Alien Registration- Godin, Elizabeth (Sanford, York County)

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Magnetic resonance imaging, in situ hybridization, and immunohistochemistry-based analyses of early prenatal ethanol exposure-induced central nervous system abnormalities

Fetal alcohol spectrum disorders (FASD), the collection of defects resulting from prenatal alcohol (ethanol) exposure, has been the subject of basic and clinical investigation for four decades, but remains a major public health problem. At the severe end of the spectrum is fetal alcohol syndrome (FAS), which is characterized by the presence of growth retardation, craniofacial anomalies, and brain deficits. The research described herein was designed to advance our knowledge regarding ethanol's insult to the developing brain, with much of it directed toward testing the hypothesis that the application of magnetic resonance-based imaging to the examination of brain morphology, regional volumes and fiber tracts in ethanol-exposed fetal mice would facilitate new discoveries. As with other teratogens, it is well known that the type and severity of abnormality induced by ethanol is dependent upon the dose, timing, and pattern of maternal exposure. For this study, the CNS dysmorphology resulting from acute gestational day (GD) 7 maternal ethanol administration was examined in fetal mice utilizing state of the art imaging techniques. This time in mouse development is consistent with that in the third week of human gestation. Magnetic resonance microscopy (MRM) allowed for linear, volumetric and 3-dimensional morphologic analyses of ethanol-induced alterations in the fetal CNS and diffusion tensor imaging (DTI) provided for assessment of fiber tract abnormalities. In addition, routine histological techniques were utilized for detailed examination of the ventromedian forebrain in ethanol-exposed embryos and fetuses. Major new findings from these studies include the following regarding the consequences of acute GD7 ethanol exposure in mice 1) cerebral cortical heterotopias are induced; a discovery that was facilitated by MRM-based analyses, 2) fiber tract abnormalities involving the corpus callosum, anterior commissure, and fornix/fimbria occur, as evidenced by DTI, 3) fiber tract abnormalities, as identified in fetal mice, persist into periadolescent stages, 4) ventral forebrain insult preferentially involving the preoptic area and medial ganglionic eminences reduces Olig2 and GABA expression and alters the morphology of somatostatin-expressing cells. Overall, the results of this work promise to aid in clinical recognition, diagnosis, and prevention of FASD

A Pharmacology-Based Enrichment Program for Undergraduates Promotes Interest in Science

There is a strong need to increase the number of undergraduate students who pursue careers in science to provide the “fuel” that will power a science and technology–driven U.S. economy. Prior research suggests that both evidence-based teaching methods and early undergraduate research experiences may help to increase retention rates in the sciences. In this study, we examined the effect of a program that included 1) a Summer enrichment 2-wk minicourse and 2) an authentic Fall research course, both of which were designed specifically to support students\u27 science motivation. Undergraduates who participated in the pharmacology-based enrichment program significantly improved their knowledge of basic biology and chemistry concepts; reported high levels of science motivation; and were likely to major in a biological, chemical, or biomedical field. Additionally, program participants who decided to major in biology or chemistry were significantly more likely to choose a pharmacology concentration than those majoring in biology or chemistry who did not participate in the enrichment program. Thus, by supporting students\u27 science motivation, we can increase the number of students who are interested in science and science careers

Repairing the Leaky Pipeline: A Motivationally Supportive Intervention to Enhance Persistence in Undergraduate Science Pathways

The current study reports on the efficacy of a multi-faceted motivationally designed undergraduate enrichment summer program for supporting science, technology, engineering and math (STEM) persistence. Structural equation modeling was used to compare summer program participants (n = 186), who participated in the program between their first and second years in college, to a propensity score matched comparison sample (n = 401). Participation in the summer program positively predicted science motivation (self-efficacy, task value), assessed eight months after the end of the program (second year in college). The summer enrichment program was also beneficial for science persistence variables, as evidenced by significant direct and indirect effects of the program on science course completion during students’ third year of college and students’ intentions to pursue a science research career assessed during the third year of college. In general, the program was equally beneficial for all participants, but ancillary analyses indicated added benefits with respect to task value for students with relatively lower prior science achievement during the first year of college and with respect to subsequent science course taking for males. Implications for developing effective interventions to reduce the flow of individuals out of STEM fields and for translating motivational theory into practice are discussed

Ventromedian forebrain dysgenesis follows early prenatal ethanol exposure in mice

