Sunday, November 24, 2024
11/24/2024
DESCRIPTION (provided by applicant): Both genetic and environmental factors play significant roles in influencing and perhaps causing neurodevelopmental disorders such as autism, mental retardation, and schizophrenia. Recent advances in genetic analysis have revealed a number of genes linked to familial forms of these disorders. Very little is known, however, about how the environment may contribute to these disorders, or how the environment may interact with identified genetic causes. We propose that abnormal microbial colonization of the gut during development leads to aberrant expression levels of genes that are involved in brain development, specifically in synapse formation. We hypothesize that incorrect microbial colonization of the gut may exacerbate or drive behavioral deficits by promoting aberrant synapse formation that results in altered neuronal circuitry and function. We propose to examine interactions between early gut colonization by the microbiota and expression of synaptic cell adhesion molecules, such as Neuroligins, during development in zebrafish. This model provides an unparalleled opportunity to study the consequences of altered gut microbial colonization on synapse formation, development of neuronal circuitry, neuronal activity, and behavior, because we can manipulate both host genetics and microbial communities and follow development of defined neuronal populations in real time in living juveniles and adults. We also propose to determine whether there is a critical period during which colonization by a microbiota whose members express specific traits is required for normal synapse development, and to learn how the microbiota signals to the developing brain to promote the normal synapse formation required for normal behavior. Finally, we will test directly whether a dysbiotic, pro-inflammatory microbiota can alter synapse development, formation of neuronal circuitry, neuronal activity, and behavior, in both young and adult animals. Our proposed experiments will provide the first comprehensive view of how microbial signals affect development of neuronal anatomy and physiology and how this affects behavior at later stages of development and in adults. Revealing and characterizing an interaction between the microbiota and the genes that drive synapse formation would have a dramatic impact on current treatment approaches for individuals diagnosed with neurodevelopmental disorders.
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