Behavior begins prior to birth, and is the foundation upon which all subsequent behavior is based. Understanding early neurobehavioral development is of paramount importance, as evidenced by recent findings linking prenatal insults to developmental disabilities, such as autism or cerebral palsy, and also to late onset neuropathophysiologic disorder such as Parkinson's disease and schizophrenia. The candidate has considerable experience with in vivo direct observation of behavior in the rat fetus, and has also developed a battery of behavioral measures for use in detecting prenatal neural insult after a toxin exposure. These studies were the first experimental demonstration of the sensitivity of behavioral measures to detect neural insult in the fetus, and also the first to reveal the possible pattern of behavioral development probable in the Fetal Basis of Adult Disease (FeBAD). Based on these results, the candidate has developed a theory of developmental pathways which encompasses two long-term goals: (1) to gain an understanding of how the interaction among developmental mechanisms, epigenetic phenomena, and prenatal insults produce the multiple developmental pathways characteristic of FeBAD; and (2) to develop sensitive measures of behavioral assessment in the fetus that will enable detection of neural insults leading either to developmental disabilities or FeBAD. In order to test initial hypotheses from the theory, the candidate has recently adapted the direct in vivo observation technique for use with the fetal mouse. This technique will allow her to take advantage of genetically altered mice now available. In this application she has proposed a multi-level, integrative approach, requiring new skills in working with genetically altered mice, neurobiology, and longitudinal studies of both behavior and novel brain imaging techniques (e.g., MRI, MR spectroscopy). These skills that the candidate will acquire during the training phase will allow further testing of relevant hypotheses concerning fetal behavior, prenatal neural insults, and their connection to later emerging functional deficits, using three mouse models of Parkinson's disease, each of which represents a different developmental pathway to FeBAD: a) Pitx3, which represents 'acute' early emergence of dysfunction; b) Nurr1, which represents 'slow progressive"""""""" degeneration; and c) prenatal pesticide exposure, a 'silent vulnerability' pathway where functional deficits do not emerge until subsequent pesticide exposure in adulthood. The results of these experiments proposed in the independent phase will provide preliminary data for an R01 application to investigate more complex factors involved in the developmental pathways theory. ? ? ?
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| Kleven, Gale A; Booth, Heather M; Voogd, Marco et al. (2014) L-dopa reverses behavioral deficits in the Pitx3 mouse fetus. Behav Neurosci 128:749-59 |
| Kleven, Gale A; Ronca, April E (2009) Prenatal behavior of the C57BL/6J mouse: a promising model for human fetal movement during early to mid-gestation. Dev Psychobiol 51:84-94 |
