Elaine Y. Hsiao, Ph.D. - US grants

Maternal infection is an environmental factor that can increase the incidence of autism and schizophrenia in the offspring. In an animal model of this risk factor, respiratory infection of pregnant mice yields offspring that develop behavioral abnormalities and neuropathology consistent with those observed in autistic and schizophrenic patients. These changes can be mimicked by maternal injection of the dsRNA, poly(I:C), which evokes an anti-viral inflammatory response. Recent studies have shown that the cytokine interleukin-6 (IL-6) is necessary and sufficient and necessary for mediating the development of behavioral and transcriptional changes in this maternal immune activation (MIA) model. While IL-6 is critical for mediating the effects of MIA, the mechanism by which IL-6 acts to alter neural development is unknown. We recently demonstrated that, shortly after MIA, maternally-derived IL-6 in the placenta mediates the activation of fetal cells in the placental, and subsequent changes levels of important endocrine factors. However, elucidating the mechanism of IL-6 action in altering fetal brain development is complicated by the fact that IL-6 is also upregulated in the fetal brain after MIA. This project will investigate the pathway of IL-6 action in mediating the development of abnormal behaviors in MIA offspring. We will identify the cells that are responsive to, and activated by, MIA-induced IL-6 in the placenta and embryonic brain. We will localize IL-6Ra promoter activity in mice carrying an IL-6Ra-beta-galactosidase transgene to determine where in the fetal brain and placenta IL-6Ra is expressed. We will then use immunohistochemical methods to detect downstream responses of IL-6Ra activation, including phosphorylation of the transcription factors, STAT3 and STAT1. Importantly, this project will pinpoint specific regions and cells for which IL-6 action is critical for the development of autistic and schizophrenic endophenotypes. We will knockout IL-6R in particular cell types and regions in the fetal brain and placenta and assay behavior to determine where IL-6 action acts to alter fetal brain development. The long-term goals are to elucidate the molecular mechanisms by which IL-6 causes behavioral abnormalities relevant for autism and schizophrenia.

PROJECT SUMMARY/ABSTRACT Humans are colonized with diverse microbial communities, collectively called the commensal microbiota, that influence a wide array of biological processes. Recent studies demonstrate that in addition to their roles in nutrition, immunity and metabolism, the commensal microbiota also plays a fundamental role in the development and function of the nervous system, in addition to several complex host behaviors. The proposed research training program aims to uncover the mechanisms underlying the interaction between specific commensal microbes and the nervous system, and to elucidate the impact of these relationships on host physiology. Specifically, the proposed research will examine the role of commensal microbes on host serotonin (5-hydroxytrypatmine, 5-HT) metabolism, with aims to define the specific steps of the 5-HT pathway that are affected by commensal microbes, identify the particular microbial species and factors that affect host 5-HT, and apply these microbial 5-HT modulators toward ameliorating symptoms in models of 5-HT-related disease. Findings from these studies will advance our current understanding of how the commensal microbiota affects health and disease, and will further explore the innovative prospect of developing novel, microbe-based therapeutics, which can be readily modified for better function, regulatory control, targeting and delivery. The proposed studies on the interaction between the commensal microbiota and nervous system fills a novel area of multidisciplinary research that integrates not only neurobiology and microbiology, but also biochemistry (in the dissection of molecular alterations in the 5-HT pathway), chemical engineering (in the nanofabrication of microfluidic devices for high-throughput confinement, cultivation and functional screening of endogenous species of the microbiome) and molecular and behavioral neuroscience (in the investigation of pathologies seen in mouse models of serotonin-deficiency). My proposed training will span five years of independent research as a Senior Research Fellow at the California Institute of Technology. This title is typically reserved for individuals with previous post-doctoral experience and serves as a transitional stage toward advancing into a junior faculty position. Approximately one year after the award is conferred, I will recruit one full-time technician, with significant previous experience in laboratory research. I will also begin mentoring up to two biology or chemistry undergraduate students per year through Caltech's summer research program.