Methods for in vivo behavioral observation of the mouse fetus

描述(由申请人提供)：发育中神经系统的产前损伤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障碍，如脑瘫、自闭症或智力低下。通常，这些残疾直到生命的第二年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亟需的干预和治疗。诊断可能会出现延误，因为人们对从神经损伤到出现明显功能障碍之间发生的功能发育的即时变化知之甚少。由于运动障碍是许多发育障碍的标志，早期运动功能障碍的个体发育可能对了解这些障碍的起源至关重要。更重要的是，如果能够确定运动功能障碍的早期指标，就可以在最有益的时候尽早开始治疗或治疗。目前的产前神经侮辱动物模型为此类评估的发展提供了希望。使用可以直接在体内观察大鼠或小鼠胎儿的方法，可以详细量化自发的肢体运动和肢体间协调的缺陷。然而，直接观察啮齿动物胎儿的环境并不等同于通过超声波观察人类胎儿的环境，而使用超声波在宫内观察啮齿动物胎儿的方法对胎儿主体的行为产生了很大的影响。为了克服这些障碍，我们将开发一种创新的使用高分辨率超声波对小鼠胎儿进行行为观察的方法，将这项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天地，通过对动物模型中胎儿行为的非侵入性观察来推进发育障碍的研究。我们预计，这些研究将在产前行为发育方面开辟一个新的研究领域，利用转基因小鼠、环境侮辱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。公共卫生相关性声明这项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，允许对胎儿行为进行类似的比较。这些新方法还将为开发新的诊断测试奠定基础，以检测人类胎儿的发育障碍。最终，这些方法的应用将增加我们对发育障碍的了解，从而能够预防、产前检测和治疗。

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.