Hippocampal IncRNAs and Memory Consolidation

 描述（由申请人提供）：开发成功的认知障碍（如痴呆症）治疗方法是神经科学的主要目标。开发认知障碍新疗法的关键是理解记忆如何编码、维持和最终消除的分子和细胞基础。在这里，我们建议研究一类新的候选人，长非编码RNA（lncRNA）的贡献，上下文恐惧记忆，一种形式的联想记忆，其中动物形成强烈的关联的恐惧经验的背景。由于lncRNA作为转录和翻译调节因子的潜在作用，阐明lncRNA在神经元通信和长期记忆（LTM）储存中的功能将有助于识别用于开发认知障碍治疗剂的新靶点。基于我们自己的初步数据，这一提议的中心假设是海马中lncRNA表达的特定变化介导了情境恐惧记忆的巩固。为了验证这一假设，我们将使用上下文恐惧条件反射（CFC）的范例，产生持久的恐惧记忆在小鼠作为一种行为测定，然后确定是否表达特定的lncRNA在CA1，CA3和海马齿状回（DG）神经元的上下文恐惧记忆的巩固是至关重要的。这项拟议研究的预期结果是，一旦确定了在情境恐惧记忆储存期间受到调节的特定lncRNA，它们可能会被操纵，从而产生治疗创伤后障碍等疾病的新的创新方法。

 DESCRIPTION (provided by applicant): Developing successful treatments for cognitive disorders such as dementia is a major goal in neuroscience. Key to the development of novel therapeutics for cognitive disorders is the understanding of the molecular and cellular basis of how memories are encoded, maintained and eventually erased. Here we propose to study the contribution of a novel class of candidates, long-noncoding RNAs (lncRNAs), to contextual fear memory, a form of associative memory in which an animal forms strong association of a fearful experience to a context. Because of the potential roles of lncRNAs as regulators of transcription and translation, elucidating lncRNA function in neuronal communication and long-term memory (LTM) storage will facilitate identification of novel targets for developing therapeutics for cognitive disorders. The central hypothesis of this proposal, based on our own preliminary data, is that specific changes in the expression of lncRNAs in the hippocampus mediate the consolidation of contextual fear memories. To test this hypothesis, we will use the contextual fear-conditioning (CFC) paradigm that produces long-lasting fear memories in mice as a behavioral assay and then determine whether expression of specific lncRNAs in CA1, CA3 and dentate gyrus (DG) neurons of the hippocampus are critical for the consolidation of contextual fear memories. An anticipated outcome of this proposed research is that once the specific lncRNAs that are regulated during contextual fear memory storage are identified, they may be manipulated pharmacologically, producing new and innovative approaches to the treatment of disorders such as post-traumatic disorders.