Ethanol exposure on gestational day (GD) 7 in the mouse has previously been shown to result in ventromedian forebrain deficits along with facial anomalies characteristic of fetal alcohol syndrome (FAS). To further explore ethanol's teratogenic effect on the ventromedian forebrain in this mouse model, scanning electron microscopic and histological analyses were conducted. For this, time mated C57Bl/6J mice were injected with 2.9 g/kg ethanol or saline twice, at a four hour interval, on their 7th day of pregnancy. On GD 12.5, 13 and 17, control and ethanol-exposed specimens were collected and processed for light and scanning electron microscopic analyses. Gross morphological changes present in the forebrains of ethanol-exposed embryos included cerebral hemispheres that were too close in proximity or rostrally united, enlarged foramina of Monro, enlarged or united lateral ventricles, and varying degrees of hippocampal and ventromedian forebrain deficiency. In GD 12.5 control and ethanol-exposed embryos, in situ hybridization employing probes for Nkx2.1 or Fzd8 to distinguish the preoptic area and medial ganglionic eminences (MGE) from the lateral ganglionic eminences, respectively, confirmed the selective loss of ventromedian tissues. Immunohistochemical labeling of oligodendrocyte progenitors with Olig2, a transcription factor necessary for their specification, and of GABA, an inhibitory neurotransmitter, showed ethanol-induced reductions in both. To investigate later consequences of ventromedian forebrain loss, MGE-derived somatostatin-expressing interneurons in the subpallial region of GD 17 fetal mice were examined, with results showing that the somatostatin-expressing interneurons that were present were dysmorphic in the ethanol-exposed fetuses. The potential functional consequences of this insult are discussed

Genesis of teratogen-induced holoprosencephaly in mice

Evidence from mechanical, teratological, and genetic experimentation demonstrates that holoprosencephaly (HPE) typically results from insult prior to the time that neural tube closure is completed and occurs as a consequence of direct or indirect insult to the rostral prechordal cells that induce the forebrain or insult to the median forebrain tissue, itself. Here, we provide an overview of normal embryonic morphogenesis during the critical window for HPE induction, focusing on the morphology and positional relationship of the developing brain and subjacent prechordal plate and prechordal mesoderm cell populations. Subsequent morphogenesis of the HPE spectrum is then examined in selected teratogenesis mouse models. The temporal profile of Sonic Hedgehog expression in rostral embryonic cell populations and evidence for direct or indirect perturbation of the Hedgehog pathway by teratogenic agents in the genesis of HPE is highlighted. Emerging opportunities based on recent insights and new techniques to further characterize the mechanisms and pathogenesis of HPE are discussed

Magnetic Resonance Microscopy Defines Ethanol-Induced Brain Abnormalities in Prenatal Mice: Effects of Acute Insult on Gestational Day 8

Magnetic resonance microscopy (MRM), magnetic resonance imaging (MRI) at microscopic levels, provides unprecedented opportunities to aid in defining the full spectrum of ethanol’s insult to the developing brain. This is the first in a series of reports that, collectively, will provide an MRM-based atlas of developmental stage-dependent structural brain abnormalities in a Fetal Alcohol Spectrum Disorders (FASD) mouse model. The ethanol exposure time and developmental stage examined for this report is gestational day (GD) 8 in mice, when the embryos are at early neurulation stages; stages present in humans early in the fourth week postfertilization

Magnetic resonance microscopy-based analyses of the brains of normal and ethanol-exposed fetal mice

The application of magnetic resonance microscopy (MRM) to the study of normal and abnormal prenatal mouse development has facilitated discovery of dysmorphology following prenatal ethanol insult. The current analyses extend this work, providing a regional brain volume-based description of normal brain growth and illustrating the consequences of gestational day (GD) 10 ethanol exposure in the fetal mouse

Magnetic Resonance Microscopy Defines Ethanol-Induced Brain Abnormalities in Prenatal Mice: Effects of Acute Insult on Gestational Day 7

This magnetic resonance microscopy (MRM)-based report is the 2nd in a series designed to illustrate the spectrum of craniofacial and central nervous system (CNS) dysmorphia resulting from single- and multiple-day maternal ethanol treatment. The study described in this report examined the consequences of ethanol exposure on gestational day (GD) 7 in mice, a time in development when gastrulation and neural plate development begins; corresponding to the mid- to late 3rd week post-fertilization in humans. Acute GD 7 ethanol exposure in mice has previously been shown to result in CNS defects consistent with holoprosencephaly (HPE) and craniofacial anomalies typical of those in Fetal Alcohol Syndrome (FAS). MRM has facilitated further definition of the range of GD 7 ethanol-induced defects