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

啮齿动物体感皮层晶须图可塑性过程中快速去抑制的电路基础

• 批准号: 9143176
• 负责人: Melanie Ann Gainey
• 金额: $ 2.66万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9143176
• 关键词: Affect; Animals; Autistic Disorder; Biological Models; Brain; Cells; Cerebral cortex; Data; Development; Electrophysiology (science); Epilepsy; Equilibrium; Fragile X Syndrome; Future; Health; Housing; Impairment; Injury; Interneurons; Label; Learning; Link; Maps; Measures; Mediating; Modeling; Molecular; Mus; Neurodevelopmental Disorder; Neurons; Neurosciences; Parvalbumins; Phase; Positioning Attribute; Recurrence; Regulation; Reporting; Research; Rett Syndrome; Rodent; Sensory; Sensory Deprivation; Shapes; Silicon; Slice; Somatosensory Cortex; Synapses; Synaptic plasticity; Techniques; Testing; Training; Transgenic Mice; Vibrissae; Visual Cortex; Whole-Cell Recordings; Work; autism spectrum disorder; base; career; chronic pain; deprivation; design; experience; feeding; in vivo; insight; mouse model; nervous system disorder; neural circuit; neurophysiology; neurotransmission; novel; optogenetics; receptive field; research study; response; sensory input; somatosensory; transmission process

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.

描述（由申请人提供）：感觉经验如何调节大脑皮层的回路功能？这个问题已经在啮齿动物的躯体感觉（S1）皮层中得到了深入的研究，其中胡须经验或剥夺驱动了（L）2/3层中胡须感受野图的可塑性，其基础已经在电路和突触水平上进行了研究。大多数先前的工作都集中在兴奋性电路，经历经典的赫布可塑性在响应晶须剥夺。然而，最近的工作表明，经验也驱动了快速减少抑制（去抑制）在L2/3以下的晶须剥夺，这是一个重要的新的一步晶须地图可塑性。我们还不了解快速解除抑制的电路基础，包括涉及哪些投射和突触，以及解除抑制如何在功能上影响体内的感觉反应。 在这里，我建议确定突触和电路的基础上快速解除抑制S1。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否主要发生在L2/3的前馈输入中，或者在L2/3循环回路中，然后确定其功能被剥夺改变的特定突触。这些记录将在具有荧光标记的小清蛋白（PV）阳性中间神经元的转基因小鼠中进行，以进行有效的靶向记录。接下来，我将使用硅四极记录来确定快速去抑制是否会在活体S1神经元的放电率或感受野中产生可检测的变化 在麻醉的老鼠身上。最后，我将确定是否前馈和经常性的L2/3电路， 脆性X综合征模型小鼠，Fmr 1-/-，响应于胡须剥夺而经历快速去抑制。 这些实验将提供（1）回路水平的描述，说明L2/3中的哪些抑制回路，（2）哪些特定突触介导了胡须剥夺后的快速去抑制，（3）野生型小鼠回路水平去抑制的尖峰相关性描述，以及（4）Fmr 1-/-小鼠回路水平快速去抑制的描述。这些结果将进一步加深我们对大脑如何响应在发育、损伤和学习过程中正常大脑中发生的感觉输入变化的理解，并将为神经系统疾病脆性X综合征的失调提供见解。该结果也将与其他几种E-I比值异常的神经发育障碍相关，如癫痫，自闭症谱系障碍和慢性疼痛。 这个建议将给我宝贵的光遗传学和电生理学培训，将建立在我以前的可塑性分子专业知识，定位我一个独立的研究生涯。