Reversible activation of critical period plasticity in visual cortex

项目摘要/摘要 在模型系统中，弱视是由单眼剥夺(MD)引起的，它改变了刺激的选择性 初级视觉皮质中的神经元。之前利用这一模型的研究证实， MD诱导的神经选择性是兴奋性谷氨酸能皮质突触重组的结果 兴奋性皮质神经元，这是由抑制性GABA能网络调节的，由 小白蛋白阳性抑制性中间神经元(PV INS)。一个正在形成的共识是，允许的水平 为了下游兴奋性突触的可塑性，大脑皮层2/3层的PV IN回路需要抑制， 而高于或低于允许范围的抑制限制了对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， “允许”的抑制范围是通过减少PV INS的招募来实现的。 在这里，我们将2/3层PV INS上的激发可塑性确定为调节电路的关键位置 V1中的重组。我们的初步数据表明，对MD的初始反应是快速和瞬时的 消除局部锥体神经元(PYR)与PV INS的兴奋性联系。在下列日期后1天 MD，我们发现大约50%的本地L2/3PyràPV-IN连接被消除。重要的是，来自远端的突触 L2/3PIR和来自第四层PIRS的激发保持不变。这种要么全有要么全不消除的特定 连接与突触结构的丧失一致，是一过性的，并在3之后恢复到控制值 医学博士的日子。我们的初步结果还表明，MD诱导的近端L2/3的消除 PYRàPV INS的输入依赖于mGluR5的激活，并被活性非依赖性表达所抑制 神经元性五肽2(NPTX2)。我们认为依赖mGluR5和NPTX2的局部快速消除 L2/3PYRàPV INS连接是随后眼优势改变的强制性初始步骤 MD诱导的空间敏感度。因此，我们表明，NPTX2的积累可以防止L2/3PyràPV in 消除和眼优势可塑性。相反，显性负性NPTX2在成人中的表达 重新激活对MD的L2/3 PiraPV INS的消除和眼优势可塑性 我们提出了一系列多学科的实验来测试该模型的有效性，该模型结合了 昆兰实验室在评估活体生理学和柯克伍德的生理变化方面的专业知识 实验室对已识别神经元之间单个突触的变化进行评估。我们将检验这一假设 L2/3PyràPV INS兴奋性突触的消除是局部的、短暂的，并且局限于出生后 关键期2)依赖于mGluR和NPTX2信号，以及3)后续的强制性初始步骤 MD引起的眼优势和空间视力的改变。我们的模型预测，关键的 周期直接反映了L2/3PiraPV-In可塑性的丧失，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。

Project Summary/Abstract 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. Here we identify the plasticity of excitation onto layer 2/3 PV INs as a critical locus for the regulation of circuit reorganization in V1. Our preliminary data demonstrate that the initial response to MD is a rapid and transient elimination of excitatory connections made by local pyramidal neurons (Pyr) onto PV INs. Following 1 day of MD, we find that ~50% of local L2/3 PyràPV-IN connections are eliminated. Importantly, synapses from distal L2/3 Pyrs and excitation from layer 4 Pyrs remains unchanged. This all-or-none elimination of specific connections coincides with the loss of synaptic structure, is transient, and returns to control values following 3 days of MD. Our preliminary results also demonstrate that the MD-induced elimination of proximal L2/3 PyràPV INs inputs depends on mGluR5 activation and is inhibited by expression of activity-independent neuronal pentraxin 2 (NPTX2). We propose that the rapid mGluR5 and NPTX2-dependent elimination of local L2/3 PyràPV INs connection is an obligatory initial step for subsequent changes in ocular dominance and spatial acuity induced by MD. Accordingly, we show that accumulation of NPTX2 prevents L2/3 PyràPV IN elimination and ocular dominance plasticity. Conversely, expression of dominant negative NPTX2 in adults reactivates the elimination of L2/3 PyràPV INs and ocular dominance plasticity in response to MD 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 physiology 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 Pyrà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 PyràPV-IN plasticity, which departs from many widely-held assumptions regarding developmental changes in synaptic plasticity in the mammalian cortex.