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

描述（由申请人提供）：考虑到潜在神经元过程的动态和分布性质，感觉记忆形成研究中的一个关键问题涉及行为相关刺激的长期印痕是如何以及在何处产生和存储的。在听觉学习和记忆的案例中，行为学和电生理学证据表明听觉皮层发挥了关键作用，但在那里运作的分子机制使记忆形成和维持尚不清楚。特别是，尽管潜在的分子机制发生了变化，但编码刺激-行为关联的神经元网络如何能够启动并保持突触连通性的变化？我们建议使用听觉恐惧条件反射范式来发现听觉皮质神经元中DNA的构象状态是否被改变以允许或抑制可塑性相关基因的表达，以及这是否由已知的经验依赖的可塑性过程触发以建立持久的听觉记忆。我们的长期目标是揭示听觉皮层中特定细胞类型形成稳定记忆的分子机制。本研究的目的是证明BDNF-TrkB级联在调节大量大脑区域中成人经验依赖的突触可塑性方面是至关重要的，在恐惧条件反射过程中，它改变了听觉皮质神经元中突触可塑性相关基因的表观遗传状态，这是听觉学习的一个强大模型。我们的中心假设是，在恐惧与听觉线索关联的巩固和储存过程中，听觉皮层中的BDNF-TrkB通路上调，导致目标可塑性基因的表观遗传调控。这一连串的事件导致编码恐惧记忆的突触稳定下来。我们将用两个具体目标来检验这一假设。首先，我们将确定在听觉恐惧条件反射后，听觉皮层神经元中介导突触可塑性的机制中涉及的特定基因是否被表观遗传修饰。其次，我们将确定听觉恐惧条件反射过程中听觉皮层中的BDNF-TrkB信号是否对这些基因的表观遗传状态/表达变化和恐惧学习都是必要的。我们的建议的意义在于，通过展示学习过程中核心感觉皮层区域的表观遗传修饰，它开创了一条新的研究路线——将学习和记忆的分子研究的现代概念与感觉皮层对听觉记忆的贡献的研究结合起来。通过使用一种新的方法将表观遗传学研究的目标定位于特定的细胞类型，这里选择神经元而不是神经胶质细胞作为原理证明的目的，我们正在为未来的研究奠定基础，这些研究将分离不同的神经元间细胞和锥体细胞类型在记忆分子维持中的作用。最后，获得这些能力来进一步破译感觉学习和记忆的分子和神经机制，将有助于开发新的药理学靶点来治疗涉及感觉记忆功能障碍的疾病，如创伤后应激障碍（PTSD）。

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).