Administrative Supplement: Reversible activation of critical period plasticity in visual cortex

母公司裁决摘要 弱视在模型系统中由单眼剥夺（MD）诱导，其改变了视觉系统的功能。 初级视皮层神经元的刺激选择性。利用该模型的先前研究 建立了由MD引起的神经选择性的变化是由重组引起的， 兴奋性皮层神经元上的兴奋性突触， 由小清蛋白阳性抑制性中间神经元组成的抑制性GABA能网络 (PV INs）。一个正在形成的共识是， 皮质层2/3是下游兴奋性突触可塑性所必需的， 高于或低于允许范围会限制对MD的响应。因此，委员会认为， 抑制的发育加强触发了关键期的开始;在后期阶段， 抑制的“允许”范围是通过减少PV IN的募集来实现的。 我们提出了一系列多学科的实验来测试这个模型的有效性， 联合收割机结合Quinlan实验室在体内生理变化评估方面的专业知识， 柯克伍德实验室在评估已识别神经元之间单个突触的变化方面的研究。 我们将检验L2/3 Pyr->PV INs兴奋性突触的消除是1） 局部、短暂且局限于出生后关键期2）依赖于mGluR和NPTX 2 信号和3）一个强制性的初始步骤，随后的变化，眼优势， MD诱导的空间视敏度。我们的模型预测，关键时期的结束反映了 直接导致L2/3 Pyr->PV-IN可塑性的丧失，这与许多广泛持有的 关于哺乳动物皮层突触可塑性发育变化的假设。 补充活动，以扩大在母奖（扩大在研究 设计师） 通过锥体神经元的去抑制增强可塑性的模型，包括在 父母奖，假设神经元活动的增加通过以下方式促进可塑性： 相关尖峰然而，在任何模型中都很少有证据支持这一预测 系统，尤其是在体内。这是昆兰实验室的一名新研究生，劳拉·伊克谢尔 Castillo提出，在清醒时测量整个初级视觉皮层的神经元活动， 头部固定小鼠通过长期植入微电极阵列。她会衡量 多个时间点的网络活动、锋电位相关性和锋电位-相位同步性的变化 在小鼠关键期单眼剥夺前后。我们预测 单眼剥夺1天后，我们观察到断开连接的时间点 局部兴奋驱动PV中间神经元，将有成对相关性增加 近端神经元之间和尖峰相位耦合的增加。这将是短暂的， MD 3天后恢复正常对照值。这些预测是一致的， 延长家长奖的工作。

Summary/Abstract of parent award Amblyopia is induced in model systems by monocular deprivation (MD), which changes the stimulus selectivity of neurons in the primary visual cortex. Prior research utilizing this model established that the changes in neural selectivity induced by MD result from the reorganization of excitatory glutamatergic cortical synapses onto excitatory cortical neurons, which is regulated by an inhibitory GABAergic network composed of parvalbumin positive inhibitory interneurons (PV INs). An emerging consensus is that a permissive level of inhibition from PV IN circuits in cortical layer 2/3 is required for plasticity at downstream excitatory synapses, and that inhibition above or below the permissive range constrains the response to MD. Accordingly, developmental strengthening of inhibition triggers the onset of the critical period; at later stages, the “permissive” range of inhibition is achieved by reductions the recruitment of PV INs. We propose a series of multidisciplinary experiments to test the validity of this model that combine the expertise of the Quinlan lab in the assessment of physiological changes in vivo and the Kirkwood lab in the assessment of changes in single synapses between identified neurons. We will test the hypothesis that the elimination of L2/3 Pyr->PV INs excitatory synapses is 1) local, transient and confined to a postnatal critical period 2) dependent on mGluR and NPTX2 signaling and 3) an obligatory initial step for subsequent changes in ocular dominance and spatial acuity induced by MD. Our model predicts that the end of the critical period reflects directly the loss of L2/3 Pyr->PV-IN plasticity, which departs from many widely-held assumptions regarding developmental changes in synaptic plasticity in the mammalian cortex. Supplemental activities to expand the that proposed in the parent award (expanded in research design) Models of enhanced plasticity via disinhibition of pyramidal neurons, including the one tested in the parent award, assume that the increase in neuronal activity promotes plasticity through correlative spiking. However, there is very little evidence to support this prediction in any model system, especially in vivo. Here a new graduate student in the Quinlan lab, Laura Ixchel Castillo, proposes to measure neuronal activity throughout the primary visual cortex in awake head-fixed mice through chronically-implanted micro electrodes arrays. She will measure changes in network activity, spike correlation and spike-phase synchrony at multiple time points before and after monocular deprivation during the mouse critical period. We predict that following 1 day of monocular deprivation, the time point at which we observed the disconnection of local excitatory drive to PV Interneurons, there will be an increase in pairwise correlation between proximal neurons and an increase in spike-phase coupling. This will be transient, and return to normal control values by 3 days of MD. These predictions are consistent with, and extend, the work of the parent award.