Small RNA-mediated regulation of adult neuronal plasticity in vivo

描述（由申请人提供）：成年脊椎动物脑可塑性相当普遍，在理解神经退行性疾病以及中枢神经系统损伤的逆转方面极其重要，但其控制尚未得到很好的理解。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，与快速的大脑变化一致。最近的研究表明小RNA在神经元发育和分化中的作用。研究还表明，从鱼类到哺乳动物，这些RNA的作用是保守的。在这里，我们提出了一系列的实验，使用一个独特的硬骨鱼模型系统，具有良好的特征神经元的变化，是塑料和社会控制。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。在这个物种中，当雄性在社会地位上上升时，含有促性腺激素释放激素（GnRH 1）的神经元的体积增加八倍，并增加它们的树突分支。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，这种变化就会逆转。通过实验操纵社会地位的能力将使我们能够评估小RNA在体内介导成人大脑可塑性中的作用。我们将首先确定与鱼类经历社会地位上升，社会地位下降和无地位变化的不同阶段相关的小RNA。然后，我们将通过实验操纵靶向小RNA的水平，以确定这些分子在调节大脑神经元可塑性中的因果作用。然后，可以测试调节GnRH 1神经元可塑性的分子，以绘制经历可塑性的大脑其他区域。这项工作将揭示是否以及哪些小RNA参与调节神经元可塑性。由于GnRH 1系统在脊椎动物中是保守的，因此这项工作的结果将与所有脊椎动物相关。 公共卫生相关性：我们将鉴定小RNA，并确定它们在体内调节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大脑中起作用，将对了解健康和疾病中大脑的变化如何调节具有广泛的应用。

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.