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.