Single-cell computation in auditory brainstem and its impact on cortical coding and behavior

听觉脑干中的单细胞计算及其对皮质编码和行为的影响

• 批准号: 10455326
• 负责人: Nace L Golding
• 金额: $ 10.06万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455326
• 关键词: Anatomy; Animals; Auditory; Auditory Perception; Auditory area; Auditory system; Axon; Behavior; Behavioral; Binding; Biological Models; Biophysics; Brain; Brain Stem; Brain imaging; Cell physiology; Cells; Cochlea; Cochlear nucleus; Code; Complex; Computer Models; Computing Methodologies; Data; Decision Making; Dendrites; Detection; Disease; Ear; Electron Microscopy; Electrophysiology (science); Elements; Experimental Models; Frequencies; Gene Expression Profiling; Goals; Head; Hearing; Image; In Vitro; Individual; Inferior Colliculus; Learning; Link; Methods; Midbrain structure; Modeling; Molecular; Molecular Analysis; Morphology; Mouse Strains; Mus; Neurons; Octopus; Output; Pattern; Perception; Performance; Physiological; Physiology; Play; Population; Positioning Attribute; Process; Property; Psychometrics; Resolution; Role; Sensory; Shapes; Speech; Stimulus; Stream; Study models; Synapses; System; Testing; Thalamic structure; Time; Training; Translating; Travel; Whole-Cell Recordings; Work; auditory pathway; auditory thalamus; awake; base; biophysical analysis; brain cell; cell type; confocal imaging; experimental study; in vivo; insight; millisecond; multidisciplinary; nervous system disorder; neuronal circuitry; novel strategies; optogenetics; parallel processing; patch sequencing; predictive modeling; reconstruction; response; sensory input; sensory mechanism; sensory system; sound; spatiotemporal; spiral ganglion; success; tool; transcriptome sequencing; two-photon; voltage

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.

项目摘要 理解神经元计算如何建立对外部世界的感知是我们研究的基础。 了解大脑是如何工作的这与感觉系统特别相关，在感觉系统中， 代表不同感觉特征的输入必须被重新组合以产生感知。如何个性化 感觉回路早期阶段的神经元处理并行输入，以及这些回路元件后来如何贡献 大脑皮层的计算是完全未知的。研究已经证明 给定输入沿着给定神经元的树突的定时、位置和强度是所使用的关键策略 来编码感官特征。然而，如何在单个神经元中的输入的这种树突整合， 对动物整体感知的贡献还不清楚。 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 发生在同一时间目前，很少有人知道如何或在哪里可以编码这种定时信息。 听觉系统以其跨学科的易处理性为解决这一问题提供了一个理想的系统 方法及其已知的编码能力，即使是微小的时间差异。具体来说，我们将利用 一种独特的细胞类型在听觉耳蜗核，称为章鱼细胞，作为研究这个问题的模型， 小细胞类如何对行为和感知回路做出贡献。章鱼细胞在所有的 哺乳动物物种，并且众所周知通过以下方式以亚毫秒精度编码时间输入： 初级感觉输入沿着其大而广泛的树突的整合。我们建议开展一项多- 实验室，章鱼细胞的分子和生物物理特性的综合分析，并跟踪这些单一的 细胞计算沿着听觉通路进行转换，以促进动物最终的听觉感知 因此行为也是如此。使用小鼠作为模型系统，我们将应用新的测序方法， 高分辨率脑成像和单细胞重建，以创建一个全面的布线图， 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场所，因此可以 实验和计算模型的时序信息是如何编码在单细胞水平。最后我们 将研究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 for auditory听觉behavior行为.通过利用分子、生物物理、电生理、行为和计算 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的一般原则， 单细胞计算及其对系统级电路功能的影响，具有广泛的影响， 理解平行的信息流是如何被整合以产生感官知觉的。