The role of local microcircuits in shaping sensory cortical activity and perception

项目摘要/摘要 皮质功能障碍与许多神经疾病有关，包括癫痫、精神分裂症和 卒中。大多数皮质连接是局部的，这意味着局部微回路应该是主导的。 锥体神经元感受场的贡献者，因此，知觉。皮质微电路主题包括 反复的兴奋和抑制，它调节相似调谐的种群之间的相互作用，与饲料- 前向激发和侧向抑制，它们调节着不同调谐的种群之间的相互作用。 在体内研究这些基序具有挑战性，因为锥体神经元具有不同的功能 调谐通常是混合的，需要细胞分辨率的微扰方法来探测微电路 功能。这一提议的目的是检验局部微电路相互作用塑造神经的假设 自然主义行为中的接受场，这些相互作用有助于感知。我们专注于 小鼠初级触觉躯体感觉皮层(VS1)，来自单个胡须的感觉输入输出到 被称为“桶”的皮质小块，使单独的胡须感觉表征易于处理 到全面记录和随后的干扰。在之前发表的工作中，我们演示了 能够记录和分类桶中大部分层(L)2/3的神经元。在这里，我们提供了初步数据 展示了使用多光子消融来损伤桶中已识别神经元的小亚群的能力， 从而克服了以前对探索重复扩增在 相似的调谐神经元。对单须小鼠的初步实验表明，VS1中的反复兴奋 L2/3放大了神经元对胡须触摸的反应，但不放大那些对胡须运动的反应， 而且这种反复出现的抑制并不会对触摸反应产生可测量的影响。进一步的初步数据 在有两个胡须的小鼠身上发现，来自单一胡须反应神经元的前馈兴奋形成 多晶须反应和交叉晶须抑制在单晶须神经元损伤后下降。 最后，初步的桶级损伤实验调和了该领域最近的争议，并表明 VS1是辨别行为所必需的，但不是检测行为所必需的。我们提出了三个目标来检验1)是否 反复相互作用--神经元的兴奋性和抑制性VS1L2/3反应 晶须；2)调节到不同晶须的L2/3兴奋性触摸神经元是否通过前馈相互作用 激发以产生多晶须感受场，并通过侧抑制来产生交叉晶须 抑制；3)单个VS1桶是否对知觉有贡献，以及L2/3是否反复兴奋 在VS1中有助于感知。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，桶状损伤，以及定量头部固定的小鼠行为。我们的 长期目标是理解感觉微电路计算及其如何塑造知觉。

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.