Synaptic Non-coding RNA BC1 and Prenatal Stress-induced Alcohol Use Disorder

突触非编码 RNA BC1 与产前压力诱发的酒精使用障碍

• 批准号: 9979150
• 负责人: Erbo Dong
• 金额: $ 22.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979150
• 关键词: Alcohol consumption; Amygdaloid structure; Anxiety; BC1 RNA; Behavior; Behavioral; Biological Assay; Brain; Brain region; Complex; Cytoskeleton; Dendritic Spines; Dependovirus; Development; Disease; Environment; Epigenetic Process; Etiology; Exhibits; Exposure to; FRAP1 gene; Foundations; Functional disorder; Genetic; Genetic Translation; Goals; HDAC2 gene; Hippocampus (Brain); Histone Deacetylase; Infusion procedures; Investigation; Label; Life; Link; Measures; Medial; Mediating; Mental Depression; Mental disorders; Messenger RNA; Metabolic; Molecular; Mood Disorders; Morphology; Mus; Neurons; Nuclear Extract; Pharmacology; Phenotype; Phosphotransferases; Pilot Projects; Play; Prefrontal Cortex; Pregnancy; Prevalence; Prevention strategy; Proteins; Proto-Oncogene Proteins c-akt; Public Health; RNA; Repression; Role; Series; Slice; Small Interfering RNA; Stress; Synapses; Synaptic plasticity; Synaptosomes; Techniques; Testing; Time; Transcript; Translating; Translations; Tropomyosin; Untranslated RNA; Vertebral column; alcohol comorbidity; alcohol use disorder; anxiety-like behavior; base; comorbidity; density; design; insight; knock-down; mouse model; neurodevelopment; novel; offspring; overexpression; postsynaptic density protein; prenatal; prenatal stress; protein expression; receptor; restraint stress; synaptic function; treatment strategy; young adult

Alcohol use disorder (AUD) is often accompanied by psychiatric affective disorders, including anxiety and depression. With the rising prevalence in the USA and worldwide, AUD/affective disorder has become a serious public health issue. Unfortunately, effective prevention and treatment strategies for this disorder are hampered by our lack of understanding of the mechanisms underlying its development and progression. The goal of this proposal is to identify a previously unrecognized mechanism by which stress-driven deficiency of BC1 RNA induces cortical synaptic dysfunction, which underlies the comorbidity of AUD/affective disorders. Recently, we discovered, for the first time, a causal link between epigenetic dysregulation of synaptic molecules in the medial prefrontal cortex (mPFC) and AUD/affective disorder phenotypes in the offspring of prenatally restraint stressed dams (here defined as PRS mouse). We found that young adult PRS mice exhibited heightened anxiety- like behaviors which were associated with increased ethanol consumption compared to non-stressed (NS) offspring. Further studies revealed that the behavioral deficits in PRS mice were characterized by a decrease in cortical dendritic spine density and key synaptic molecules that govern spine formation and function, including PSD95 (post synaptic density 95) and ARC (activity regulated cytoskeleton associated protein). BC1 RNA (brain cytoplasmic1 RNA, here defined as BC1), a long non-coding RNA highly expressed in mammalian cortex, plays a pivotal role in neuronal translational control and is essential for synaptic plasticity. Our pilot studies show that BC1 expression was significantly decreased in synaptoneurosomes prepared from mPFC of PRS mice compared to NS counterparts. Strikingly, RNA pull-down with BC1 probe revealed highly enriched mRNAs encoding key synaptic proteins, including PSD95 and ARC, suggesting that these mRNAs could be modulated by BC1 in tuning synaptic functions. In addition, prenatal stress elicited overexpression of histone deacetylases (HDACs) which resulted in the reduction of BC1. Taken together, BC1 may be a key factor in the development of AUD/affective disorder comorbidity. We hypothesize that epigenetic repression of BC1 induced by prenatal stress will disrupt local translation of mRNAs at dendritic synapses, which will alter synaptic development and function, contributing to the comorbidity of AUD/affective disorders. The targeted normalization of cortical BC1 will restore synaptic function and rescue AUD-like behaviors in PRS mice. The hypothesis will be tested in our unique mouse model of AUD/affective disorders using a series of cutting-edge molecular approaches. This project will set a foundation for intricate studies aimed at defining the novel role(s) of non-coding RNA(s) in regulating synaptic function to advance our understanding of the complex interplay between stress and the development of comorbidity of AUD/affective disorders. This could have far-reaching implications in the targeted design and development of new pharmacological agents towards the treatment of these disorders at epigenetic levels.

酒精使用障碍（AUD）通常伴有精神情感障碍，包括焦虑和焦虑。 萧条随着美国和世界范围内患病率的上升，AUD/情感障碍已成为严重的 公共卫生问题。不幸的是，这种疾病的有效预防和治疗策略受到以下因素的阻碍： 我们缺乏对其发展和进展机制的了解。这个目标 一项建议是确定一种以前未被认识到的机制，通过这种机制，压力驱动的BC 1缺陷 RNA诱导皮质突触功能障碍，这是AUD/情感障碍共病的基础。 最近，我们第一次发现了突触分子的表观遗传失调与神经细胞凋亡之间的因果关系。 产前约束后代的内侧前额叶皮质（mPFC）和AUD/情感障碍表型 应激母鼠（此处定义为PRS小鼠）。我们发现年轻的成年PRS小鼠表现出高度的焦虑- 与非应激（NS）相比，与乙醇消耗量增加相关的类似行为 后代进一步的研究表明，PRS小鼠的行为缺陷的特征是， 皮质树突棘密度和控制棘形成和功能的关键突触分子，包括 突触后密度95（PSD 95）和ARC（活性调节细胞骨架相关蛋白）。BC1 RNA （脑细胞质1 RNA，这里定义为BC 1），一种在哺乳动物皮层中高度表达的长的非编码RNA， 在神经元翻译控制中起关键作用，并且对于突触可塑性是必不可少的。我们的初步研究表明 从PRS小鼠mPFC制备的突触神经小体中BC 1表达显著降低， 与NS的对比。引人注目的是，BC 1探针的RNA下拉显示了高度富集的mRNA 编码关键的突触蛋白，包括PSD 95和ARC，这表明这些mRNAs可以通过 BC 1调节突触功能。此外，产前应激引起组蛋白去乙酰化酶的过度表达 （HDAC），这导致BC 1的减少。综上所述，BC 1可能是发展中的一个关键因素， AUD/情感障碍共病。我们推测，产前应激诱导的BC 1的表观遗传抑制 将破坏树突突触处mRNA的局部翻译，这将改变突触发育和功能， 导致AUD/情感障碍的共病。皮质BC 1的目标正常化将 恢复PRS小鼠的突触功能并挽救AUD样行为。这个假设将在我们的 使用一系列尖端的分子方法建立了独特的AUD/情感障碍小鼠模型。这个项目 这将为旨在确定非编码RNA在调节细胞凋亡中的新作用的复杂研究奠定基础。 突触功能，以促进我们对压力和发育之间复杂相互作用的理解， AUD/情感性精神障碍的合并症。这可能对目标设计产生深远影响， 开发新的药理学试剂，在表观遗传水平上治疗这些疾病。