Activity-dependent regulation of Sonic hedgehog signaling incortical astrocytes

项目摘要 了解中枢神经系统适应新体验的机制， 环境是神经科学的基本目标。根据经验和神经活动， 神经元经历基因表达和突触组织的变化， 适应虽然在历史上被认为是神经元的简单支持细胞，但星形胶质细胞 越来越多的人认识到突触的重要组成部分，调节突触 连接性和功能。这表明，神经元之间的相互作用， 星形胶质细胞可能参与经验依赖性突触可塑性。分子 经验依赖性脑损伤中神经元与星形胶质细胞相互作用的机制 活动并没有得到很好的理解。在以前的研究中，我们确定星形胶质细胞是主要的 细胞类型转导Sonic hedgehog（Shh）信号传导，来源于出生后和 成人皮质选择性破坏星形胶质细胞中的Shh活性损害结构和功能 皮质神经元的特性，表明Shh信号是适当的 开发电路的建立。在这项研究中，我们建议检查活动的作用， 调节嘘信号。我们将使用一个丰富的环境与复杂的刺激，包括 新奇，增加身体活动和社会互动，以调查经验的作用 刺激嘘。在目标1中，我们将识别促进经验依赖性Shh的刺激 活动，并确定它是否是模态特定的。在目标2中，我们将使用基因标记 策略和化学遗传学方法来识别启动经验依赖性的细胞 Shh信号传导并确定神经元活动是否刺激Shh活性。这些数据将 为进一步阐明分子程序的机理研究奠定基础 由Shh信号介导的活性依赖性神经元-星形胶质细胞通讯启动。

PROJECT ABSTRACT Understanding the mechanisms by which the CNS adapts to novel experiences and changing environments is a fundamental goal of neuroscience. Following experience and neural activity, neurons undergo changes in gene expression and synaptic organization that facilitate such adaptation. Though historically regarded as simple support cells for neurons, astrocytes are gaining increasing recognition as essential elements of the synapse, modulating synaptic connectivity and function. This suggests that reciprocal interactions between neurons and astrocytes are likely to be involved in experience-dependent synaptic plasticity. The molecular mechanisms underlying neuronal interactions with astrocytes during experience-dependent activity are not well understood. In previous studies, we identified astrocytes as the predominant cell type transducing Sonic hedgehog (Shh) signaling derived from neurons in the postnatal and adult cortex. Selective disruption of Shh activity in astrocytes impairs structural and functional properties of cortical neurons, demonstrating that Shh signaling is required for the proper establishment of developing circuits. In this study, we propose to examine the role of activity in regulating Shh signaling. We will use an enriched environment with complex stimuli that include novelty, increased physical activity and social interactions, to investigate the role of experience in stimulating Shh. In Aim 1, we will identify the stimuli that promote experience-dependent Shh activity and determine whether it is modality-specific. In Aim 2, we will use genetic marking strategies and chemogenetic approaches to identify the cells that initiate experience-dependent Shh signaling and determine whether neuronal activity stimulates Shh activity. These data will lay the foundation for further mechanistic studies aimed at elucidating the molecular programs initiated by activity-dependent neuron-astrocyte communication mediated by Shh signaling.