Dynamic Homeostatic Plasticity within Cerebellar Circuitry

获取外部世界新知识、记住这些知识并利用这些信息做出适当和适应性行为的能力背后的机制，是人类长期以来的兴趣所在。神经元之间突触连接的经验依赖可塑性被普遍认为是神经回路获取和存储新信息的细胞机制，通常被称为学习和记忆。本项目研究调节突触可塑性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和接近缺乏活动的可塑性能力的机制。如此复杂的体内平衡任务是如何在大脑中完成的，人们知之甚少。在这里，这些自我平衡机制在mormyrid鱼的小脑中进行了研究，其小脑回路及其输出和输入都是明确的，可以进行详细的检查。结合电生理、成像和药理学方法，研究人员描述了小脑浦肯野细胞在突触输入长期增强和长期抑制期间输入/输出关系的变化，并开始阐明其潜在机制。研究结果将对理解学习和记忆的神经基础具有广泛的意义。该项目还涉及到西雅图地区的小学和中学，教授电鱼的行为可塑性。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，通常被称为学习和记忆。研究最多的可塑性形式包括长期增强（LTP）和抑郁（LTD）。Hebbian可塑性在一个正循环中运作，导致失控的神经元活动，并需要额外的补偿过程来稳定神经回路。许多形式的内稳态可塑性被认为提供了这种补偿作用。然而，与Hebbian突触可塑性不同，证明形式的稳态可塑性需要非常不同的时间过程来诱导（数小时到数天与秒到分钟）。此外，模型研究表明，在实验中观察到的稳态塑性的缓慢进化不足以防止Hebbian塑性的不稳定。该项目研究了快速的代偿性突触过程，该过程可能潜在地防止与Hebbian可塑性的正反馈性质相关的不稳定性。研究者使用双全细胞记录对小脑切片修复，发现浦肯野细胞输出突触到其靶细胞上的强度分别在同一细胞输入突触的LTD和LTP后上调和下调。在这里，体外电生理、成像和药理学方法的结合扩展了这些观察结果，以检查细胞输入突触在Hebbian可塑性后的输出传递的双向调节的特征和机制。建立这种快速、动态的稳态可塑性及其潜在机制将对突触可塑性的基本过程产生有价值的见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.