Exploring Anatomical and Circuit Plasticity Deficits in Fmr1 Mice During Tactile Learning

项目摘要 脆性X综合征（FXS）是导致智力障碍的主要遗传原因。没有已知的治疗方法 FXS或治疗，扭转集体病理。我们对于如何在一个特定的时间内 FXS通过改变神经回路导致精神障碍。这项研究的长期目标是 发展对FXS的理解，将学习障碍与神经回路的特定变化联系起来。 FXS的特征性症状包括智力下降、学习缺陷和对 感官刺激FXS源于FMR 1基因功能丧失;缺乏功能性fmr 1基因的小鼠 表现出与FXS相似的几种表型。在两个差距杂交中，fmr 1突变小鼠显示出有趣的缺陷 任务，一个自由行为的胡须依赖触觉学习任务，以及头部固定的胡须依赖 触觉学习任务中心假设是，触觉学习的障碍是由减少的 树突棘稳定性和初级躯体感觉皮层的过敏性触摸反应 减弱生长抑素表达（SOM）的中间神经元的活性。这项提案的实验将确定 fmr 1基因的缺失在多大程度上破坏了脊柱的稳定性、触觉学习和电路动力学， 任务绩效在我们强有力的初步数据的指导下，我们将在两个相关的具体问题中探讨这一假设。 目标。在目标1中，纵向双光子体内成像与自动头部固定晶须相结合， 依赖性触觉学习任务，以评估fmr 1突变小鼠中SOM中间神经元的活性是否降低 降低树突棘的稳定性并损害学习能力。在目标2中，将复杂的电生理学 在同一个头部固定的物体定位过程中对触须位置进行高速跟踪， 触觉辨别和皮层代表的传入感觉活动在躯体感觉 皮质异常fmr 1突变小鼠，如果SOM中间神经元的功能减弱， 赤字这种方法特别具有创新性，因为作为学习基础的突触变化是 在整个任务获取过程中纵向测量。此外，打破麻醉的现状， 在主动感知行为期间量化表示触摸的皮层电路动态。的 该提案意义重大，因为它垂直地推进了我们对FXS机制的了解， 分析，从突触到电路再到行为。此外，它还为这些先进的 技术应用于其他皮层和大脑区域，以建立对大脑皮层的全面了解。 FXS模型系统中的神经回路缺陷这项建议完全符合关键的使命目标 NINDS和NIMH提供了详细的和综合的知识，如何突触的功能， 神经系统疾病中的神经回路被破坏。最终，由此产生的改进电路的理解 功能障碍有可能导致治疗，改善生活质量的大约1在5000 患有脆性X综合征的人

Project Abstract Fragile X Syndrome (FXS) is a leading inheritable cause of mental impairment. There is no known cure for FXS or treatment that reverses the collective pathology. There is a fundamental gap in our knowledge of how FXS causes mental impairments through alteration of neural circuitry. The long-term goal of this research is to develop an understanding of FXS that links learning impairments to specific changes in neural circuits. Characteristic symptoms of FXS include reduced intellectual abilities, learning deficits, and hypersensitivity to sensory stimuli. FXS arises from a loss-of-function in the FMR1 gene; mice lacking a functional fmr1 gene exhibit several phenotypes similar to FXS. Fmr1 mutant mice display an intriguing deficit on both the gap cross task, a freely-behaving whisker-dependent tactile learning task, as well as a head-fixed whisker-dependent tactile learning task. The central hypothesis is that impairments in tactile learning are driven by reduced dendritic spine stability and hypersensitive touch responses in primary somatosensory cortex resulting from attenuated activity of somatostatin-expressing (SOM) interneurons. Experiments in this proposal will determine the extent to which loss of the fmr1 gene disrupts spine stability, tactile learning, and circuit dynamics during task performance. Guided by our strong preliminary data, we will pursue this hypothesis in two related specific aims. In Aim 1, longitudinal two-photon in vivo imaging is combined with an automated head-fixed whisker- dependent tactile learning task to evaluate if reduced activity of SOM interneurons in fmr1 mutant mice decreases dendritic spine stability and impairs learning. In Aim 2, sophisticated electrophysiology is combined with high-speed tracking of whisker position during this same head-fixed object localization to quantify the extent to which tactile discrimination and cortical representations of afferent sensory activity in somatosensory cortex are abnormal fmr1 mutant mice and if attenuated function of SOM interneurons contributes to this deficit. This approach is particularly innovative because the synaptic changes that underlie learning are measured longitudinally throughout task acquisition. Furthermore, breaking from the anesthetized status quo, the cortical circuit dynamics that represent touch are quantified during active perceptual behavior. The proposal is significant because it vertically advances our knowledge of FXS mechanisms across levels of analysis, from synapse to circuit to behavior. Additionally, it opens new horizons for these advanced techniques to be applied to other cortical layers and brain regions to build a comprehensive understanding of neural circuit defects in a premier FXS model system. This proposal squarely meets the key mission objectives of the NINDS and NIMH to provide detailed and integrated knowledge of how the function of synapses and circuits is disrupted in neurological disorders. Ultimately, the resulting improved understanding of circuit dysfunction has the potential to lead to therapies that improve the quality of life for the roughly 1 in 5,000 people born with Fragile X Syndrome.