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

描述（由申请人提供）：感觉记忆形成研究中的一个关键问题涉及如何以及在何处创建和存储行为相关刺激的长期印迹，考虑到潜在神经元过程的动态和分布式性质。在听觉学习和记忆的情况下，行为和电生理学证据指出听觉皮层发挥了关键作用，但使记忆形成和维持的分子机制尚不清楚。特别是，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接的变化，尽管底层分子机制发生了变化？我们建议使用听觉恐惧条件反射范式来发现听觉皮层神经元中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性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。这里的目的是证明，BDNF-TrkB级联，这是至关重要的调节成人经验依赖性突触可塑性在大量的大脑区域，修改突触可塑性相关的基因在听觉皮层神经元的表观遗传状态在恐惧条件反射，听觉学习的一个强大的模型。我们的中心假设是，在巩固和存储的恐惧协会的听觉线索，BDNF-TrkB途径上调听觉皮层导致的表观遗传调控的目标可塑性基因。这一系列事件导致编码恐惧记忆的突触稳定。我们将以两个具体目标来检验这一假设。首先，我们将确定是否有特定的基因参与的机制，介导突触可塑性的表观遗传修饰后，听觉恐惧条件反射在听觉皮层的神经元。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信号传导是否对这些基因的表观遗传状态/表达和恐惧学习的变化都是必要的。我们的建议的意义在于，通过展示在学习过程中核心感觉皮层区域的表观遗传修饰，它启动了一个新的研究路线，将学习和记忆的分子研究中的现代概念与感觉皮层对听觉记忆的贡献的调查相结合。通过使用一种新的方法来靶向特定细胞类型的表观遗传学研究，在这里选择的原则证明的目的是神经元，而不是神经胶质细胞，我们正在为未来的研究奠定基础，将解离不同的interneuronal和锥体细胞类型的分子维持记忆的贡献。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，然后将能够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，例如创伤后应激障碍（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).