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Mark E. Hahn and Neelakanteswar Alum. Panlilio, Jennifer Martinez. Joint Program in Oceanography/Applied Ocean Science and Engineering. Massachusetts Institute of Technology. Department of Biology. Woods Hole Oceanographic Institution. Joint Program in Oceanography/Applied Ocean Science and Engineering Massachusetts Institute of Technology. Department of Biology Woods Hole Oceanographic Institution 2019-10-11T20:35:27Z 2019-10-11T20:35:27Z 2019 2019 This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. Thesis: Ph. D., Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Department of Biology; and the Woods Hole Oceanographic Institution), 2019 Cataloged from student-submitted PDF version of thesis. Includes bibliographical references. Harmful algal blooms (HABs) can produce potent neurotoxins that accumulate in seafood and affect human health. One HAB toxin of concern is domoic acid (DomA), a glutamate analog produced by the marine diatom Pseudo-nitzschia spp. Current regulatory limits are designed to prevent acute neurotoxicity in adult humans. However, research shows that low-level exposure during early life can lead to long-term changes in behavior, neural connectivity, and brain morphology. To determine the underlying mechanisms of developmental toxicity, this dissertation used zebrafish as a tool to: i) Establish the developmental window of susceptibility for DomA toxicity, ii) Characterize the behavioral consequences of exposures, and iii) Identify the cellular targets and processes perturbed by DomA. I found that DomA exposure particularly at 2 days post fertilization (dpf) led to altered startle response behavior, myelination defects, and the downregulation of axonal and myelin structural genes. Using vital dyes and immunolabeling, I assessed DomA-induced alterations in cells required for the startle response. I found no differences in the number of sensory neuromasts or in the sensory cranial ganglia structures that detect the acoustic stimuli. However, the majority of DomA-treated larvae lacked one or both Mauthner cells - hindbrain neurons critical for fast startle responses. DomA-treated larvae also had oligodendrocytes with fewer and shorter myelin sheaths, and appeared to aberrantly myelinate neuronal cell bodies. The loss of the Mauthner neurons and their axons may lead to a cellular environment where oligodendrocytes myelinate neuronal cell bodies in the absence of adequate axonal targets. Indeed, pharmacological treatment that reduced the oligodendrocyte number also led to the reduction in the number of these aberrant, myelinated cell bodies. These results indicate that exposure to DomA at a particular period in neural development targets specific cell types, disrupts myelination in the spinal cord, and leads to prolonged behavioral deficits. These mechanistic insights support hazard assessments of DomA exposures in humans during critical periods in early development. "Funding for my research came from the Ocean Ventures Fund, Hill family foundation, Woods Hole Sea grant NA14OAR4170074, and the Woods Hole Center for Oceans and Human Health (COHH), which is jointly funded by the National Institutes of Health (P01ES02192, P01ES028938), and the National Science Foundation (OCE-1314642, OCE-1840381). My funding came from the National Institutes of Health (NIH) P01ES021923-04S1, the Ocean Ridge Initiative Fellowship, the Von Damm Fellowship, and the MIT/WHOI Joint Program Academic Programs Office"--Page 5 by Jennifer Martinez Panlilio. Ph.D. Ph.D. Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Department of Biology; and the Woods Hole Oceanographic Institution) 318 pages eng Massachusetts Institute of Technology MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 Joint Program in Oceanography/Applied Ocean Science and Engineering. Biology. Woods Hole Oceanographic Institution. Algae. Neurotoxic agents. Health. Domoic acid. Impacts of developmental exposures to the harmful algal bloom toxin domoic acid on neural development and behavior Thesis 1121593147 application/pdf 2019-10-11T21:37:13Z Publication unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="e8ff184d-cfc6-4d40-8ce2-a436593ab3e3"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>eng</Language> <Title>Impacts of developmental exposures to the harmful algal bloom toxin domoic acid on neural development and behavior</Title> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2019</PublicationDate> <Authors> <Author> <DisplayName>Panlilio, Jennifer Martinez.</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>http://dspace.mit.edu/handle/1721.1/7582</License> <Keyword>Joint Program in Oceanography/Applied Ocean Science and Engineering.</Keyword> <Keyword>Biology.</Keyword> <Keyword>Woods Hole Oceanographic Institution.</Keyword> <Abstract>Harmful algal blooms (HABs) can produce potent neurotoxins that accumulate in seafood and affect human health. One HAB toxin of concern is domoic acid (DomA), a glutamate analog produced by the marine diatom Pseudo-nitzschia spp. Current regulatory limits are designed to prevent acute neurotoxicity in adult humans. However, research shows that low-level exposure during early life can lead to long-term changes in behavior, neural connectivity, and brain morphology. To determine the underlying mechanisms of developmental toxicity, this dissertation used zebrafish as a tool to: i) Establish the developmental window of susceptibility for DomA toxicity, ii) Characterize the behavioral consequences of exposures, and iii) Identify the cellular targets and processes perturbed by DomA. I found that DomA exposure particularly at 2 days post fertilization (dpf) led to altered startle response behavior, myelination defects, and the downregulation of axonal and myelin structural genes.</Abstract> <Abstract>Using vital dyes and immunolabeling, I assessed DomA-induced alterations in cells required for the startle response. I found no differences in the number of sensory neuromasts or in the sensory cranial ganglia structures that detect the acoustic stimuli. However, the majority of DomA-treated larvae lacked one or both Mauthner cells - hindbrain neurons critical for fast startle responses. DomA-treated larvae also had oligodendrocytes with fewer and shorter myelin sheaths, and appeared to aberrantly myelinate neuronal cell bodies. The loss of the Mauthner neurons and their axons may lead to a cellular environment where oligodendrocytes myelinate neuronal cell bodies in the absence of adequate axonal targets. Indeed, pharmacological treatment that reduced the oligodendrocyte number also led to the reduction in the number of these aberrant, myelinated cell bodies.</Abstract> <Abstract>These results indicate that exposure to DomA at a particular period in neural development targets specific cell types, disrupts myelination in the spinal cord, and leads to prolonged behavioral deficits. These mechanistic insights support hazard assessments of DomA exposures in humans during critical periods in early development.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>