Activity-dependent neuronal transcription and its importance in brain development and function

神经元活动刺激依赖活动的信号网络和基因表达，以改变突触的发育和可塑性。我的研究项目提出了两个基本问题：依赖活动的神经元转录是如何调节的？这个过程对神经元的发育和功能有何贡献？我们的长期目标是了解不同神经元中活性依赖转录的调节及其对这些神经元生理的影响。这包括识别依赖活性的基因、细胞信号网络和转录调节因子，以及神经元亚型特有的结果。*目前，我的研究集中在转录调节因子Capicua在活动依赖的神经元转录中的作用。Capicua作用于RASmitogen激活蛋白激酶(MAPK)途径的下游，调节基因的表达。RASMAPK信号对神经元活性依赖的转录是重要的，但Capicua是否在这一过程中发挥作用尚不清楚。在这个方案中，我们关注下丘脑的一组神经元，即室旁核(PVN)，因为这些神经元可以被多种方法可靠和选择性地刺激，为研究活动依赖的转录提供了一种可访问的方法。我们的短期目标是研究Capicua在PVN神经元活性依赖转录调控中的作用。下丘脑室旁核神经元产生催产素(OXT)和精氨酸加压素(AVP)，这是生理和行为中两个重要的神经肽调节因子。我们可以监测PVN中活性依赖转录的影响，并了解这一过程在调节适应行为中的意义。*基于我们令人兴奋的初步数据，我们假设Capicua调节PVN中活性依赖的神经元转录。在拟议的研究中，我们将确定Capicua在PVN中RASMAPK信号转导中的作用(目标1)。我们将在PVN中鉴定全基因组Capicua调控的活性依赖转录(目标2)。最后，为了评估这一过程对PVN神经元生理和功能的重要性，我们将研究活性依赖转录对PVN神经元生理的影响。(目标3)*我们的研究将阐明Capicua在活性依赖转录调控中的作用。重要的是，我们将开始了解这一过程在神经细胞中的复杂性，表明细胞信号通路受到反馈调节的控制。Capicua调控的活性依赖基因的清单将扩大我们对PVN神经元正常功能所必需的基因和蛋白质网络的理解。我们的工作将阐明OXT和AVP这两种重要的生理激素的合成调节，并为正常神经元发育和适应性神经行为的调节提供洞察力。

Neuronal activity stimulates activity-dependent signaling networks and gene expression to modify synapse development and plasticity. My research program asks two fundamental questions: How is activity-dependent neuronal transcription regulated? How does this process contribute to neuronal development and function? Our long-term objective is to understand the regulation of activity-dependent transcription in different neurons and its effects on the physiology of these neurons. This includes the identification of activity-dependent genes, cellular signaling networks and transcriptional regulators, and neuronal subtype-specific outcomes. ******Currently, my research is centered on the role of a transcriptional regulator, named capicua, in activity-dependent neuronal transcription. Capicua acts downstream of the RASmitogen-activated protein kinase (MAPK) pathway to regulate gene expression. The RASMAPK signaling is important for neuronal activity-dependent transcription, but whether capicua plays a role in this process is unknown. In this proposal, we focus on a cluster of neurons in the hypothalamus, the paraventricular nucleus (PVN), because these neurons can be reliably and selectively stimulated by multiple approaches, providing an accessible way to study activity-dependent transcription. Our short-term objective is to investigate the role of capicua in the regulation of activity-dependent transcription of PVN neurons. PVN neurons produce oxytocin (Oxt) and arginine vasopressin (Avp), two crucial neuropeptide regulators of physiology and behavior. We can monitor the effects of activity-dependent transcription in PVN and understand the significance of this process in modulating adaptive behavior.******Based on our exciting preliminary data, we hypothesize that capicua regulates activity-dependent neuronal transcription in the PVN. In the proposed studies, we will define the role of capicua in RASMAPK signaling in the PVN (Aim 1). We will identify genome-wide capicua-regulated activity-dependent transcription in the PVN (Aim 2). Lastly, to assess the importance of this process on the physiology and function of PVN neurons, we will investigate the impact of activity-dependent transcription on the physiology of PVN neurons. (Aim 3).******Our studies will shed light on the role of capicua in regulation of activity-dependent transcription. Importantly, we will begin to understand the complexity of this process in neuronshow the cellular signaling pathways are kept in check by feedback regulation. The list of capicua-regulated activity-dependent genes will broaden our understanding of the networks of genes and proteins important for normal function of the PVN neurons. Our work will shed light on the regulation of the synthesis of Oxt and Avp, two physiologically important hormones, and provide insight into normal neuronal development and the regulation of adaptive neurobehaviour.**