The influence of complex gut microbiota on central nervous system development and adult cognition and behavior

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Project Summary Neuropsychiatric conditions such as mood and anxiety disorders are increasingly diagnosed in children, and studies comparing the incidence in identical and fraternal twins suggest that environmental factors contribute as much as genetics to disease risk. Several recent studies using animal models have revealed that the bacterial populations present in the gastrointestinal tract (i.e., the gut microbiota, GM) have a strong influence on host behavior including anxiety- and stress-related behavior, and depressive behavior. Moreover, studies comparing germ-free mice and those with a normal GM have revealed associations between these different behavioral profiles and the production of several neurotransmitters and other neuroactive molecules in the central nervous system (CNS). Notably, the most active periods of neurodevelopment, wherein synapse formation and production of various neuroactive molecules are upregulated in the neonatal brain, occur at the same time as the initial seeding and maturation of the GM. Despite this, very little is known regarding the influence of the early life GM and subsequent susceptibility to anxiety-related behavior or anxiety disorders. Similarly, while studies of germ-free mice have clearly shown the influence of the GM on host neurodevelopment and behavior, very little is known regarding the differences in the GM of affected and unaffected individuals with different complex, naturally occurring GM profiles. Thus, our long-term objectives are to identify and characterize the primary pathways and mechanisms through which the early life GM influences host susceptibility to anxiety-related behavior and gene expression, in the context of different naturally occurring GM. To do so, our Specific Aims are 1) to characterize the gene expression patterns throughout development in the CNS of mice colonized with one of two GM profiles associated with either susceptibility or resistance to anxiety-related behavior, using both global gene expression and targeted (gene specific) approaches, and 2) to characterize the microbial composition and gene expression throughout the first several weeks of life, using similar global and targeted approaches. The birth dam serves as the primary source of bacteria colonizing the newborn and her GM is also relevant to the developing fetus in utero as they share a bloodstream. Thus, to determine the relative contribution of pre- and post-natal GM exposures, as well as windows of vulnerability to post-natal therapeutic manipulation, litters will be cross-fostered between dams harboring the susceptible or protective GM profiles within 24 hours of birth or at 7 days of age. While the immediate goal of these projects is to identify the specific microbial functions and host pathways associated with the development of anxiety-related behavior later in life, the same GM profiles developed and maintained in our lab for over 20 generations have shown similar protection or susceptibility to clinical signs in a mouse model of autism, and the data generated in the proposed project will have far-reaching implications, including the development of possible preventive measures for pregnant women or neonates via probiotic supplements.