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

我们的记忆是如何在几年、几十年甚至是一生中保持不变的，我们对此知之甚少。该项目研究长期记忆的机制。该项目的一个指导性假设是，记忆并不是以神经元之间连接的变化形式存储在大脑中，而是以神经元核的修改形式存储在大脑中。该项目的一个主要目标是确定介导编码长期记忆的核修饰的过程。来自拟议项目的数据可以促进开发记忆障碍的新疗法，包括阿尔茨海默病和创伤后应激障碍。此外，该项目还提高了代表性不足或经济上处于不利地位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夏季研究学院（SRA）提供的关于记忆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有关的本科生提供暑期本科生研究经验（BRI SURE）有机会在夏季参加主要研究者实验室的指导性研究。最近，首席研究员发现，海蜗牛的长期记忆（LTM）似乎是通过核变化储存在神经元中的。在Astrasia中与LTM储存有关的一种类型的核变化是表观遗传变化;然而，基因组变化也可能在编码LTM中起关键作用。可能介导LTM的一种类型的基因组变化是反转录转座。拟议的项目调查了反转录转座子在南极洲的LTM中的潜在参与。具体来说，研究人员测试是否需要反转录的突触记忆，长期促进（LTF）的感觉运动突触在分离的细胞培养。为了实现这一目标，研究人员测试逆转录酶抑制剂和DNA双链断裂抑制剂是否会破坏LTF。该项目还确定了触发核变化的非编码RNA（ncRNA）的种类，这些核变化编码了一种形式的非联想记忆，即虹吸管撤回反射的长期敏化（LTS）。RNA-seq和小RNA-seq都将对从经LTS训练和未经训练的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进行。对RNA-seq数据进行差异表达分析以鉴定潜在的记忆诱导ncRNA;然后通过使用分离的细胞培养物中的感觉和运动神经元进行的生物测定来评估候选ncRNA的记忆效能。来自拟议项目的数据可能会显着改变对大脑如何编码记忆的思考。反过来，这可能会导致人工智能（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记忆突触模型的严重影响。最后，从拟议的项目的结果可能会促进开发新的治疗记忆障碍，包括阿尔茨海默氏症和创伤后应激障碍。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.