MiRNA-mediated mechanisms of long-term traumatic and non-traumatic memory storage

 描述（由申请人提供）：了解大脑如何多年稳定地保持记忆痕迹对各种神经精神疾病具有重要意义，从与年龄相关的认知下降到成瘾和创伤后应激障碍（PTSD）。然而，尽管有明确的临床重要性，该领域的记忆维持的理解是在其婴儿期。虽然已经确定了数千种记忆最初形成的机制，但只有三种存储机制是已知的。这一点很重要，因为最近的研究结果表明，确定控制致病记忆存储的独特机制为选择性擦除提供了目标。越来越多的人认为，记忆是由树突棘上兴奋性突触的结构和功能可塑性支持的，肌动蛋白细胞骨架的严格调节提供了支架。作为翻译抑制因子的内源性RNA，microRNA具有灵活性和广泛的基因组范围，这表明它们的生物学特性。 双向调节可能是一种能够协调大脑所需的复杂性的机制，以维持持久记忆痕迹的结构完整性。这项来自microRNA表达谱分析的额外初步数据表明，肌动蛋白细胞骨架的调节是与杏仁核学习后一个月microRNA持续改变相关的最重要途径，杏仁核是大脑的情感记忆中心，也是PTSD的关键参与者。因此，推动这一提议的核心假设是，microRNA通过维持学习诱导的结构可塑性来促进记忆痕迹的长期稳定性。此外，拟议的实验将研究PTSD样记忆的microRNA谱，由以下假设指导：创伤记忆的持续性是通过在杏仁核内招募额外的独特的microRNA来实现的。与已经实现的药物相关记忆的选择性破坏类似，目前的目标是确定可以用来消除创伤记忆的独特机制。该提案详细介绍了一种创新方法，以了解microRNA及其转录后靶点如何有助于杏仁核内记忆的长期维持。一个多学科的，在体内的方法将被用来实现本项目的主要目标：（1）确定持续的microRNA的变化对维持一个“远程”（30天）的记忆和结构可塑性的影响。(2)确定持续的microRNA变化对维持创伤记忆的独特功能影响。拟议的工作将建立管理创伤性和非创伤性记忆存储的microRNA谱，并建立它们对记忆、结构可塑性、肌动蛋白动力学和翻译后靶点的功能影响。通过统一两个密集的研究领域，记忆的核和突触机制，我们希望这项提案能够确定参与记忆痕迹的长期结构稳定的新机制，以及一组独特的microRNA，当有针对性时，将能够选择性地擦除PTSD样记忆。

 DESCRIPTION (provided by applicant): Understanding how the brain stably maintains a memory trace for years has significant implications for a variety of neuropsychiatric disorders, from age-related cognitive decline to addiction and post-traumatic stress disorder (PTSD). Yet, despite the clear clinical importance, the field's understanding of memory maintenance is in its infancy. While thousands of mechanisms for how a memory initially forms have been identified, only three storage mechanisms are known. This is important, as recent findings indicate that identification of unique mechanisms governing the storage of pathogenic memories provides targets for their selective erasure. There is a growing consensus that memory is supported by structural and functional plasticity at excitatory synapses on dendritic spines, with tight regulation of the actin cytoskeleton providing the scaffolding. microRNAs, endogenous RNAs that act as translational repressors, have a flexibility and wide genomic range that suggests their bidirectional modulation may be a mechanism capable of coordinating the complexity required for the brain to maintain the structural integrity of a long-lasting memory trace. Additional preliminary data in this proposal from microRNA expression profiling indicates that regulation of the actin cytoskeleton is the most significant pathway associated with the microRNAs persistently altered one month after learning in the amygdala, the brain's emotional memory center and a critical participant in PTSD. Thus, the central hypothesis driving this proposal is that microRNAs contribute to the long-term stability of a memory trace by maintaining learning-induced structural plasticity. In addition, the proposed experiments will investigate the microRNA profile of a PTSD-like memory, guided by the hypothesis that the persistence of a traumatic memory is subserved by the recruitment of an additional, unique set of microRNAs within the amygdala. Similar to the selective disruption of a drug-associated memory that has been achieved, the current goal is to identify unique mechanisms that can be exploited to erase a traumatic memory. This proposal details an innovative approach to understanding how microRNAs and their post-transcriptional targets contribute to the long-term maintenance of a memory within the amygdala. A multidisciplinary, in vivo approach will be utilized to achieve the primary goals of this project: (1) To determine the impact of persistent microRNA changes on the maintenance of a "remote" (30-day old) memory and structural plasticity. (2) To determine the functional impact of persistent microRNA changes unique to the maintenance of a traumatic memory. The proposed work will establish the microRNA profile governing traumatic and non-traumatic memory storage and establish their functional impact on memory, structural plasticity, actin dynamics and the post-translational targets. By unifying two areas of intense research, nuclear and synaptic mechanisms of memory, we expect this proposal to identify novel mechanisms participating in the long-term, structural stabilization of a memory trace, as well as a set of unique microRNAs that, when targeted, will enable selective erasure of a PTSD-like memory.