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Rapid inhibitory circuit plasticity as a homeostatic mechanism in cerebral cortex

快速抑制回路可塑性作为大脑皮层的稳态机制

基本信息

批准号：
10318639
负责人：
Daniel Feldman
金额：
$ 34.41万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2023-11-30
项目状态：
已结题

项目摘要

Experience robustly regulates the development and function of GABAergic inhibitory circuits in cerebral cortex, but the purpose of this inhibitory circuit plasticity is unclear. Recent findings in rodent somatosensory (S1) and visual cortex suggest that inhibitory plasticity may contribute to homeostatic stabilization of firing rate in cortical networks. We recently discovered that during competitive map plasticity in S1, sensory deprivation weakens parvalbumin (PV) inhibitory circuits very rapidly (< 1 day). This is faster than classical homeostatic mechanisms like synaptic scaling, and promotes firing rate stability in the S1 network. We propose that PV circuit plasticity functions as a rapid, bidirectional homeostat, operating on the time scale of hours, and that its role is to stabilize cortical firing rate. We propose that it accomplishes this by adaptively altering PV circuit gain and excitation-inhibition (E-I) ratio in local pyramidal cells as a function of the recent history of network activity. This rapid inhibitory plasticity may be a major contributor to controlling firing rate in cerebral cortex. Here, we test this hypothesis, using L2/3 of mouse whisker S1 cortex as a model system. In Aim 1, we use slice physiology and layer-specific optogenetics to measure how whisker deprivation alters the gain of L4-L2/3 feedforward and L2/3-L2/3 recurrent inhibitory circuits, and quantify the dynamics of this plasticity. We test whether direct chemogenetic modulation of pyramidal cell firing rate induces inhibitory circuit plasticity, whether this is bidirectional, and whether it is general across cortical areas. In Aim 2, we use dual whole-cell recording to identify the specific synaptic and cellular changes that mediate rapid inhibitory plasticity in PV and Somatostatin (SOM) circuits. In Aim 3, we use 2-photon calcium imaging and chronic extracellular unit recording to characterize firing rate homeostasis in L2/3, determine its magnitude and dynamics across age, and measure its relationship to inhibitory circuit plasticity. Breakdown of inhibitory homeostasis could contribute to circuit dysfunction in autism, schizophrenia, and other disorders. In Aim 4, we test this hypothesis by asking whether inhibition or inhibitory homeostasis is disrupted in cortex in several transgenic mouse models of autism. Preliminary data show that excitation-inhibition ratio is disrupted in common across four genetically unrelated mouse models. This provides key support for the long-held E-I ratio model of autism. Overall, this project will reveal whether inhibitory circuit plasticity is an important mechanism for rapid homeostasis of cortical firing rate, and whether its disruption may contribute to neurological disease.

经验有力地调节大脑中 GABA 能抑制回路的发育和功能皮层，但这种抑制电路可塑性的目的尚不清楚。啮齿动物体感的最新发现（S1）和视觉皮层表明抑制可塑性可能有助于放电的稳态稳定皮质网络中的速率。我们最近发现，在 S1 的竞争性地图可塑性过程中，感官剥夺会非常迅速地（< 1 天）削弱小清蛋白 (PV) 抑制回路。这比经典更快突触缩放等稳态机制，并促进 S1 网络中放电率的稳定性。我们提出光伏电路可塑性充当快速、双向稳态器，在时间尺度上运行小时，并认为其作用是稳定皮质放电率。我们建议它通过自适应地实现这一点改变局部锥体细胞中的光伏电路增益和激励抑制（E-I）比作为最近的函数网络活动的历史记录。这种快速的抑制可塑性可能是控制燃烧速率的主要因素。大脑皮层。在这里，我们使用小鼠胡须 S1 皮层的 L2/3 作为模型系统来测试这个假设。在目标 1 中，我们使用切片生理学和层特异性光遗传学来测量胡须剥夺如何改变增益 L4-L2/3 前馈和 L2/3-L2/3 循环抑制电路，并量化这种可塑性的动态。我们测试锥体细胞放电率的直接化学遗传学调节是否诱导抑制电路可塑性，这是否是双向的，以及是否是跨皮质区域的普遍现象。在目标 2 中，我们使用双全细胞记录以确定介导快速抑制的特定突触和细胞变化 PV 和生长抑素 (SOM) 电路中的可塑性。在目标 3 中，我们使用 2 光子钙成像和慢性细胞外单位记录来表征 L2/3 中的放电率稳态，确定其大小和跨年龄的动态，并测量其与抑制电路可塑性的关系。抑制性稳态的破坏可能导致自闭症、精神分裂症、和其他疾病。在目标 4 中，我们通过询问抑制或抑制性稳态来检验这一假设在几种自闭症转基因小鼠模型中，大脑皮层受到破坏。初步数据显示，四种遗传不相关的小鼠模型的兴奋抑制比均受到破坏。这提供了关键支持长期持有的自闭症 E-I 比率模型。总的来说，这个项目将揭示抑制电路是否可塑性是皮质放电率快速稳态的重要机制，及其是否被破坏可能会导致神经系统疾病。