Dynamic Homeostatic Plasticity within Cerebellar Circuitry

小脑回路内的动态稳态可塑性

• 批准号: 1929489
• 负责人: Victor Han
• 金额: $ 60万
• 依托单位: University of Washington
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1929489&HistoricalAwards=false
• 关键词: Dynamic; Homeostatic; Plasticity; within; Cerebellar

The mechanisms that underlie the ability to acquire new knowledge about the external world, to remember it, and to use the information to behave appropriately and adaptively is a long-standing interest of humankind. Experience-dependent plasticity of the synaptic connections between neurons is generally accepted as the cellular mechanism with which a neural circuitry acquires and stores new information, commonly known as learning and memory. This project studies the homeostatic mechanisms that regulate the positive feedback nature of synaptic plasticity, that is, the mechanisms that bound activity levels within an appropriate dynamic range to preserve the ability of plasticity near saturation of activity as well as near absence of activity. How such complex homeostatic tasks are accomplished in the brain is poorly understood. Here, these homeostatic mechanisms are studied in the cerebellum of the mormyrid fish, whose cerebellar circuitry as well as its outputs and inputs are well defined and accessible for detailed examination. Using a combination of electrophysiological, imaging, and pharmacological approaches, the investigators characterize changes in the input/output relationships of cerebellar Purkinje cells during long-term potentiation and long-term depression of synaptic input to these cells, and begin to elucidate the underlying mechanisms. The results will have broad implications for understanding of the neural substrates of learning and memory. The project also involves outreach to Seattle area elementary and middle schools, to teach about behavioral plasticity of electric fish. Synaptic plasticity is generally accepted as the cellular mechanism with which a neural circuitry acquires and stores new information, commonly known as learning and memory. The most studied forms of plasticity include Hebbian long-term potentiation (LTP) and depression (LTD). Hebbian plasticity operates in a positive loop, leading to runaway neuronal activity and requiring additional compensatory processes to stabilize the neural circuitry. Many forms of homeostatic plasticity have been suggested as providing such compensatory role. However, unlike Hebbian synaptic plasticity, the demonstrated forms of homeostatic plasticity require very different time courses to be induced (hours to days versus seconds to minutes). Furthermore, modeling studies suggest that the slow evolution of homeostatic plasticity observed in experiments is insufficient to prevent instabilities of Hebbian plasticity. This project examines rapid, compensatory synaptic processes that could potentially prevent the instabilities associated with the positive feedback nature of Hebbian plasticity. Using dual whole-cell recording in slice reparations of the mormyrid cerebellum, the investigator has found that the strength of a Purkinje cells output synapses onto their target cells is up- and downregulated following LTD and LTP at the same cell’s input synapses, respectively. Here, a combination of in-vitro electrophysiological, imaging, and pharmacological approaches extend these observations to examine the characteristics and mechanisms underlying this bidirectional regulation of a cell’s output transmission following Hebbian plasticity at its input synapses. Establishment of this form of rapid, dynamic homeostatic plasticity and its underlying mechanisms will yield valuable insights into elementary processes of synaptic plasticity.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

获得关于外部世界的新知识，记住它，并使用信息以适当和适应性地行为的能力的基础机制是人类的长期兴趣。神经元之间突触连接的经验依赖性可塑性通常被认为是神经回路获取和存储新信息的细胞机制，通常称为学习和记忆。本项目研究调节突触可塑性的正反馈性质的稳态机制，即将活动水平限制在适当的动态范围内以保持活动接近饱和以及活动接近缺失的可塑性能力的机制。人们对大脑如何完成如此复杂的自我平衡任务知之甚少。在这里，这些稳态机制的研究在小脑的mormyrid鱼，其小脑电路，以及其输出和输入的定义和访问详细的检查。使用电生理学，成像和药理学的方法相结合，研究人员的特点在小脑浦肯野细胞的输入/输出关系的变化，在长时程增强和长时程抑制突触输入这些细胞，并开始阐明潜在的机制。这些结果将对理解学习和记忆的神经基质产生广泛的影响。 该项目还涉及到西雅图地区的小学和中学，教授有关电鱼的行为可塑性。突触可塑性通常被认为是神经回路获取和存储新信息的细胞机制，通常称为学习和记忆。研究最多的可塑性形式包括Hebbian长时程增强（LTP）和抑制（LTD）。赫布可塑性在正循环中运作，导致神经元活动失控，需要额外的补偿过程来稳定神经回路。许多形式的稳态可塑性被认为提供了这种补偿作用。然而，与赫布突触可塑性不同的是，所展示的稳态可塑性形式需要非常不同的时间过程来诱导（数小时到数天与数秒到数分钟）。此外，建模研究表明，在实验中观察到的稳态可塑性的缓慢演变是不足以防止赫布可塑性的不稳定性。本项目研究快速，补偿性突触过程，可能会防止与赫布可塑性的正反馈性质相关的不稳定性。使用双全细胞记录在切片修复的海马小脑，研究人员发现，浦肯野细胞输出突触到其靶细胞的强度上调和下调后，LTD和LTP在同一个细胞的输入突触，分别。在这里，在体外电生理，成像和药理学方法的组合扩展这些观察，以检查这种双向调节细胞的输出传输后，在其输入突触的赫布可塑性的特点和机制。建立这种形式的快速，动态稳态可塑性及其潜在机制将产生有价值的见解突触plasticity.This奖项反映了NSF的法定使命的基本过程，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

项目成果

Diversity of cellular physiology and morphology of Purkinje cells in the adult zebrafish cerebellum

• DOI: 10.1002/cne.25435
• 发表时间: 2023-02-01
• 期刊: JOURNAL OF COMPARATIVE NEUROLOGY
• 影响因子: 2.5
• 作者: Magnus，Gerhard;Xing，Junling;Han，Victor Z. Z.
• 通讯作者: Han，Victor Z. Z.