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是，鉴于潜在神经过程的动态和分布性质，如何以及在哪里创建和存储与行为相关的刺激的长期印记。就听觉学习和记忆而言，行为和电生理证据表明，听觉皮质发挥了关键作用，但那里形成和维持记忆的分子机制尚不清楚。具体地说，编码刺激-行为关联的神经元网络如何能够启动和保持突触连接的变化，尽管潜在的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揭示听觉皮质神经元中DNA的构象状态是否发生改变，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质中特定细胞类型招募形成稳定记忆的分子机制。在此，我们的目的是证明BDNF-TrkB级联反应在调节成人大量脑区经验依赖性突触可塑性方面起关键作用，它在恐惧条件反射过程中改变了听觉皮质神经元突触可塑性相关基因的表观遗传状态，这是一种强大的听觉学习模型。我们的中心假设是，在与听觉线索相关的恐惧的巩固和存储过程中，BDNF-TrkB通路在听觉皮质上调，导致目标可塑性基因的表观遗传调节。这一系列事件导致编码恐惧记忆的突触稳定。我们将通过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作用后，在听觉皮质神经元中，与介导突触可塑性的机制有关的特定基因是否发生了表观遗传修饰。其次，我们将确定听觉恐惧条件作用期间听觉皮质中的BDNF-TrkB信号是否对这些基因的表观遗传状态/表达的变化和恐惧学习是必要的。我们的提议的意义在于，通过展示学习过程中核心感觉皮层区域的表观遗传修饰，它开启了一条新的路线--一项融合了学习和记忆分子研究的现代概念与感觉皮层对听觉记忆贡献的调查的研究。通过使用一种新的方法来针对特定类型的细胞进行表观遗传学研究，这里选择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，这些研究将分离不同的神经元和锥体细胞类型在记忆的分子维持中的作用。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，将有助于开发新的药物靶点来治疗与感觉记忆功能障碍有关的疾病，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).