Elucidation of RNA-Based Mechanisms of Long-Term Memory Storage

阐明基于 RNA 的长期记忆存储机制

• 批准号: 2050850
• 负责人: David Glanzman
• 金额: $ 60万
• 依托单位: University of California-Los Angeles
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2050850&HistoricalAwards=false
• 关键词: Elucidation; RNA; Based; Mechanisms; Long

How our memories persist more-or-less unchanged for years, decades, and, in some cases, for lifetime remains poorly understood. The project investigates the mechanisms that underlie long-term memory. A guiding hypothesis of the project is that memories are not stored in the brain as changes in the connections between neurons but, rather, as modifications in the nuclei of neurons. A major goal of the project is to identify the processes that mediate the nuclear modifications that encode long-term memory. Data from the proposed project could facilitate the development of novel treatments for disorders of memory, including Alzheimer’s disease and posttraumatic stress disorder. In addition, the project enhances the scientific literacy of high school and undergraduate students from underrepresented or economically disadvantaged backgrounds. This goal is accomplished through formal lectures on the neurobiology of memory to be offered in UC Santa Barbara’s Summer Research Academy (SRA), as well as giving high school students in the SRA and undergraduates associated with UCLA’s Brain Research Institute Brain Research Institute Summer Undergraduate Research Experience (BRI SURE) the opportunity to participate in guided research in the Principal Investigator’s laboratory during the summer.Recently, the principal investigator has discovered that long-term memory (LTM) in the marine snail Aplysia appears to be stored in neurons by nuclear changes. One type of nuclear change that has been implicated in LTM storage in Aplysia is epigenetic changes; however, genomic changes may also play a critical role in encoding LTM. A type of genomic change that may mediate LTM is retrotransposition. The proposed project investigates the potential involvement of retrotransposons in LTM in Aplysia. Specifically, the investigators test whether retrotransposition is required for a type of synaptic memory, long-term facilitation (LTF) of Aplysia sensorimotor synapses in dissociated cell culture. To accomplish this objective, the investigators test whether inhibitors of reverse transcriptase and of DNA double-strand breaks disrupt LTF. The project also identifies species of non-coding RNAs (ncRNAs) that trigger nuclear changes that encode a form of non-associative memory in Aplysia, long-term sensitization (LTS) of the siphon-withdrawal reflex. Both RNA-seq and small RNA-seq will be performed on RNA extracted from the identified sensory and motor neurons dissociated from the central nervous system of LTS-trained and untrained animals. Differential expression analyses on the RNA-seq data is carried out to identify potential memory-inducing ncRNAs; the mnemonic potency of the candidate ncRNAs then is assessed through bioassays performed using sensory and motor neurons in dissociated cell culture. Data from the proposed project can, potentially, significantly alter thinking about how the brain encodes memory. This, in turn, could lead to new approaches to artificial intelligence (AI). At present, models of machine learning in AI are heavily influenced by synaptic models of memory that are based on neuroscientific findings. Finally, results from the proposed project may facilitate the development of novel treatments for disorders of memory, including Alzheimer’s disease and posttraumatic stress disorder.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

我们的记忆是如何在几年、几十年、甚至在某些情况下终生保持不变的，人们仍然知之甚少。该项目研究了构成长期记忆的机制。该项目的一个指导性假设是，记忆不是作为神经元之间连接的变化存储在大脑中，而是作为神经元核的修改存储在大脑中。该项目的一个主要目标是确定参与编码长期记忆的核修饰的过程。来自拟议项目的数据可能有助于开发治疗记忆障碍的新方法，包括阿尔茨海默病和创伤后应激障碍。此外，该项目还提高了来自代表性不足或经济困难背景的高中生和本科生的科学素养。这一目标是通过在加州大学圣巴巴拉分校夏季研究院(SRA)提供关于记忆的神经生物学的正式讲座来实现的，以及为SRA的高中生和与加州大学洛杉矶分校脑研究所大脑研究所暑期本科生研究体验(BRI Sure)相关的本科生提供机会，参加夏季首席研究员实验室的指导研究。最近，首席研究人员发现，海洋蜗牛Aplysia的长期记忆(LTM)似乎是通过核变化储存在神经元中的。一种与海兔LTM储存有关的核变化是表观遗传学变化；然而，基因组变化也可能在编码LTM中发挥关键作用。一种可能介导LTM的基因组变化是逆转座。这项拟议的项目调查了反转录转座子在海兔LTM中的潜在参与。具体地说，研究人员测试了在分离的细胞培养中，海兔感觉运动型突触的长时程易化(LTF)的突触记忆是否需要逆转位。为了实现这一目标，研究人员测试了逆转录酶和DNA双链断裂的抑制剂是否会干扰LTF。该项目还确定了触发核变化的非编码RNA(NcRNAs)的种类，这些变化编码了海藻中一种形式的非联想记忆，即虹吸-撤退反射的长期敏感化(LTS)。RNA-SEQ和小RNA-SEQ都将在从LTS训练和未训练动物的中枢神经系统分离的已识别感觉和运动神经元中提取的RNA上进行。对RNA-SEQ数据进行差异表达分析以确定潜在的诱导记忆的ncRNAs；然后通过使用分离细胞培养中的感觉和运动神经元进行生物测试来评估候选ncRNAs的助记力。这项拟议项目的数据可能会极大地改变人们对大脑如何编码记忆的思考。这反过来可能导致人工智能(AI)的新方法。目前，人工智能中的机器学习模型受到基于神经科学发现的突触记忆模型的严重影响。最后，拟议项目的结果可能有助于开发新的记忆障碍治疗方法，包括阿尔茨海默病和创伤后应激障碍。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。