Impact of Prenatal Ethanol on BLA Synaptic Plasticity

摘要 怀孕期间饮酒和酗酒的发生率非常高，这可能导致 胎儿酒精谱系障碍（Fetal Alcohol Spectrum Disorders）最常见的一 产前酒精暴露（PAE）的后果是在青春期出现焦虑症， 这在暴露于中等水平的乙醇后令人惊讶地观察到-这是一种常见的模式， 怀孕期间饮酒尽管有这些令人信服的流行病学数据， 中度PAE诱导的焦虑的潜在机制尚未得到很好的理解。突触活动和可塑性 在基底外侧杏仁核（BLA）中，部分是通过内侧前额叶皮质的输入来驱动的 （mPFC），并与焦虑样行为的调节和表达相关。此外，BLA 突触活性和可塑性由强啡肽/κ阿片受体（DYN/KOR）系统调节， 也与焦虑样行为的改变有关。尽管研究表明PAE可以改变 mPFC功能，增加BLA可塑性，并降低杏仁核KOR水平（与所观察到的效果相反 成年后暴露于乙醇），是否中度PAE水平更可能出现在怀孕 女性影响这些目标以及高度脆弱时期这些改变之间的相互作用 青春期的发育期是未知的。我们最近描述了一个中度PAE模型的特征 使用在妊娠第12天（G）单次暴露于蒸发的乙醇，在此期间， 杏仁核开始出现，在青少年后代中产生增加的社交焦虑样行为。 基于此，我们假设中度G12 PAE通过以下方式增加青春期的焦虑样行为： 增强mPFC-β-BLA突触可塑性，降低DYN/KOR功能。为了验证我们的假设，目标1将 使用体外研究方法检查中度G12 PAE对mPFC β BLA突触可塑性改变的影响， 光遗传学和电生理学工具。目的2将测试中等G12 PAE对KOR调节的影响 使用分子、电生理和体内研究相结合的方法， 光遗传学和行为药理学相结合。这些创新的研究将测试新颖和独特的 围绕中度PAE的长期影响的假设，并描述了特定于 缺乏类似焦虑的行为

Abstract The incidence of alcohol drinking and alcohol abuse during pregnancy is strikingly high which can lead to a spectrum of deficits in offspring termed Fetal Alcohol Spectrum Disorders. One of the most common consequences of prenatal alcohol exposure (PAE) is the emergence of anxiety disorders in adolescence, which are surprisingly observed following exposure to moderate levels of ethanol – a common pattern of alcohol consumption in pregnancy. Despite these compelling epidemiological data, the neurobiological mechanisms underlying moderate PAE-induced anxiety are not well understood. Synaptic activity and plasticity within the basolateral amygdala (BLA) is driven, in part, through inputs from the medial prefrontal cortex (mPFC), and are associated with regulation and expression of anxiety-like behaviors. Additionally, BLA synaptic activity and plasticity is modulated by the dynorphin/kappa opioid receptor (DYN/KOR) system that is also associated with alterations in anxiety-like behaviors. Although studies have shown that PAE can alter mPFC function, increase BLA plasticity, and reduce amygdala KOR levels (an effect opposite of what is seen following exposure to ethanol in adulthood), whether moderate PAE at levels more likely seen in pregnant women affects these targets and the interaction(s) between these alterations during the highly vulnerable developmental period of adolescence are unknown. We have recently characterized a model of moderate PAE using a single exposure to vaporized ethanol on gestational day (G) 12, a developmental epoch during which the amygdala begins to appear, that produces increased social anxiety-like behaviors in adolescent offspring. Based on this, we hypothesize that moderate G12 PAE increases anxiety-like behavior in adolescence through enhanced mPFCBLA synaptic plasticity and reduced DYN/KOR function. To test our hypothesis, Aim 1 will examine the impact of moderate G12 PAE on alterations in mPFCBLA synaptic plasticity using in vitro optogenetic and electrophysiological tools. Aim 2 will test the effect of moderate G12 PAE on KOR modulation of mPFCBLA synaptic plasticity using a combination of molecular, electrophysiological and in vivo optogenetics coupled with behavioral pharmacology. These innovative studies will test novel and unique hypotheses surrounding the long-term effects of moderate PAE and describe neural mechanisms specific to deficits in anxiety-like behaviors.