upon which all subsequent behavior is based. Understanding this early neurobehavioral development is of vital importance, as evidenced by recent findings linking prenatal insults to both developmental disabilities such as autism or cerebral palsy, and also to late onset neuromotor degeneration such as Parkinson's disease. My prior work with in vivo direct observation of behavior in the rodent fetus has demonstrated the sensitivity of behavioral measures to detect toxin-induced neural insult prenatally, and also the first to reveal the possible pattern of fetal behavioral development probable in the Fetal Basis of Adult Disease (FeBAD). Based on these results, 1 developed a Theory of Developmental Pathways which encompasses two long-term goals: (1) To gain an understanding of how the interaction between 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 this application, I propose a multi-level, integrative approach utilizing genetically altered mice, immunohistochemistry, quantification of brain metabolites with NMR spectroscopy, and longitudinal studies of behavior. This multi-level approach tests relevant hypotheses concerning fetal behavior, prenatal neural insults, and their connection to later emerging functional deficits. Central to these studies are three mouse models of Parkinson's disease, each of which represents a different Developmental Pathway to FeBAD: (1) Pitx3, representing 'Acute'early emergence of dysfunction;(2) Nr4a2/Nurrl, typifying 'Slow Progressive'degeneration;and (3) prenatal pesticide exposure, a 'Silent Vulnerability pathway where functional deficits do not emerge until subsequent insult through pesticide exposure in adulthood. The results of these experiments will provide preliminary data for an ROl proposal investigating more complex factors involved in my Theory of Developmental Pathways.
(See Instructions): The public health relevance of this research is to identify connections between prenatal insults, changes in fetal behavioral functioning, and disorders of the nervous system, both those in close proximity to the Insult, such as autism, or those of late onset, such as Parkinson's disease. Ultimately, this research may reveal pathways to the prevention, early detection, and treatment of developmental disabilities and FeBAD.
| Bellinger, S A; Lucas, D; Kleven, G A (2015) An ecologically relevant guinea pig model of fetal behavior. Behav Brain Res 283:175-83 |
| Brewer, Jacob S; Bellinger, Seanceray A; Joshi, Prianca et al. (2014) Enriched open field facilitates exercise and social interaction in 2 strains of guinea pigs (Cavia porcellus). J Am Assoc Lab Anim Sci 53:344-55 |
| Kleven, Gale A; Joshi, Priyanka; Voogd, Marco et al. (2013) Prenatal ontogeny of the dopamine-dependent neurobehavioral phenotype in Pitx3-deficient mice. Eur J Neurosci 37:1564-72 |
