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以被描述为 “发育迟缓”(一种行为在关键时期不能发展)， “回归”(一种行为在正确的时间发展起来，但随后就失去了 表现出发育迟缓的进展速度)，或“侵入”(出现 在形式或频率上异常的行为)。症状出现的时间段可能 代表环境毒物在大脑中积累到 早期暴露的临界水平或有害影响变得明显 通过扰乱大脑正常发育的通路。此外， 某些个体可能对毒物更敏感，因为基因 (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设 很适合进行测试。在这一建议中，提出了一种新的研究范式 毒物诱导性发育障碍合并系统性 对男性和女性发育迟缓、退化和/或侵扰的评估 将培育出三个品系的小鼠。这将包括一个特征 正常情况下关键行为的个体发生：a)空中翻正 反射和平衡木性能；b)水迷宫(隐蔽平台)和 被动回避行为；c)水迷宫(可见平台)，主动 回避、刻板印象和自我伤害行为。这些行为有 与小脑、海马体和纹状体有关，已知的大脑区域 与发育障碍有关，并被认为是铅和 甲基汞。行为个体发育将与神经回路和 突触的形成和低剂量暴露对突触的破坏效应 毒物对每种行为的发展将分三次进行评估 超过全剂量反应曲线的点数。因此，具体目标是：1) 描述这些行为在这三个品系中的正常发育 2)评价急性和慢性低剂量暴露对小鼠的影响 铅和甲基汞对每个菌株在三个时间段的这些行为的影响 3)神经发育正常与神经成熟的关系 回路和突触发生与毒物诱导的干扰程度 神经行为发育到形态、神经回路和 神经化学措施；以及，4)在此背景下评估结果 以以下问题的形式出现的新范式：接触毒物 导致神经行为迟缓、退化和/或侵扰 这些品系的雄性或雌性小鼠是否发育？

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?