Cellular basis of visually-guided behavior during development

描述(由申请人提供)：生物体利用传入的感官信息以有意义的方式调整其运动输出的过程是与环境成功互动的基础。调节感觉运动整合的神经回路在早期发育过程中的正确连接对生物体的生存至关重要。在神经电路的发展过程中，电路结构和电路内单个神经元的信号特性都发生了深刻的变化。然而，甚至在这些回路完全成熟之前，生物体就可以开始与环境进行有意义的互动。这表明，根据感觉处理和行为的神经回路的发育状态，可以采用不同的策略来执行它们的功能。发生这种情况的过程仍然不清楚。由于一些人类神经发育障碍被认为是由于早期发育过程中不适当的神经回路形成所致，因此了解这些回路发育的基本机制是很重要的。我们的建议侧重于非洲爪哇蝌蚪发育中的视顶盖，作为解决这些问题的模型系统。顶盖和它的哺乳动物同源物上丘，接受来自视网膜和其他感官形式的直接输入。它的功能是整合视觉和其他感官信息，并将其转化为定向行为。众所周知，蝌蚪会迅速游离接近的物体，这种回避行为需要顶盖内的局部电路进行处理。目前还不知道这些局部回路是如何发展的，也不知道这个回路的组织和反应特性的发育变化如何与视觉引导的运动行为有关。我们建议使用行为分析、体内和体外电生理学以及神经元群体的体内钙成像相结合的方法来研究顶盖如何整合视觉信息并将其转化为视觉回避行为。在第一个目标中，我们描述了触发视觉回避的刺激类型，并提出了关于这些刺激如何在顶盖编码的具体假设。在第二个目标中，我们通过特别关注顶盖神经元内在兴奋性的作用，视网膜顶盖突触的特性，以及局部抑制的作用，来研究顶盖神经元编码行为相关刺激的机制。这些实验将阐明已知的在顶盖单细胞和网络水平上发生的多种发育过程如何协同工作，以优化其将视觉输入转化为运动行为的能力。了解神经回路调节多种特性以实现稳定功能的基本机制将为了解中枢神经系统补偿发育缺陷的能力提供重要的见解，为神经发育和视觉障碍的早期治疗开辟几条治疗途径。 公共卫生相关性：许多神经和精神疾病，包括自闭症、精神分裂症、癫痫和弱视，并不总是与明确的神经病理特征相关联。相反，它们被认为是由于不同大脑区域内微电路水平的异常功能造成的，其中许多异常被认为是在这些电路最初形成时的发育过程中出现的。因此，了解大脑微电路在发育过程中建立的基本机制，以及这些微电路如何以及何时出现功能特性，是理解神经电路在某些神经疾病期间异常发育的关键一步，对于开发新的治疗策略也很重要。

DESCRIPTION (provided by applicant): The process by which organisms use incoming sensory information to adjust their motor output in meaningful ways is fundamental to a successful interaction with their environment. Correct wiring during early development of neural circuits mediating this sensorimotor integration is essential for organism survival. In developing neural circuits both circuit architecture and the signaling properties of individual neurons within the circuit undergo profound changes. However, organisms can begin to interact meaningfully with their environment even before these circuits are fully mature. This suggests that neural circuits underlying sensory processing and behavior can employ different strategies to carry out their function, based on the circuit's developmental state. The process by which this occurs remains obscure. Since several human neurodevelopmental disorders are believed to result from inappropriate neural circuit formation during early development, it is important to understand the basic mechanisms by which these circuits develop. Our proposal focuses on the developing optic tectum of the Xenopus laevis tadpole as a model system to address these issues. The tectum, and its mammalian homologue the superior colliculus, receive direct input from the retina as well as from other sensory modalities. It functions to integrate visual and other sensory information, and transform this into orienting behavior. Tadpoles are known to rapidly swim away from approaching objects, and this avoidance behavior requires processing by local circuits within the tectum. It is not known how these local circuits develop, nor how developmental changes in the organization and response properties of this circuit relate to visually guided motor behavior. We propose to use a combination of behavioral analyses, in vivo and in vitro electrophysiology and in vivo Ca++ imaging of neuronal populations, to address how the tectum integrates visual information and transforms it into visual avoidance behavior. In the first aim we characterize the types of stimuli which trigger visual avoidance and address specific hypotheses about how these stimuli are encoded in the tectum. In the second aim, we address the mechanisms by which neurons in the tectum encode behaviorally relevant stimuli, by focusing specifically on the role of tectal neuron intrinsic excitability, the properties of retinotectal synapses, and the role of local inhibition. These experiments will elucidate how multiple developmental processes known to occur at the single cell and network levels in the tectum, can work together to optimize its ability to transform visual input into motor behavior. Understanding the basic mechanisms by which neural circuits adjust multiple properties to achieve stable function will provide important insight into the ability of the CNS to compensate for developmental deficits, opening several therapeutic avenues for the early treatment of neurodevelopmental and vision disorders. PUBLIC HEALTH RELEVANCE: Many neurological and psychiatric disorders including autism, schizophrenia, epilepsy and amblyopia are not always clearly associated with a well defined neuropathological profile. Rather, they are believed to result from abnormal functioning at the level of microcircuits within different brain regions, and many of these abnormalities are thought to arise during development when these circuits are first formed. Understanding the basic mechanisms by which the microcircuitry of the brain becomes established during development, and how and when functional properties of these microcircuits emerge, is therefore a crucial step towards understanding why neural circuits develop abnormally during some neurological disorders, and is important for developing novel therapeutic strategies.