The gut and its microbial community exert a powerful influence on brain and behavior. Importantly, the microbiota influence anxiety-like and social behaviors-phenotypes of great relevance to modeling and understanding disorders of human social functioning. Transmission of microbiota from mothers to offspring begins perinatally. This issue is of translational importance: disorders such as prematurity, and autistic syndromes involve gut microbiota dysfunction (dysbiosis) and neurobehavioral problems. A construct of a shared and coregulated Mother-Offspring Microbiome (M-OM) is applied. The M-OM forms and functions perinatally. It regulates mother-offspring interactions, is mutually regulated by the participants, and contributes to offspring neurobehavioral development. The prenatal and postnatal status of the maternal microbiome is hypothesized to affect postnatal development of sociality - a core component of behavioral health. Alterations in sociality are expected to prove to be mediated by neuroendocrine and immune signals to the vagus nerve, which itself is affected by the gut microbiota. A mouse model of M-OM is used for a program of mechanistic studies of the developing HPA axis and forebrain anatomy as well as measures of the microbiota and of cytokines. Sociality is measured via anatomical, and physiological variables. The hypotheses of altered M-OM function will be tested with antimicrobial bacterial depletion and maternal stress.
The Specific Aims will guide tests of the following hypotheses:
Aim 1. There exists an integrated Maternal-Offspring Microbiome (M-OM), so that perinatal disruption of the maternal microbiota alters early development of sociality in the offspring via identifiable pathways involving the offsprings' immune system, HPA axis, and the corticolimbic structure and function of the developing brain.
Aim 2. The Maternal-Offspring Microbiolme (M-OM) is bi-directionally regulated by a suite of behavioral interactions. Offspring rendered dysbiotic by maternal antibiotic treatment will elicit differential nurturance from the mother which can be shown to channel the development of the offspring into social phenotypes relevant to models of human behavioral disorders including autism.
Aim 3. Early disruptions of the Maternal-Offspring Microbiome will have enduring effects on the development of behavior, detectable even after weaning and the attainment of independence from dysbiotic maternal behavior. The proposed program will enter new territories where mechanisms of the maternal microbiome are in mutual regulation with maternal behavior and, through the mother, with offspring immunity, HPA function, and social development, an outcome of broad clinical importance.
A mouse model will be used to study how disruptions in the maternal gut microbiome during the perinatal period can affect the offspring microbiome and, through specific mechanisms of the immune system, stress physiology, and behavior, alter the development of sociality in the offspring. Antibiotics and maternal stress will be used to disrupt the maternal microbiome; both are seen in clinical settings, especially in the newborn intensive care unit, where gut dysbiosis is prevalent and is associated with cognitive and behavioral problems.
