All animals, including humans, live in close association with a huge collection of microbes (the “microbiotaâ€) that inhabits every exposed surface (e.g., our skin and digestive tract). Most of these microbes are bacteria and reside in the gut. Recent studies have shown that the gut microbiota influences the brain and behavior of adults, and many of these effects are assumed to be due to altered neural development. However, few studies have actually studied effects of microbes on the developing brain. Because the womb is sterile, mammals first encounter microbes at the moment of birth. The investigators on this project recently reported differences in the brain within the first hours after birth between mice that encountered a normal microbiota versus no microbiota at all. This project will determine whether the effects are due purely to postnatal exposure to microbes, or whether exposure of the mother during pregnancy also plays a role. Specific brain regions affected by the first exposure to microbes will be identified, and the investigators will examine the route by which microbes signal to the brain, as well as how various changes to the microbiota affect brain development. Humans routinely alter the microbiota of infants, either by hygiene practices or antibiotic treatment of the mother. Thus, in addition to addressing basic scientific questions about the relationship between our microbes and our developing brains, this work also has important implications for obstetric practices.
Striking differences were recently found in developmental neuronal cell death, colonization of the brain by microglia, and the expression of pro-inflammatory cytokines between mice born into a conventional environment versus those born into an environment devoid of microbes (germ-free, GF). Remarkably, these differences were already present 10-14 hours after birth, but were not seen prior to parturition. Effects were also brain region-specific, with the paraventricular and arcuate nucleus of the hypothalamus showing large effects. By cross-fostering mice that are gestated GF to conventionally colonized mothers within an hour of birth, this project will establish whether the effects are due purely to postnatal microbe exposure, or whether maternal factors also play a role. The impact of selective perturbations to the microbiota on the brain and gut microbiota will be examined by treating dams with non-absorbable antibiotics and, in a complementary approach, by examining the brains of newborn mice colonized with a defined, but markedly reduced microbiota. This project will also use chemical vagotomies of newborns to test the hypothesis that microbes signal the brain at birth via the vagus nerve. Throughout evolutionary history all mammals have been born into an environment replete with micro-organisms. Thus, our brains may be “microbiota-dependent,†in a similar way that developing sensory systems are “experience-dependent.†This is a fundamental concept that could change textbooks on neural development.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
