The circuit basis for rapid disinhibition during whisker map plasticity in rodent somatosensory cortex

描述(申请人提供)：感觉体验如何调节大脑皮层的回路功能？这个问题在啮齿类动物的躯体感觉(S1)皮层中已经得到了深入的研究，其中胡须经验或剥夺在层(L)2/3的胡须感受野MAP中驱动可塑性，其基础已经在电路和突触水平上进行了研究。大多数以前的工作都集中在兴奋回路上，它经历了经典的Hebbian可塑性，以回应胡须被剥夺。然而，最近的工作表明，经验也推动了晶须剥夺后L2/3中抑制(去抑制)的快速减少，这是晶须映射可塑性的主要新步骤。我们还不清楚快速去抑制的电路基础，包括涉及哪些投射和突触，以及去抑制如何在体内影响感觉反应。在这里，我建议确定S1内快速解除抑制的突触和回路基础。我将使用全细胞神经生理学和光遗传学技术来确定快速去抑制是主要发生在L2/3的前馈输入中，还是发生在L2/3循环回路中，然后识别其功能因剥夺而改变的特定突触。这些记录将在转基因小鼠中进行，转基因小鼠带有小白蛋白(PV)阳性神经元，并被荧光标记以进行有效的靶向记录。接下来，我将利用硅四极管的记录，确定快速解除抑制是否会在活体内产生可检测到的S1神经元放电频率或感受野的变化 在麻醉的小鼠身上。最后，我将确定前馈和递归L2/3电路是否在 脆性X综合征模型小鼠Fmr1-/-对胡须剥夺的反应是快速解除抑制。这些实验将提供(1)电路级别的描述，(2)L2/3中哪些抑制电路，(2)以及哪些特定的突触，介导胡须剥夺后的快速去抑制，(3)电路水平去抑制在野生型小鼠中的相关描述，以及(4)在Fmr1/-小鼠中快速去抑制的电路水平描述。这一结果将进一步加深我们对正常大脑在发育、损伤和学习过程中对感觉输入变化的反应，并将为神经疾病--脆性X综合征的调节失调提供见解。这一结果也将与其他几种E-I比率异常的神经发育障碍有关，如癫痫、自闭症谱系障碍和慢性疼痛。这项提议将给我提供宝贵的光遗传学和电生理培训，这些培训将建立在我之前在可塑性方面的分子专业知识的基础上，为我的独立研究生涯奠定基础。

DESCRIPTION (provided by applicant): How does sensory experience regulate circuit function in the cerebral cortex? This question has been intensively studied in rodent somatosensory (S1) cortex, where whisker experience or deprivation drive plasticity in the whisker receptive field map in layer (L) 2/3, whose basis has been studied at circuit and synaptic levels. Most prior work has focused on excitatory circuits, which undergo classical Hebbian plasticity in response to whisker deprivation. However, recent work shows that experience also drives a rapid reduction in inhibition (disinhibition) in L2/3 following whisker deprivation, which is a major novel step in whisker map plasticity. We do not yet understand the circuit basis for rapid disinhibition, including which projections and synapses are involved, and how disinhibition functionally affects sensory responses in vivo. Here I propose to determine the synaptic and circuit basis of rapid disinhibition within S1. I will use whole-cell neurophysiology and optogenetic techniques to identify whether rapid disinhibition occurs primarily in feed-forward inputs to L2/3, or in L2/3 recurrent circuits, and then to identify the specific synapses whose function is altered by deprivation. These recordings will be performed in transgenic mice with parvalbumin (PV)-positive interneurons fluorescently labeled for efficient targeted recordings. Next, I will determine whether rapid disinhibition produces detectable changes in firing rates or receptive fields of S1 neurons in vivo, using silicon tetrode recordings in anesthetized mice. Finally, I will determine whether feed-forward and recurrent L2/3 circuits in the Fragile X syndrome model mouse, Fmr1 -/-, undergo rapid disinhibition in response to whisker deprivation. These experiments will provide (1) a circuit-level description of which inhibitory circuits in L2/3, (2) and which specific synapses, mediate rapid disinhibiton following whisker deprivation and (3) a description of the spiking correlates of circuit-level disinhibition n the wildtype mouse, and (4) a circuit-level description of rapid disinhibition in the Fmr1 -/- mouse. The results will further our understanding of how the brain responds to changes in sensory input that occur in normal brains during development, injury, and learning and will provide insight on dysregulation in the neurological disorder, Fragile X syndrome. The results will also be relevant to several other neurodevelopmental disorders in which E-I ratio is abnormal, such as epilepsy, autism spectrum disorders, and chronic pain. This proposal will give me valuable optogenetic and electrophysiological training that will build on my previous molecular expertise on plasticity to position me for an independent research career.