Epigenetics of neuronal plasticity in auditory cortex in a sensory memory model

感觉记忆模型中听觉皮层神经元可塑性的表观遗传学

• 批准号: 8570510
• 负责人: Robert C Liu
• 金额: $ 22.31万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8570510
• 关键词: Acetylation; Address; Adult; Amygdaloid structure; Animals; Area; Association Learning; Auditory; Auditory area; Behavior; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Cues; Cytoskeleton; DNA; Development; Disease; Epigenetic Process; Event; Exposure to; Foundations; Fright; Functional disorder; Future; Gene Expression; Genes; Genetic Status; Genetic Transcription; Goals; Health; Histone Acetylation; Hour; Interneurons; Intervention; Investigation; Knowledge; Learning; Maintenance; Maps; Mediating; Mediator of activation protein; Memory; Memory Disorders; Mental disorders; Methodology; Methylation; Mission; Modeling; Modification; Molecular; Molecular Conformation; Mus; Nature; Neuroglia; Neuronal Plasticity; Neurons; Pathology; Pathway interactions; Phase; Play; Post-Traumatic Stress Disorders; Process; Proteins; Public Health; Pyramidal Cells; Recruitment Activity; Regulation; Research; Role; Sensory; Sensory Process; Signal Transduction; Site; Stimulus; Synapses; Synaptic plasticity; Tars; Testing; Time; Work; cell type; classical conditioning; conditioned fear; conditioning; experience; gene repression; innovation; neuromechanism; novel; prevent; public health relevance; sensory cortex; sound

DESCRIPTION (provided by applicant): A key question in the study of sensory memory formation concerns how and where the long-term engram of a behaviorally relevant stimulus is created and stored, given the dynamic and distributed nature of the underlying neuronal processes. In the case of auditory learning and memory, behavioral and electrophysiological evidence point to a key role played by the auditory cortex, but the molecular mechanisms operating there to enable memory formation and maintenance are unknown. In particular, how are networks of neurons encoding a stimulus-behavior association able to initiate and retain changes in their synaptic connectivity despite turnover in the underlying molecular machinery? We propose to use an auditory fear conditioning paradigm to dis- cover whether the conformational state of DNA in auditory cortical neurons is altered to permit or repress the expression of plasticity-related genes, and whether this is triggered by known experience-dependent plasticity processes to establish persistent auditory memories. Our long-term goal is to reveal the molecular mechanisms that are recruited by specific cell types in the auditory cortex to form stable memories. The objective here is to demonstrate that the BDNF-TrkB cascade, which is critical in regulating adult experience-dependent synaptic plasticity in a large number of brain areas, modifies the epigenetic status of synaptic plasticity-related genes in auditory cortical neurons during fear conditioning, a robust model of auditory learning. Our central hypothesis is that during the consolidation and storage of fear associations to auditory cues, the BDNF-TrkB pathway is upregulated in the auditory cortex leading to the epigenetic regulation of the target plasticity genes. This chain of events results in the stabilization of synapses that encode fear memories. We will test this hypothesis with two specific aims. First, we will determine whether specific genes implicated in the machinery that mediates synaptic plasticity are epigenetically modified in neurons in the auditory cortex after auditory fear conditioning. Second, we will determine whether BDNF-TrkB signaling in the auditory cortex during auditory fear conditioning is necessary for both changes in the epigenetic status/expression of those genes and fear learning. Our proposal's significance lays in the fact that by demonstrating epigenetic modifications in a core sensory cortical area during learning, it initiates a new line a research that merges modern concepts from molecular studies of learning and memory with investigations of sensory cortical contributions to auditory memories. By using a novel methodology to target epigenetic studies to specific cell types, chosen here for proof-of- principle purposes to be neurons rather than glial cells, we are laying the foundation for future studies that will dissociate the contributions of different interneuronal and pyramidal cell types n the molecular maintenance of memories. Finally, gaining these abilities to further decipher the molecular and neural mechanisms of sensory learning and memory will then enable the development of new pharmacological targets to treat disorders involving sensory memory dysfunction, such as post-traumatic stress disorder (PTSD).

描述（由申请人提供）：在研究感觉记忆形成的研究中，一个关键问题涉及在基本神经元过程的动态和分布性质的情况下创建和存储行为相关刺激的长期范围。在听觉学习和记忆的情况下，行为和电生理学证据表明听觉皮层起着关键作用，但是在那里运行以实现记忆形成和维持的分子机制是未知的。特别是，尽管基本分子机械的转换，神经元网络如何编码刺激行为的关联能够启动和保留其突触连通性的变化？我们建议使用听觉恐惧调节范式来覆盖听觉皮质神经元中DNA的构象状态是否改变以允许或抑制与可塑性相关的基因的表达，以及这是否是由已知的经验依赖性可塑性过程触发的，以建立持久性记忆。我们的长期目标是揭示由听觉皮层中特定细胞类型募集的分子机制，形成稳定的记忆。这里的目的是证明，BDNF-TRKB级联对于调节大量大脑区域的成人经验依赖性突触可塑性至关重要，它可以修饰恐惧调节过程中听觉皮质神经元中突触可塑性相关基因的表观遗传学状态，这是一种强大的听觉学习模型。我们的中心假设是，在合并和存储恐惧关联与听觉线索期间，BDNF-TRKB途径在听觉皮层中被上调，导致目标可塑性基因的表观遗传调节。这一事件链导致编码恐惧记忆的突触稳定。我们将以两个具体的目的检验这一假设。首先，我们将确定在听觉恐惧调节后，在听觉皮层中的神经元中，在介导突触可塑性的机械上涉及的特定基因是否在神经元中进行了表观修饰。其次，我们将确定在听觉恐惧调节过程中听觉皮层中的BDNF-TRKB信号是否对于这些基因的表观遗传状态/表达和恐惧学习的两种变化都是必要的。我们的提议的意义揭示了一个事实，即通过在学习过程中证明核心感觉皮质区域中的表观遗传学修饰，它启动了一项新系列一项研究，从学习和记忆的分子研究与对听觉记忆的感觉皮质贡献的研究合并了现代概念。通过使用一种新的方法将表观遗传学研究靶向特定的细胞类型，此处被选为原理证明是神经元而不是神经胶质细胞，我们为将来的研究奠定了基础，以解离不同的神经元和锥体细胞的贡献，n分子维持记忆的分子维持。最后，获得这些能力以进一步破译感觉学习和记忆的分子和神经机制将使新的药理学靶标的发展以治疗涉及感觉记忆功能障碍的疾病，例如创伤后应激障碍（PTSD）。