Single-Cell Computation in Auditory Brainstem and its Impact on Cortical Coding and Behavior

项目摘要 了解神经元计算如何建立对外部世界的感知是我们 了解大脑是如何工作的。这与感觉系统尤其相关，在感觉系统中，异质性 代表不同感觉特征的输入必须重新组合才能产生感知。如何个性化 感觉回路早期阶段的神经元处理平行输入，以及这些回路元件后来是如何起作用的 将输入绑定在一起的皮质计算是完全未知的。研究表明， 所使用的关键策略是沿给定神经元的树突的给定输入的时间、位置和强度 由大脑对感觉特征进行编码。然而，在单个神经元中输入的树突整合是如何 有助于动物的整体感知是不被理解的。 为了从相同的初始刺激中重新组合不同的特征，大脑需要确定哪些特征 同时发生的。目前，人们对这种定时信息可能如何或在哪里编码知之甚少。 听觉系统提供了一个理想的系统来解决这个问题，基于它对跨学科的处理能力。 方法及其已知的对时间上的微小差异进行编码的能力。具体地说，我们将利用 听觉耳蜗核中一种独特的细胞类型，称为章鱼细胞，作为研究这一问题的模型 小细胞类如何对行为和知觉回路做出贡献。章鱼细胞在所有 哺乳动物物种和众所周知的编码时间输入以亚毫秒精度通过 初级感觉输入沿其大而广泛的树突整合。我们建议开展一项多层次的 实验室，综合分析章鱼细胞的分子和生物物理性质，并追踪这些单一的 细胞计算沿着听觉通路进行转换，以促进动物的最终听觉感知 以及由此产生的行为。以鼠标为模型系统，我们将应用新的排序方法以及 高分辨率脑成像和单细胞重建，以创建全面的接线图 章鱼细胞及其听觉输入。通过产生选择性接触章鱼细胞的小鼠品系，我们将 是研究章鱼细胞体外和体内生理学的理想位置，因此桥 如何在单个信元级别对定时信息进行编码的实验和计算模型。最后，我们 将研究计时信息是如何通过记录大量的 中脑、丘脑和皮质的神经元，然后评估时间编码的功能相关性 用于听觉行为。通过利用分子、生物物理、电生理、行为和计算 对于这种模型细胞类型的研究方法，这些研究将使我们能够提取出 单胞计算及其对系统级电路功能的影响 了解平行信息流是如何整合以产生感官知觉的。

Project Abstract Understanding how neuronal computations build up a perception of the external world is fundamental to our understanding of how the brain works. This is particularly relevant to sensory systems, where heterogenous inputs representing distinct sensory features must be re-assembled to generate a perception. How individual neurons in early stages of sensory circuits process parallel inputs, and how these circuit elements later contribute to cortical computations that bind the inputs together is completely unknown. Studies have demonstrated that the timing, position and strength of a given input along the dendrite of a given neuron is a critical strategy used by the brain to encode sensory features. However, how such dendritic integrations of inputs in single neurons contribute to an animal's overall perception is not understood. To re-assemble diverse features from the same initial stimulus, the brain needs to determine which features occurred at the same time. Currently, little is known about how or where this timing information might be encoded. The auditory system offers an ideal system to tackle this question based on its tractability to interdisciplinary methods and its known ability to encode even miniscule differences in timing. Specifically, we will take advantage of a unique cell type in the auditory cochlear nucleus, called octopus cells, as a model to investigate the question of how small cell classes contribute to behavioral and perceptual circuits. Octopus cells are prominent in all mammalian species and are well known to encode temporal inputs with submillisecond precision through integration of primary sensory inputs along their large and extensive dendrites. We propose to carry out a multi- lab, integrated analysis of the molecular and biophysical properties of octopus cells and to track how these single cell computations are transformed along the auditory pathway to contribute to an animal's final auditory percept and hence behavior. Using the mouse as a model system, we will apply new sequencing methods together with high resolution brain imaging and single cell reconstructions to create a comprehensive wiring diagram of octopus cells and their auditory inputs. By generating mouse strains for selective access to octopus cells, we will be ideally positioned to investigate the in vitro and in vivo physiology of octopus cells and therefore bridge experimental and computational models for how timing information is encoded at the single cell level. Lastly, we will study how timing information propagates to higher auditory centers by recording from large populations of neurons in the midbrain, thalamus, and cortex and then assessing the functional relevance of temporal coding for auditory behavior. By leveraging molecular, biophysical, electrophysiological, behavioral, and computational approaches toward the study of this model cell type, these studies will allow us to extract general principles of single cell computations and their effects on systems-level circuit function, with broad implications for understanding how parallel streams of information are integrated to generate sensory perception.