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）通常伴有精神病情感障碍，包括焦虑和 沮丧。随着美国和全球范围内的越来越多的流行率，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 我们对其发展和发展的机制缺乏了解。目标的目标 提案是确定以前未认识到的机制 RNA诱导皮质突触功能障碍，这是AUD/情感障碍的合并症的基础。 最近，我们首次发现了突触分子表观遗传失调之间的因果关系。 在产前约束的后代中，内侧前额叶皮层（MPFC）和AUD/情感障碍表型 压力大坝（此处定义为PRS小鼠）。我们发现年轻的成年PRS小鼠表现出焦虑症 - 与非压力（NS）相比，与乙醇消耗增加有关的行为 后代。进一步的研究表明，PRS小鼠的行为缺陷的特征是减少 皮质的树突状脊柱密度和关键突触分子，这些分子控制脊柱形成和功能，包括 PSD95（突触密度95后）和ARC（活性调节的细胞骨架相关蛋白）。 BC1 RNA （脑细胞质1 RNA，此处定义为BC1），这是一种在哺乳动物皮质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，对于突触可塑性至关重要。我们的试点研究表明 从PRS小鼠的MPFC制备的突触瘤体中，BC1表达显着降低 与NS同行相比。引人注目的是，用BC1探针下拉的RNA显示出高度富集的mRNA 编码包括PSD95和ARC在内的密钥突触蛋白，表明这些mRNA可以通过 BC1在调整突触函数中。另外，产前应激引起组蛋白脱乙酰基酶的过表达 （HDAC）导致BC1减少。综上所述，BC1可能是发展的关键因素 AUD/情感障碍合并症。我们假设产前应激引起的BC1表观遗传抑制 将破坏树突突触中mRNA的局部翻译，这将改变突触的发展和功能， 有助于AUD/情感障碍的合并症。皮质BC1的靶向归一化将 恢复PRS小鼠中的突触功能并挽救类似音音的行为。假设将在我们的 使用一系列尖端分子方法的AUD/情感障碍的独特小鼠模型。这个项目 将为旨在定义非编码RNA的新作用在调节中的新作用的复杂研究基础 突触功能以提高我们对压力与发展之间复杂相互作用的理解 AUD/情感障碍合并症的合并症。这可能在目标设计和 在表观遗传学水平的这些疾病治疗这些疾病方面开发新的药理学剂。