Neuroendocrine control of synaptic connectivity.

派：Buelow，Hannes E. 项目摘要 大多数动物的总体身体结构遵循双侧对称。一些器官，如心脏和 肝脏打破了这种大体的解剖对称性，而其他结构，如大脑，则表现出肤浅的 两侧对称的解剖结构。尽管如此，很长一段时间以来，人们一直知道地球的两个半球 人脑有不同的功能，神经科学和心理学中的许多经典例子都有 显示了不对称性在大脑功能中的重要性。例如，更高级别的认知能力，如 语言、空间定向、注意和视觉加工呈现左-右(L-R)功能不对称 人类。值得注意的是，许多神经精神疾病包括自闭症谱系障碍，抑郁症， 精神分裂症和创伤后应激障碍显示出大脑偏侧的缺陷，进一步强调了 脑功能偏侧化的重要性。不足为奇的是，神经精神疾病通常有遗传和， 因此，可能是发展的组成部分。这些情况中的大多数也受到环境的影响 然而，环境如何与连通性对接在很大程度上仍是未知的。我们已经确定了一个 线虫两对感觉神经元之间的不对称突触联系 优雅的衣服会随着经验而变化。重要的是，此连接是由信元控制的 通过胰岛素信号自主地脱离其他细胞，而胰岛素信号又受经验的调节。这提供了一种 在分子水平和单细胞分辨率下研究环境如何变化的范式 以经验依赖的方式对神经电路进行硬连接。这项提案的目标是调查 以线虫为模型系统的这种连接的发育、可塑性和功能方面的研究。在……里面 具体目标1，我们将确定经验改变连接的机制。我们会 确定是否需要转录或翻译，以及是否需要神经元活动 足够了，在哪些单元格中。在特定的目标2中，我们将确定胰岛素信号在控制 突触连接。具体地说，我们将测试哪些胰岛素样激动剂和拮抗剂在哪些方面发挥作用 细胞影响连接性的变化；受体在哪里发挥作用，在什么遗传背景下发挥作用。最后，在 具体目标3，我们将确定连通性的变化如何转化为信息流的变化 行为采用全脑钙成像和行为学实验。总而言之，我们的研究计划旨在 建立环境改变突触硬连接和行为的机制 非对称突触连接的上下文。

PI: Buelow, Hannes E. Project Summary The general body plan of most animals follows a bilateral symmetry. Some organs such as the heart and liver break this gross anatomical symmetry, while other structures such as the brain display a superficial bilaterally symmetric anatomy. Nonetheless, it has been known for a long time that the two hemispheres of the human brain serve distinct functions, and many classical examples in neuroscience and psychology have shown the importance of asymmetry in brain function. For example, higher order cognitive abilities such as language, spatial orientation, attention, and visual processing exhibit left-right (L-R) functional asymmetries in humans. Of note, many neuropsychiatric conditions including autism spectrum disorders, depression, schizophrenia, and post-traumatic stress disorder display defects in brain laterality, further underscoring the importance of lateralized brain function. Not surprisingly, neuropsychiatric conditions often have a genetic and, hence possibly, a developmental component. Most of these conditions are also influenced by environmental factors, yet how the environment interfaces with connectivity remains largely unknown. We have identified an asymmetric synaptic connection between two pairs of sensory neurons in the nematode Caenorhabditis elegans that changes in response to experience. Importantly, this connection is controlled cell-non- autonomously from other cells by insulin signaling, which in turn is regulated by experience. This provides a paradigm to investigate, on a molecular level and in single cell resolution, how the environment can change hardwiring of a neural circuit in an experience-dependent manner. The goal of this proposal is to investigate the developmental, plastic and functional aspects of this connection using C. elegans as a model system. In Specific Aim 1, we will determine the mechanisms by which experience changes connectivity. We will determine whether transcription or translation is required and whether neuronal activity is necessary and sufficient, and in which cells. In Specific Aim 2, we will determine the role of insulin signaling in controlling synaptic connectivity. Specifically, we will test which insulin-like agonists and antagonists function in which cells to effect the changes in connectivity; where the receptor functions and in which genetic context. Lastly, in Specific Aim 3, we will determine how changes in connectivity translate into changes in information flow and behavior using whole brain calcium imaging and behavioral experiments. In sum, our research program aims to establish the mechanisms, by which the environment changes synaptic hardwiring and behavior in the context of an asymmetric synaptic connection.