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: 10222797
• 负责人: Simon Peron
• 金额: $ 34.73万
• 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/10222797
• 关键词: Ablation; Afferent Neurons; American; Animals; Area; Behavior; Behavioral; Calcium; 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; base; cellular targeting; cost; design; experimental study; hippocampal pyramidal neuron; in vivo; nervous system disorder; novel; receptive field; relating to nervous system; response; 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.

项目概要/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 中风。大多数皮质连接是局部的，这意味着局部微电路应该是主要的 锥体神经元感受野的贡献者，因此，感知。皮质微电路图案包括 反复的兴奋和抑制，介导相似调整的群体之间的相互作用，以及饲料 前向兴奋和侧向抑制，介导明显调谐的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 调谐经常混合在一起，需要细胞分辨率微扰方法来探测微电路 功能。该提案的目的是测试局部微电路相互作用塑造神经网络的假设 自然行为期间的感受野，并且这些相互作用有助于感知。我们专注于 小鼠初级触须体感皮层（vS1），其中来自单个胡须的感觉输入输出到 被称为“桶”的小块皮层，使单个胡须的感官表征成为易于处理的目标 进行全面记录和随后的扰动。在之前发表的作品中，我们展示了 能够记录和分类桶中大多数层 (L) 2/3 神经元。在此，我们提供初步数据 展示了使用多光子消融对桶中已识别神经元的小子集进行损伤的能力， 从而克服了先前对探索循环放大作用的实验的限制 类似地调整神经元。单晶须小鼠的初步实验表明，vS1 中的反复兴奋 L2/3 放大了针对胡须触摸的神经元的反应，但不放大针对胡须运动的神经元的反应， 并且反复抑制不会对触摸反应产生可测量的影响。进一步的初步数据 在长有两根胡须的小鼠中，单胡须响应神经元的前馈激发会形成形状 多晶须反应以及单晶须神经元损伤后交叉晶须抑制下降。 最后，初步的桶状损伤实验解决了该领域最近的争议，并表明 vS1 对于辨别行为是必要的，但对于检测行为不是必需的。我们提出三个目标测试 1) 是否 反复相互作用 – 兴奋性和抑制性 – 调整神经元的 vS1 L2/3 反应 胡须； 2）L2/3兴奋性触觉神经元是否通过前馈调节到不同的胡须相互作用 激发产生多晶须感受野，并通过侧抑制产生交叉晶须 抑制; 3）单个vS1桶是否有助于感知，以及L2/3循环激励是否 vS1 有助于感知。所提出的工作涉及大规模双光子的新颖组合 钙成像、多光子消融、桶状损伤和定量头部固定小鼠行为。我们的 长期目标是了解感觉微电路计算以及它们如何塑造感知。