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

神经元活动刺激活动依赖的信号网络和基因表达来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控的？这个过程对神经元的发育和功能有何影响？我们的长期目标是了解不同神经元中活动依赖性转录的调控及其对这些神经元生理的影响。这包括活性依赖基因的鉴定，细胞信号网络和转录调节因子，以及神经元亚型特异性结果。目前，我的研究主要集中在一种名为capicua的转录调节因子在活动依赖性神经元转录中的作用。Capicua作用于ras -丝裂原活化蛋白激酶（MAPK）通路的下游，调节基因表达。RAS-MAPK信号对于神经元活动依赖性转录很重要，但capicua是否在这一过程中发挥作用尚不清楚。在本研究中，我们将重点放在下丘脑的一组神经元，即室旁核（PVN）上，因为这些神经元可以通过多种方法被可靠地和选择性地刺激，从而为研究活动依赖性转录提供了一种可行的方法。我们的短期目标是研究capicua在PVN神经元活性依赖性转录调控中的作用。PVN神经元产生催产素（Oxt）和精氨酸加压素（Avp），这两种重要的神经肽调节生理和行为。我们可以监测PVN中活性依赖性转录的影响，并了解这一过程在调节适应行为中的意义。基于我们激动人心的初步数据，我们假设capicua调节PVN中活动依赖性的神经元转录。在拟议的研究中，我们将定义capicua在PVN中RAS-MAPK信号传导中的作用（目的1）。我们将在PVN中鉴定全基因组capicua调节的活性依赖性转录（目的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，我们将研究活动依赖性转录对PVN神经元生理的影响。(3)为目标。我们的研究将阐明capicua在调节活性依赖性转录中的作用。重要的是，我们将开始了解神经元中这一过程的复杂性——细胞信号通路是如何通过反馈调节来控制的。capicuna调节的活性依赖基因的列表将扩大我们对PVN神经元正常功能重要的基因和蛋白质网络的理解。我们的工作将阐明两种生理上重要的激素Oxt和Avp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见解。

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 RAS-mitogen-activated protein kinase (MAPK) pathway to regulate gene expression. The RAS-MAPK 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 RAS-MAPK 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 neurons-how 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.