Rapid inhibitory circuit plasticity as a homeostatic mechanism in cerebral cortex

经验有力地调节大脑中GABA能抑制回路的发育和功能 但这种抑制回路可塑性的目的尚不清楚。啮齿动物躯体感觉的最新发现 (S1)和视觉皮质提示抑制可塑性可能有助于放电的动态平衡稳定 大脑皮层网络中的比率。我们最近发现，在S1的竞争性MAP可塑性过程中，感觉 剥夺会非常迅速地削弱小白蛋白(PV)抑制回路(&lt；1天)。这比古典音乐快多了 动态平衡机制，如突触伸缩，并促进S1网络中的放电率稳定性。我们 提出光伏电路可塑性作为一个快速的双向恒定器，在时间尺度上运行 它的作用是稳定大脑皮层的放电率。我们认为，它通过自适应地实现这一点 局部锥体细胞PV电路增益和激发抑制比(E-I)随新近的变化 网络活动历史记录。这种快速抑制可塑性可能是控制脑内放电频率的主要因素。 大脑皮层。 在这里，我们使用小鼠晶须S1皮层的L2/3作为模型系统来检验这一假设。在目标1中， 我们使用切片生理学和特定层光遗传学来测量胡须剥夺如何改变 L4-L2/3前馈和L2/3-L2/3循环抑制回路，并量化这种可塑性的动力学。 我们测试了锥体细胞放电速率的直接化学发生调制是否会诱导抑制电路 可塑性，这是否是双向的，以及是否在大脑皮层区域普遍存在。在目标2中，我们使用DUAL 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)回路的可塑性。在目标3中，我们使用双光子钙成像和慢性 细胞外单位记录表征L2/3放电频率的动态平衡，测定其幅度和 年龄动态，并测量其与抑制回路可塑性的关系。 抑制动态平衡的破坏可能导致自闭症、精神分裂症、 和其他障碍。在目标4中，我们通过询问抑制性或抑制性动态平衡来检验这一假设 在几个自闭症转基因小鼠模型中，大脑皮质中的这种基因被破坏。初步数据显示，在四种遗传无关的小鼠模型中，兴奋-抑制比率共同受到干扰。这提供了关键 支持自闭症长期持有的E-I比率模型。总体而言，该项目将揭示抑制电路 可塑性是皮层放电率快速稳态的重要机制，它的破坏是否 可能会导致神经系统疾病。

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.