Small RNA-mediated regulation of adult neuronal plasticity in vivo

描述(申请人提供)：成年脊椎动物的大脑可塑性在了解神经退行性疾病以及中枢神经系统损伤的逆转方面相当普遍和极其重要，但其控制还不是很清楚。现在已知，小RNA是一种转录后调节机制，具有快速的作用过程，与大脑的快速变化相一致。最近的研究表明，小RNA在神经元发育和分化中发挥了作用。研究还表明，从鱼类到哺乳动物，这些RNA的作用都是保守的。在这里，我们提出了一系列实验，使用一种独特的硬骨鱼模型系统，具有良好的表征神经元变化，这些变化是可塑性的，并在社会控制下。我们将使用这个系统来评估小RNA在体内神经可塑性中的作用(S)。在这种物种中，当男性的社会地位上升时，含有促性腺激素释放激素(GnRH1)的神经元体积增加八倍，树突分支也增加。这些形态变化发生在社会地位上升的3-5天内，当动物的社会地位下降时，情况就会逆转。在实验中操纵社会地位的能力将使我们能够评估小RNA在体内调节成人大脑可塑性中的作用。我们将首先识别与经历社会地位上升、社会下降和地位不变的鱼类的不同阶段相关的小RNA。然后，我们将通过实验操作靶向小RNA的水平，以确定这些分子在调节脑神经元可塑性方面的因果作用。然后，可以测试调节GnRH1神经元可塑性的分子，以绘制大脑其他可塑性区域的图谱。这项工作将揭示是否以及哪些小RNA参与调节神经元的可塑性。由于GnRH1系统在脊椎动物中是保守的，这项工作的结果将适用于所有脊椎动物。 公共卫生相关性：我们将识别小RNA，并确定它们在调节体内神经元可塑性变化中的作用。了解这些小RNA是否以及如何在脊椎动物的大脑中发挥作用，将在理解大脑在健康和疾病中的变化是如何调节的方面具有广泛的应用。

DESCRIPTION (provided by applicant): Adult vertebrate brain plasticity is fairly widespread and extremely important in understanding neurodegenerative disease as well as reversal of central nervous system injuries yet its control is not well understood. Small RNAs are now known to be a post-transcriptional mechanism of regulation with a rapid course of action, consonant with rapid brain changes. Recent studies have shown a role for small RNAs in neuron development and differentiation. It has also been shown that the action of these RNAs is conserved from fish to mammals. Here we propose a series of experiments using a unique teleost fish model system with well-characterized neuronal changes that are plastic and under social control. We will use this system to assess the role(s) of small RNAs in neural plasticity in vivo. In this species, when a male ascends in social status, the gonadotropin releasing hormone (GnRH1) containing neurons increase eightfold in volume and increase their dendritic branching. These morphological changes occur within 3-5 days of social ascent and are reversed when the animal descends in social status. The ability to manipulate social status experimentally will allow us to assess the role of small RNAs in mediating adult brain plasticity in vivo. We will first identify small RNAs associated with distinct phases of fish undergoing social ascent, social descent and no status change. We will then experimentally manipulate levels of the targeted small RNAs to identify the causal role of these molecules in regulating plasticity in brain neurons. Molecules regulating plasticity in GnRH1 neurons can then be tested to map other regions of the brain undergoing plasticity. This work will reveal whether and which small RNAs participate in regulating neuronal plasticity. Since the GnRH1 system is conserved across vertebrates, the results from this work will be relevant for all vertebrates. PUBLIC HEALTH RELEVANCE: We will identify small RNAs and determine their role in regulating plastic changes of neurons in vivo. Understanding whether and how these small RNA act in the vertebrate brain will have wide reaching application in understanding how brain changes in health and disease are regulated.