(provide by applicant) Behavioral manifestations of developmental disorders may be characterized as """"""""retardation"""""""" (a behavior fails to develop during a critical period), """"""""regression"""""""" (a behavior develops at the right time but then is lost or exhibits a stunted rate of progression), or """"""""intrusion"""""""" (appearance of behaviors aberrant in form or frequency). The period when symptoms appear may represent a time when environmental toxicants have accumulated in brain to critical levels or the deleterious effects of early exposure become manifest through perturbation of normal development of brain pathways. Furthermore, certain individuals may be more sensitive to toxicants because of a genetic (perhaps immune-related) predisposition. Within this framework, the hypothesis that toxicants are causally involved in developmental disorders lends itself well to testing. ln this proposal, a new paradigm for the study of toxicant-induced developmental disorders incorporating systematic assessment of retardation, regression and/or intrusions in male and female mice of three strains will be developed. This will include a characterization of the ontogeny of key behaviors under normal conditions: a) mid-air righting reflex and balance beam performance; b)water maze (hidden platform) and passive avoidance behavior; and c)water maze (visible platform), active avoidance, and stereotypic and self-injurious behavior. These behaviors have been linked to cerebellum, hippocampus, and striatum, brain areas known to be involved in developmental disorders and known to be targets of lead and methylmercury. The behavioral ontogeny will be linked to neural circuitry and synapse formation and the disruptive effects of low dose exposure to each toxicant on the development of each behavior will be assessed at three time points over full dose-response curves. Thus, the specific aims are: 1) characterize the normal development of these behaviors in these three strains of mice; 2) evaluate the effects of acute and chronic low dose-exposure to lead and methylmercury on these behaviors in each strain at each of three time points; 3) correlate the normal development with maturation of neural circuitry and synaptogenesis and the magnitude of toxicant-induced disruption of neurobehavioral development to morphological, neural circuitry, and neurochemical measures; and, 4) evaluate the outcome in the context of this new paradigm in the form of the following question: did toxicant exposure result in retardation, regression and/or intrusions in the neurobehavioral development of male or female mice of these strains?
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