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

酒精使用障碍(AUD)通常伴有精神情感障碍，包括焦虑和 抑郁症。随着美国和全世界发病率的上升，AUD/情感障碍已经成为一种严重的 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 我们对其发展和进展背后的机制缺乏了解。这样做的目的是 建议找出一种以前未被认识到的机制，通过这种机制，Bc1的压力驱动缺陷 RNA导致皮质突触功能障碍，这是AUD/情感障碍共病的基础。 最近，我们首次发现了突触分子的表观遗传失调之间的因果联系。 产前束缚后代的内侧前额叶皮质与AUD/情感障碍表型 应力坝(这里定义为PRS鼠标)。我们发现年轻的成年小鼠表现出高度的焦虑- 与非应激(NS)相比，与酒精消耗量增加相关的相似行为 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脊柱形成和功能的关键突触分子，包括 PSD95(突触后密度95)和ARC(活性调节细胞骨架相关蛋白)。Bc1 RNA (脑细胞质1RNA，这里定义为Bc1)，是一种在哺乳动物皮质中高度表达的长非编码RNA， 在神经元的翻译控制中起着关键作用，对突触的可塑性是必不可少的。我们的初步研究表明 小鼠mPFC制备的突触神经体中bc1的表达显著降低 与NS同行相比。引人注目的是，Bc1探针的RNA下拉显示高度浓缩的mRNAs 编码包括PSD95和ARC在内的关键突触蛋白，这表明这些mRNAs可能受到 Bc1调节突触功能。此外，产前应激可诱导组蛋白脱乙酰酶的过度表达。 (HDAC)，这导致Bc1的减少。综上所述，Bc1可能是发展的关键因素 AUD/情感障碍共病。我们假设Bc1基因的表观遗传抑制是由产前应激引起的 将扰乱树突触的mRNAs的局部翻译，这将改变突触的发育和功能， 导致AUD/情感障碍的共病。大脑皮层bc1的靶向正常化将 恢复小鼠突触功能，挽救类AUD行为。这一假设将在我们的 使用一系列尖端分子方法建立独特的AUD/情感障碍小鼠模型。这个项目 将为复杂的研究奠定基础，这些研究旨在确定非编码核糖核酸(S)在调控中的新角色(S 突触功能促进我们对应激和发育之间复杂相互作用的理解 AUD/情感障碍共病的可能性。这可能会对目标设计和 以表观遗传学水平治疗这些疾病的新药理药物的开发。

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.