Small RNA-mediated regulation of adult neuronal plasticity in vivo

描述（由申请人提供）：成年脊椎动物的脑可塑性是相当普遍的，对理解神经退行性疾病和中枢神经系统损伤的逆转非常重要，但其控制尚不清楚。现在已知小rna是一种具有快速作用过程的转录后调节机制，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的作用都是保守的。在这里，我们提出了一系列实验，使用独特的硬骨鱼模型系统，具有良好表征的可塑性和社会控制下的神经元变化。我们将使用该系统来评估小rna在体内神经可塑性中的作用。在这一物种中，当雄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8倍，树突分支增加。这些形态变化发生在社会地位上升的3-5天内，在社会地位下降时发生逆转。通过实验操纵社会地位的能力将使我们能够评估小rna在体内调节成人大脑可塑性中的作用。我们将首先确定与经历社会上升、社会下降和没有地位变化的鱼的不同阶段相关的小rna。然后，我们将通过实验操纵目标小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。然后可以对调节GnRH1神经元可塑性的分子进行测试，以绘制大脑中其他经历可塑性的区域。这项工作将揭示小rna是否以及哪些参与调节神经元可塑性。由于GnRH1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。

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.