DEVELOPMENT OF COGNITIVE & SENSORY/MOTOR SKILLS BY METAL EXPOSURE

描述（由申请人提供） 发育障碍的行为表现可表征为 “发育迟缓”（一种行为在关键时期未能发展）， “退化”（一种行为在正确的时间发展，但随后丢失或 表现出发育迟缓的进展速度），或“侵入”（ 在形式或频率上异常的行为）。出现症状的时期可能 代表环境毒物在大脑中积累的时间， 早期暴露的临界水平或有害影响变得明显 通过扰乱大脑的正常发育此外，委员会认为， 由于遗传原因，某些人可能对毒物更敏感 （可能与免疫有关）易感性。在这一框架内， 毒物与发育障碍有因果关系的假说 很适合测试在这个提议中，一个新的研究范式 毒性引起的发育障碍， 评估男性和女性的发育迟缓、退化和/或侵入 将培育出三种品系的小鼠。这将包括一个表征 正常情况下关键行为的个体发育：a）空中翻正 反射和平衡木性能; B）水迷宫（隐藏平台）和 被动回避行为;和c）水迷宫（可见平台），主动 回避，刻板和自我伤害行为。这些行为 与小脑、海马体和纹状体有关，这些大脑区域被认为是 参与发育障碍，已知是铅的目标， 甲基汞行为个体发育将与神经回路联系起来， 突触的形成和低剂量暴露于每一个的破坏性影响 将在三个时间点评估毒物对每种行为发展的影响 在完整的剂量反应曲线上的点。因此，具体目标是：1） 表征这三种菌株中这些行为的正常发展 2）评估急性和慢性低剂量接触的影响 铅和甲基汞对各菌株上述行为影响 点; 3）将正常发育与神经成熟相关联 回路和突触发生以及毒物诱导的破坏程度 从神经行为发展到形态学，神经回路， 神经化学措施;以及，4）在此背景下评估结果 新的范例的形式，以下问题： 导致神经行为障碍、退化和/或侵入 这些品系的雄性或雌性小鼠的发育？

DESCRIPTION (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?