Cellular basis of visually-guided behavior during development

描述（由申请人提供）：生物体使用传入的感觉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。在神经回路的早期发育过程中，正确的布线介导了这种感觉运动的整合，这对生物体的生存至关重要。在开发神经回路的过程中，回路结构和回路中单个神经元的信号特性都发生了深刻的变化。然而，即使在这些回路完全成熟之前，生物体也可以开始与环境进行有意义的互动。这表明，感觉处理和行为的神经回路可以根据回路的发育状态采用不同的策略来执行其功能。这种情况发生的过程仍然不清楚。由于一些人类神经发育障碍被认为是由于在早期发育过程中不适当的神经回路形成，因此了解这些回路发育的基本机制非常重要。 我们的建议集中在非洲爪蟾蝌蚪的发展中的视顶盖作为一个模型系统来解决这些问题。顶盖和它的哺乳动物同源物上级丘直接接受来自视网膜和其他感觉器官的信息。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回路进行处理。目前还不知道这些局部回路是如何发展的，也不知道该回路的组织和反应特性的发展变化如何与视觉引导的运动行为相关。我们建议结合使用的行为分析，在体内和体外电生理和在体内Ca++成像的神经元群体，以解决如何顶盖整合视觉信息，并将其转化为视觉回避行为。在第一个目标，我们的特征类型的刺激，触发视觉回避和地址的具体假设，这些刺激是如何编码的顶盖。在第二个目标中，我们解决的机制，顶盖中的神经元编码行为相关的刺激，通过特别关注顶盖神经元的内在兴奋性的作用，retinotectal突触的特性，和局部抑制的作用。 这些实验将阐明在顶盖的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CNS补偿发育缺陷的能力提供重要见解，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学特征明确相关。相反，它们被认为是由不同大脑区域内微电路水平的异常功能引起的，并且许多这些异常被认为是在这些电路首次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，以及这些微电路的功能特性如何以及何时出现，是理解为什么神经回路在某些神经系统疾病中异常发育的关键一步，并且对于开发新的治疗策略非常重要。

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.