The role of Retinoic Acid Induced 1 (Rai1) in neural network stability

大脑具有同时保持灵活和稳定的非凡能力。这使我们能够在学习新信息的同时，将大脑的兴奋性保持在一个操作范围内。在细胞水平上，大脑使用几种机制来调节活动稳态，包括固有的膜兴奋性、突触传递和树突形态。在网络层面上，大脑使用突触尺度来实现突触强度的全局标准化。近年来，转录程序已成为调节活动稳态的重要参与者。然而，大脑如何通过转录机制同时控制这些过程尚不完全清楚。我研究计划的长期目标是阐明大脑在分子、细胞和回路水平上维持稳态活动的转录机制。为了实现这一目标，我们的短期目标将研究转录因子视黄酸诱导1 （Rai1）如何调节大脑网络的稳定性。神经缺失的Rai1增加了小鼠的大脑兴奋性，表明Rai1调节了大脑的活动稳态。我们的初步数据发现海马中的一组兴奋性神经元，即齿状回颗粒细胞（dGCs），在缺乏Rai1的情况下过度激活。Rai1如何控制dGCs的兴奋性、形态学、突触可塑性和基因表达尚不清楚。在这个发现研究项目中，我们将使用dGCs作为模型来研究位于细胞核中的转录因子Rai1如何通过耦合内在兴奋性、稳态可塑性、神经元形态和活性依赖基因表达来调节网络活动的稳定性。这项资助将使人们对控制大脑内网络稳态的转录机制的理解达到一个新的水平。此外，它将为学员提供极好的概念和技术机会，使用先进的生物信息学，形态计量学分析，单细胞分析和电生理学工具，同时发现脑功能和体内平衡的基本方面。

The brain has the remarkable capacity to be flexible and stable at the same time. This allows us to learn new information while maintaining brain excitability within an operating range. At the cellular level, the brain uses several mechanisms to regulate activity homeostasis, including intrinsic membrane excitability, synaptic transmission, and dendritic morphology. At the network level, the brain uses synaptic scaling to globally normalize synaptic strength. Transcriptional programs have recently emerged as an important player in regulating activity homeostasis. However, how the brain simultaneously controls these processes by transcriptional mechanisms is not fully understood. The long-term objective of my research program is to elucidate the transcriptional mechanism by which the brain maintains homeostatic activity on molecular, cellular, and circuit levels. To achieve this goal, our short-term objective will study how a transcription factor, Retinoic acid induced 1 (Rai1), regulates brain network stability. Neural loss of Rai1 increases brain excitability in mice, suggesting that Rai1 regulates activity homeostasis of the brain. Our preliminary data found a group of excitatory neurons in the hippocampus, the dentate gyrus granule cells (dGCs), are hyperactivated in the absence of Rai1. How Rai1 controls dGCs excitability, morphology, synaptic plasticity, and gene expression is unknown. In this Discovery Research Program, we will use the dGCs as a model to study how Rai1, a transcription factor located in the nucleus, regulates the stability of network activity by coupling intrinsic excitability, homeostatic plasticity, neuronal morphology, and activity-dependent gene expression. This grant will create a new level of understanding of transcriptional mechanisms that control network homeostasis within the brain. Moreover, it will provide excellent conceptual and technical opportunities for trainees to use advanced bioinformatics, morphometric analysis, single cell analysis, and electrophysiology tools while discovering fundamental aspects of brain function and homeostasis.