Neuroendocrine control of synaptic connectivity.

突触连接的神经内分泌控制。

• 批准号: 10522227
• 负责人: Hannes Erich Buelow
• 金额: $ 51.21万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522227
• 关键词: Adult; Afferent Neurons; Agonist; Anatomy; Animal Model; Animals; Attention; Behavior; Behavioral; Behavioral Assay; Beta Cell; Bilateral; Biological Models; Biological Process; Brain; Brain imaging; Caenorhabditis elegans; Calcium; Cells; Cerebral Dominance; Defect; Development; Electrons; Environment; Environmental Risk Factor; Exhibits; Exposure to; Foundations; Genetic; Genetic Transcription; Genetic study; Goals; Guanylate Cyclase; Heart; Hormonal; Human; Image; Individual; Insulin; Insulin Receptor; Ions; Knock-out; Label; Language; Left; Link; Liver; Locomotion; Measurable; Mediating; Mental Depression; Mental disorders; Microscopic; Molecular; Morphology; Nematoda; Neurons; Neurosciences; Neurosecretory Systems; Organ; Post-Traumatic Stress Disorders; Psychology; Research; Resolution; Role; Schizophrenia; Sensory; Shapes; Signal Pathway; Sodium Chloride; Space Perception; Structure; Sum; Synapses; Taste Buds; Testing; Time; Transgenic Organisms; Translating; Translations; Work; antagonist; autism spectrum disorder; base; behavioral study; cognitive ability; experience; experimental study; genetic manipulation; hormonal signals; imaging study; insight; insulin signaling; neural circuit; neural network; neuropsychiatric disorder; neuropsychiatry; optogenetics; programs; receptor; receptor expression; receptor function; reconstruction; response; visual processing

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.

PI：Buelow，Hannes E. 项目概要 大多数动物的总体身体结构遵循双边对称性。有些器官如心脏 肝脏打破了这种总体解剖学对称性，而大脑等其他结构则表现出表面的结构对称性。 双侧对称的解剖结构。尽管如此，人们很早就知道，大脑的两个半球 人类大脑具有不同的功能，神经科学和心理学中的许多经典例子都表明了这一点。 表明了大脑功能不对称的重要性。例如，更高阶的认知能力，例如 语言、空间定向、注意力和视觉处理表现出左右（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表现出大脑偏侧性缺陷，进一步强调了 侧化大脑功能的重要性。毫不奇怪，神经精神疾病通常具有遗传性， 因此可能是一个发展的组成部分。大多数这些条件也受到环境的影响 因素，但环境如何与连接交互仍然很大程度上未知。我们已经确定了一个 线虫线虫两对感觉神经元之间的不对称突触连接 线虫会根据经验而变化。重要的是，这种连接是受控的细胞非 通过胰岛素信号传导独立于其他细胞，而胰岛素信号传导又受到经验的调节。这提供了一个 在分子水平和单细胞分辨率上研究环境如何变化的范例 以依赖于经验的方式对神经回路进行硬连线。该提案的目的是调查 使用秀丽隐杆线虫作为模型系统来研究这种连接的发育、塑料和功能方面。在 具体目标 1，我们将确定体验改变连通性的机制。我们将 确定是否需要转录或翻译以及是否需要神经元活动，以及 足够，以及在哪个单元格中。在具体目标 2 中，我们将确定胰岛素信号在控制中的作用 突触连接。具体来说，我们将测试哪些胰岛素样激动剂和拮抗剂在其中发挥作用 细胞影响连通性的变化；受体在何处发挥作用以及在何种遗传背景下发挥作用。最后，在 具体目标 3，我们将确定连接性的变化如何转化为信息流的变化以及 使用全脑钙成像和行为实验进行行为。总之，我们的研究计划旨在 建立环境改变突触硬连线和行为的机制 不对称突触连接的上下文。