzle – there was no change in the composition of the maternal gut microbiome, even though it was she that received the exposures directly. This prompted us to wonder: what signal is conveyed from mother to offspring to influence the development of the infant microbiome? Breast milk is a vehicle for the delivery of many critical molecular drivers of infant gut development. However, to ask whether DEP/MS exposure might be altering the components of maternal milk, we needed to learn how to milk mice. Fortunately, Dr. Rendina had expertise in milking from her previous work, and we were able to successfully overcome this challenge, launching us into this new experimental territory.

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