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. 项目摘要 大多数动物的一般身体计划遵循双侧对称性。一些器官，例如心脏和 肝脏打破这种粗暴的解剖对称性，而其他结构（例如大脑）则表现出浅表 双侧对称解剖结构。尽管如此，很久以来就知道了 人的大脑发挥了不同的功能，许多神经科学和心理学中的经典例子 显示了不对称性在大脑功能中的重要性。例如，高阶认知能力，例如 语言，空间取向，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侧向缺陷，进一步强调了 横向大脑功能的重要性。毫不奇怪，神经精神疾病通常具有遗传性，并且 因此，可能是一个发展组成部分。这些条件中的大多数也受环境的影响 因素，但是环境如何与连通性互动仍然很大程度上未知。我们已经确定了 线虫炎炎的两对感觉神经元之间的不对称突触连接 庆祝经验的庆祝活动。重要的是，这种连接是控制的细胞 - 裸子 通过胰岛素信号传导从其他细胞中自主，而胰岛素信号转导受经验的调节。这提供了 以分子水平和单细胞分辨率进行调查的范式，环境如何改变 以经验依赖的方式对神经电路进行硬性。该提议的目的是调查 使用秀丽隐杆线虫作为模型系统的这种连接的发展，塑料和功能方面。在 特定目标1，我们将确定经验改变连接的机制。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，并且 足够的细胞。在特定目标2中，我们将确定胰岛素信号在控制中的作用 突触连通性。具体而言，我们将测试哪些胰岛素样激动剂和拮抗剂起作用 细胞影响连通性的变化；受体起作用和遗传环境的位置。最后，在 特定目标3，我们将确定连接性变化如何转化为信息流的变化， 使用全脑钙成像和行为实验的行为。总而言之，我们的研究计划的目标 为了建立机制，环境在这些机制中改变了突触的硬线和行为 不对称突触连接的上下文。