The Role of Local Microcircuits in Shaping Sensory Cortical Activity and Perception

局部微电路在塑造感觉皮层活动和感知中的作用

• 批准号: 10613530
• 负责人: Simon Peron
• 金额: $ 34.6万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613530
• 关键词: Ablation; Afferent Neurons; American; Animals; Area; Behavior; Behavioral; Calcium; Classification; Data; Discrimination; Disease; Epilepsy; Excitatory Synapse; Functional disorder; Goals; Head; Image; Individual; Inherited; Interneurons; Lateral; Lesion; Link; Measurable; Mediating; Movement; Mus; Neurons; Output; Perception; Physiological; Population; Public Health; Publishing; Recurrence; Resolution; Role; Schizophrenia; Sensory; Shapes; Somatosensory Cortex; Stroke; Testing; Touch sensation; Vibrissae; Work; barrel cortex; cellular targeting; cost; design; experimental study; hippocampal pyramidal neuron; in vivo; multi-photon; nervous system disorder; neural; novel; receptive field; response; sensory cortex; sensory input; two-photon

PROJECT SUMMARY / ABSTRACT Cortical dysfunction has been implicated in many neurological disorders including epilepsy, schizophrenia, and stroke. The majority of cortical connections are local, implying that local microcircuitry should be a dominant contributor to pyramidal neuron receptive fields and, therefore, perception. Cortical microcircuit motifs include recurrent excitation and inhibition, which mediate interactions between similarly tuned populations, and feed- forward excitation and lateral inhibition, which mediate interactions between distinctly tuned populations. Studying these motifs in vivo has proven challenging because pyramidal neurons with different functional tuning are often intermingled, requiring cellular-resolution perturbation approaches to probe microcircuit function. The objective of this proposal is to test the hypothesis that local microcircuit interactions shape neural receptive fields during naturalistic behavior, and that these interactions contribute to perception. We focus on mouse primary vibrissal somatosensory cortex (vS1), where sensory input from single whiskers outputs onto small patches of cortex known as `barrels', making individual whisker sensory representations tractable targets to comprehensive recording and subsequent perturbation. In previously published work, we demonstrated the ability to record and classify the majority of layer (L) 2/3 neurons in a barrel. Here, we present preliminary data demonstrating the ability to lesion small subsets of identified neurons in a barrel using multiphoton ablation, thereby overcoming the previous constraint on experiments probing the role of recurrent amplification among similarly tuned neurons. Preliminary experiments in single-whisker mice indicate that recurrent excitation in vS1 L2/3 amplifies the responses of neurons tuned to whisker touch, but not of those tuned to whisker movement, and that recurrent inhibition does not exert a measurable effect on touch responses. Further preliminary data in mice with two whiskers reveals that feed-forward excitation from single-whisker responsive neurons shapes multi-whisker responses and that cross-whisker suppression declines following single-whisker neuron lesions. Finally, preliminary barrel-scale lesion experiments reconcile recent controversies in the field and show that vS1 is necessary for discrimination but not detection behaviors. We propose three aims testing 1) whether recurrent interactions – excitatory and inhibitory – shape vS1 L2/3 responses of neurons tuned to the same whisker; 2) whether L2/3 excitatory touch neurons tuned to different whiskers interact via feed-forward excitation to generate multi-whisker receptive fields and via lateral inhibition to produce cross-whisker suppression; 3) whether individual vS1 barrels contribute to perception, and whether L2/3 recurrent excitation in vS1 contributes to perception. The proposed work involves a novel combination of large-scale two-photon calcium imaging, multiphoton ablation, barrel-scale lesions, and quantitative head-fixed mouse behavior. Our long-term goal is to understand sensory microcircuit computations and how they shape perception.

项目总结/摘要 皮质功能障碍与许多神经系统疾病有关，包括癫痫、精神分裂症和精神分裂症。 中风大多数皮层连接是局部的，这意味着局部微电路应该是主导的。 它是锥体神经元感受野的重要组成部分，因此也是感知的重要组成部分。皮层微电路图案包括 经常性的兴奋和抑制，介导类似调谐群体之间的相互作用，和饲料- 前向兴奋和侧抑制，介导明显调谐群体之间的相互作用。 事实证明，在体内研究这些基序具有挑战性，因为具有不同功能的锥体神经元 调谐通常是混合的，需要细胞分辨率微扰方法来探测微电路 功能这项建议的目的是测试假设，局部微电路相互作用塑造神经 自然主义行为的感受野，这些相互作用有助于感知。我们专注于 小鼠初级触须躯体感觉皮层（vS 1），其中来自单个触须的感觉输入输出到 被称为“桶”的小块皮层，使个体胡须的感觉表征成为易处理的目标 到全面的记录和随后的扰动。在以前发表的工作中，我们证明了 记录和分类桶中的大多数层（L）2/3神经元的能力。在这里，我们提供了初步数据， 证明了使用多光子消融来损伤桶中的小的已识别神经元子集的能力， 从而克服了先前对探索复发性扩增作用的实验的限制， 相似的神经元。在单须小鼠中的初步实验表明，vS 1中的反复兴奋 L2/3放大了对触须触摸敏感的神经元的反应，但对触须运动敏感的神经元的反应没有放大， 并且复发性抑制对触摸反应没有可测量的影响。进一步的初步数据 在有两个胡须的小鼠中显示，来自单胡须反应神经元形状的前馈激发 多须反应和单须神经元损伤后交叉须抑制下降。 最后，初步的桶规模损伤实验调和了该领域最近的争议，并表明， vS 1是辨别行为所必需的，而不是检测行为所必需的。我们提出了三个目标测试1）是否 周期性相互作用-兴奋性和抑制性-形状vS 1 L2/3响应的神经元调谐到相同的 2）L2/3兴奋性触觉神经元是否通过前馈相互作用 激发产生多须感受野，通过侧抑制产生交叉须 抑制; 3）单个vS 1桶是否有助于感知，以及L2/3是否经常性兴奋 vs 1有助于感知。拟议的工作涉及一种新的大规模双光子组合 钙成像、多光子消融、桶级损伤和定量头部固定小鼠行为。我们 长期目标是了解感觉微电路计算以及它们如何塑造感知。