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

家长奖励摘要/摘要 弱视是由单眼剥夺(MD)在模型系统中诱导的，它改变了 初级视皮层神经元的刺激选择性。使用该模型的先前研究 证实MD引起的神经选择性的改变是重组的结果 兴奋性谷氨酸能皮质突触连接到兴奋性皮质神经元，这是受调控的 由小白蛋白阳性抑制性中间神经元组成的抑制性GABA能网络 (PV Ins)。一个新出现的共识是，在电路中允许的PV In抑制水平 皮质2/3层是下游兴奋性突触可塑性所必需的，而这种抑制 高于或低于允许范围会限制对MD的反应。因此， 发育加强的抑制触发了关键期的开始；在以后的阶段， 抑制的“允许”范围是通过减少PV INS的招募来实现的。 我们提出了一系列多学科的实验来测试该模型的有效性 结合昆兰实验室在评估体内生理变化和 柯克伍德实验室对已识别神经元之间单一突触的变化进行了评估。 我们将检验这样的假设，即L2/3PYR-&GT；PV INS兴奋性突触的消除为1) 局部、短暂和受限于出生后关键期2)取决于mGluR和NPTX2 发出信号和3)随后眼睛优势改变的强制性初始步骤和 MD诱导的空间敏感度。我们的模型预测，关键时期的结束反映了 L2/3PYR-&>PV-in塑性的直接损失，这与许多广泛持有的观点不同 哺乳动物大脑皮层突触可塑性发育变化的假设。 补充活动，以扩大父母奖中建议的活动(在研究中扩大 设计) 通过抑制锥体神经元来增强可塑性的模型，包括在 家长奖，假设神经元活动的增加通过 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，尤其是在活体内。图为昆兰实验室的一名新研究生劳拉·伊克谢尔 Castillo建议在清醒状态下测量整个初级视皮层的神经元活动 通过长期植入微电极阵列的头部固定小鼠。她将测量 多个时间点的网络活动、尖峰相关性和尖峰相位同步的变化 小鼠关键期单眼剥夺前后的变化。我们预测 在单眼剥夺1天后，我们观察到连接断开的时间点 对PV中间神经元的局部兴奋驱动，将增加成对相关性。 近端神经元之间的相互作用和尖峰相耦合的增加。这将是暂时的，而且 在MD的3天内恢复到正常控制值。这些预测与，以及 延伸，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.