Abstract
Changes in resident microbiota may have wide-ranging effects on human health. We investigated whether early life microbial disruption alters neurodevelopment and behavior in larval zebrafish. Conventionally colonized, axenic, and axenic larvae colonized at 1 day post fertilization (dpf) were evaluated using a standard locomotor assay. At 10 dpf, axenic zebrafish exhibited hyperactivity compared to conventionalized and conventionally colonized controls. Impairment of host colonization using antibiotics also caused hyperactivity in conventionally colonized larvae. To determine whether there is a developmental requirement for microbial colonization, axenic embryos were serially colonized on 1, 3, 6, or 9 dpf and evaluated on 10 dpf. Normal activity levels were observed in axenic larvae colonized on 1–6 dpf, but not on 9 dpf. Colonization of axenic embryos at 1 dpf with individual bacterial species Aeromonas veronii or Vibrio cholerae was sufficient to block locomotor hyperactivity at 10 dpf. Exposure to heat-killed bacteria or microbe-associated molecular patterns pam3CSK4 or Poly(I:C) was not sufficient to block hyperactivity in axenic larvae. These data show that microbial colonization during early life is required for normal neurobehavioral development and support the concept that antibiotics and other environmental chemicals may exert neurobehavioral effects via disruption of host-associated microbial communities.
Highlights
Growing evidence indicates host-associated microbial communities play important roles in neurologic development
Axenic zebrafish exposed to heat-killed E. coli at 1, 6, 7, 8, and 9 dpf Axenic zebrafish exposed to heat-killed S. typhimurium at 1, 6, 7, 8, and 9 dpf Axenic zebrafish exposed to pam3CSK4 at 1, 6, 7, 8, and 9 dpf Axenic zebrafish exposed to Poly(I:C) at 1, 6, 7, 8, and 9 dpf show a connection between colonization status and behavior[19, 20, 28], it is unclear whether microbes exert immediate effects on behavior or whether they exhibit an early priming or imprinting effect that promotes normal neurobehavioral development
We demonstrated that conventionally colonized zebrafish exposed to broad-spectrum antibiotics were hyperactive, phenocopying locomotor hyperactivity observed in axenic larvae
Summary
Growing evidence indicates host-associated microbial communities (microbiota) play important roles in neurologic development. There is an increasing appreciation of the role of host-associated microbiota in neurogenesis[5, 6] and other basic neurodevelopmental processes like blood brain barrier formation and maintenance[7], microglia maturation[8], and myelination[9, 10] Despite this progress, the temporal requirements for microbial colonization on neurobehavioral development are not understood, and the mechanisms by which microbes mediate normal CNS development have not been clearly identified. Zebrafish assemble a diverse microbial community in their intestine[21] that varies over developmental time and, similar to humans[22], exhibits significant interindividual variation[23] These findings support the use of zebrafish as an efficient experimental model system to define mechanisms underlying host-microbiota relationships that may be relevant to human health and environmental toxicology. Pathways by which intestinal microbes modulate locomotor activity are not defined
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