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成功与环境相互作用的基础。在早期发育过程中，调节这种感觉运动整合的神经回路的正确连接对生物体的生存至关重要。在神经回路的发育过程中，回路结构和回路内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，感觉处理和行为背后的神经回路可以根据回路的发育状态，采用不同的策略来实现它们的功能。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造成的，因此了解这些回路发育的基本机制是很重要的。我们的建议侧重于发展非洲爪蟾蝌蚪的光学顶盖作为一个模型系统来解决这些问题。顶盖及其哺乳动物的同系物上丘接受来自视网膜和其他感觉方式的直接输入。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，蝌蚪会迅速地游离接近的物体，这种回避行为需要由顶盖内的局部电路处理。目前尚不清楚这些局部回路是如何发育的，也不知道这些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相关。我们建议结合行为分析，体内和体外电生理学和体内神经元群的Ca++成像，来解决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中编码的具体假设。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和局部抑制的作用，来解决顶盖神经元编码行为相关刺激的机制。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了解中枢神经系统补偿发育缺陷的能力提供重要见解，为神经发育和视力障碍的早期治疗开辟几种治疗途径。

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.