Methods for in vivo behavioral observation of the mouse fetus

描述（由申请人提供）：产前对发育中的神经系统的损害是导致儿童发育障碍的主要原因之一。这种早期神经损伤的结果通常是一种疾病，如脑瘫、自闭症或智力迟钝。通常，这些残疾直到生命的第二或第三年才被诊断出来，延误了在这一关键的早期发育阶段急需的干预和治疗。由于对神经损伤和出现明显功能障碍之间发生的功能发展的直接变化知之甚少，诊断可能会出现延误。由于运动缺陷是许多发育障碍的标志，早期运动功能障碍的个体发生对于理解这些障碍的起源可能是至关重要的。更重要的是，如果运动功能障碍的早期指标能够被识别出来，治疗或治疗就可以在最有益的时候尽早开始。目前的产前神经损伤动物模型为此类评估的发展提供了希望。使用允许直接在体内观察大鼠或小鼠胎儿的方法，可以详细量化自发肢体运动和肢体间协调缺陷。然而，直接观察啮齿动物胎儿的环境与超声观察人类胎儿的环境并不等同，利用超声观察子宫内啮齿动物胎儿的方法对胎儿主体的行为影响很大。为了克服这些障碍，我们将开发一种创新的高分辨率超声用于小鼠胎儿的行为观察，通过将这种新技术与允许直接观察胎儿啮齿动物的方法相结合。这两种方法的成功结合将开辟新的领域，通过对动物模型中胎儿行为的无创观察来推进发育障碍的研究。我们设想这些研究将为产前行为发育的研究开辟一个新的领域，即利用转基因小鼠、环境损伤和胎儿行为的超声观察来建立早期发育障碍的产前小鼠模型。本提案中概述的新方法将在动物和人类模型之间建立必要的桥梁，允许类似的胎儿行为比较。这些新方法也将为开发新的诊断测试来检测人类胎儿的发育障碍奠定基础。最终，这些方法的应用将增加我们对发育障碍的了解，从而可以预防、产前检测和治疗发育障碍。

DESCRIPTION (provided by applicant): Prenatal damage to the developing nervous system is one of the leading causes of developmental disabilities in children. The outcome of this early neural damage is typically a disorder such as cerebral palsy, autism, or mental retardation. Often these disabilities are not diagnosed until the 2nd or 3rd year of life, delaying much needed interventions and therapy during this critical early period of development. Delays in diagnosis may occur because little is known about the immediate changes in functional development that transpire between the time of neural insult and the emergence of obvious dysfunction. Because motor deficits are the hallmark of many developmental disorders, the ontogeny of early motor dysfunction may be paramount to understanding the origins of these disorders. More importantly, if early indicators of movement dysfunction could be identified, therapy or treatment could be started early when it would be most beneficial. Current animal models of prenatal neural insult hold promise for the development of such assessments. Using methods which allow direct in vivo observation of the rat or mouse fetus, detailed quantification of spontaneous limb movements and deficits in inter-limb coordination are possible. However, the environment of the rodent fetus under direct observation is not equivalent to that of the human fetus while observed through ultrasound, and methods using ultrasound to observe the rodent fetus in utero greatly impact the behavior of the fetal subject. To overcome these obstacles, we will develop an innovative use of high resolution ultrasound for behavioral observation of the mouse fetus, by combining this new technology with methods permitting direct observation of the fetal rodent. The successful integration of these two methods will break new ground, advancing the study of developmental disabilities through noninvasive observation of fetal behavior in animal models. We envision that these studies will lead to a new area of investigation in prenatal behavioral development, which will utilize transgenic mice, environmental insults, and ultrasound observation of fetal behavior to create prenatal mouse models of early developmental disabilities. PUBLIC HEALTH RELEVANCE STATEMENT The new methodology outlined in this proposal will create a necessary bridge between animal and human models, allowing similar comparisons of fetal behavior. These new methods will also lay a foundation for the development of new diagnostic tests to detect developmental disabilities in the human fetus. Ultimately, the application of these methods will increase our knowledge about developmental disabilities that will allow their prevention, prenatal detection, and cure.