Exploring epigenetic regulation of memory extinction

探索记忆消退的表观遗传规律 项目总结 这项提议的广泛目标是了解恐惧记忆是如何在大脑中消失的。消退学习是指持续暴露在与厌恶事件相关的线索中，导致对这些线索的反应减弱，这是一种修改或消除恐惧记忆的方法。然而，控制消退过程的分子机制仍然不清楚，限制了这一行为过程的治疗潜力。最近的证据表明，消退学习需要内侧前额叶皮质(MPFC)和背侧海马(DHPC)中的Egr1和DNA去甲基化酶TET1等神经元活性诱导转录因子的作用，但这两种机制是如何调控消退过程的尚不清楚。我们最近的研究表明，在出生后早期发育过程中，Egr1招募TET1来移除脑DNA上的甲基化标记，尽管这种关系是否存在于成人大脑中依赖学习的突触可塑性期间仍不明确。这项资助的目的是探索这两种蛋白质如何相互作用来控制记忆消失的过程，并有两个特定的目标。在目标1中，研究人员将结合基因敲除小鼠模型中的行为范式和全基因组下一代测序方法，确定Egr1和TET1在mPFC和DHPC中的表观遗传学作用。在目标2中，通过在mPFC和DHPC中进行有针对性的CRISPR-dCas9操作，研究人员将确定记忆消退过程中依赖于Egr1的TET1对记忆允许基因Npas4的表观遗传学作用。总而言之，该项目的成功将为我们理解Egr1/Tet1和Npas4基因在灭绝巩固过程中的表观遗传学作用提供新的见解，并显著拓宽我们对记忆消失机制的理解，这可能会导致治疗与各种精神障碍相关的恐惧记忆的新的治疗策略。

TITLE: EXPLORING EPIGENETIC REGULATION OF MEMORY EXTINCTION PROJECT SUMMARY The broad goal of this proposal is to understand how fear memories are extinguished in the brain. Extinction learning, in which continued exposure to cues associated with an aversive event result in reduced responding to these cues, has been proposed as a way to modify or erase fear memories. However, the molecular mechanisms that control the extinction process remain poorly defined, limiting the therapeutic potential of this behavioral process. Recent evidence suggests that extinction learning requires the functions of neuronal activity induced transcription factors including EGR1 and DNA demethylation enzyme TET1 in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DHPC), though it is unknown how these two mechanisms regulate the extinction process. Our recent study indicated that EGR1 recruits TET1 to remove methylation marks on brain DNA during early postnatal development, though whether such a relationship exists during learning-dependent synaptic plasticity in the adult brain remains equivocal. The purpose of this grant is to explore how these two proteins interact to control memory extinction processes with two specific aims. In Aim 1, the investigators will determine the epigenetic roles of EGR1 and TET1 in the mPFC and DHPC during the extinction of fear memory using a combination of behavioral paradigms in genetic knockout mouse models with whole-genome next generation sequencing approaches. In Aim 2, using targeted CRISPR-dCas9 manipulations in the mPFC and DHPC, the investigators will determine the epigenetic role of EGR1-dependent recruitment of TET1 to the memory permissive gene Npas4 during memory extinction. Collectively, the success of this project will provide novel insights into our understanding of the epigenetic role of Egr1/Tet1 and Npas4 genes during extinction consolidation and significantly broaden our understanding of the mechanisms underlying memory extinction, which could potentially lead to new treatment therapeutic strategies for the treatment fear memories associated with a variety of psychiatric disorders.