Groundbreaking recent studies indicate that the community of microorganisms living in the digestive tract (the gut microbiota) plays a key role in psychiatric illnesses characterized by disordered emotional and social responses. Accelerated progress has also been made in understanding neural control of anxiety and social behavior, especially with regard to the roles of the `social neuropeptides,' vasopressin and oxytocin. To date nobody has linked these two exciting fields. Two established laboratories with complementary areas of expertise have joined forces to take on this task: one focused on sex differences in the brain and the neural basis of social behavior, the other on molecular pathways underlying the relationship between the microbiome and gut health. Together, these laboratories will develop mouse models to test the overall hypothesis that the gut microbiota acts early in life to permanently program vasopressin and oxytocin systems as well as anxiety- related and social behaviors controlled by these systems. In the first experiment, brain and behavior will be compared during development and in adulthood of germ-free mice after they have been colonized at birth by gut microbiota derived from either of two strains of mice that differ significantly in social and anxiety-related behaviors as well as composition of the microbiome. The second experiment takes advantage of a recent discovery in one of the two participating laboratories that commonly used food additives, i.e., emulsifiers, have surprisingly strong effects on physiology by acting on microbiota composition and its interaction with the host. Preliminary data suggest that these effects extend to the brain and behavior, which will be tested in the current project. Together, this project will address a crucial gap in our understanding of the gut-brain axis and its role in the development of anxiety-related and social behaviors, using physiologically relevant approaches. The findings will make possible subsequent identification of the specific microbiota affecting anxiety-related and social behaviors, and the signaling pathways involved. In addition, the payoff for studying effects of the microbiota on vasopressin and oxytocin expression will go beyond understanding microbiota effects on behavior, to include effects of the microbiota on autonomic functions, metabolic syndrome, and pain, all of which are affected by microbiota and modulated by these peptides.
Psychiatric disorders characterized with disordered emotional and social behavior have been linked with abnormalities in gut microbiota, but causality is not clear. Development of neural systems that control social behavior may depend on the specific composition of gut microbiota during development. This project will develop novel mouse models to test whether the gut microbiota influences the development neuropeptide systems implicated in social and anxiety- related behaviors.
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|Fields, Christopher T; Chassaing, Benoit; Paul, Matthew J et al. (2018) Vasopressin deletion is associated with sex-specific shifts in the gut microbiome. Gut Microbes 9:13-25|
|Castillo-Ruiz, Alexandra; Mosley, Morgan; George, Arlene J et al. (2018) The microbiota influences cell death and microglial colonization in the perinatal mouse brain. Brain Behav Immun 67:218-229|
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|Fields, Christopher T; Chassaing, Benoit; Castillo-Ruiz, Alexandra et al. (2018) Effects of gut-derived endotoxin on anxiety-like and repetitive behaviors in male and female mice. Biol Sex Differ 9:7|