Impact of Prenatal Ethanol on BLA Synaptic Plasticity

摘要 怀孕期间饮酒和酗酒的发生率高得惊人，这可能导致 子代缺陷谱被称为胎儿酒精谱系障碍。最常见的一种 产前酒精暴露(PAE)的后果是青春期出现焦虑障碍， 在接触中等水平的乙醇后，令人惊讶地观察到这些变化--这是一种常见的 怀孕期间饮酒。尽管有这些令人信服的流行病学数据，但神经生物学 中度PAE诱发焦虑的潜在机制尚不清楚。突触活性与可塑性 在基底外侧杏仁核(BLA)，部分是通过内侧前额叶皮质的输入驱动的 (MPFC)，并与焦虑样行为的调节和表达有关。此外，BLA 突触活性和可塑性由强啡肽/kappa阿片受体(Dyn/KOR)系统调节，即 也与焦虑类行为的改变有关。尽管研究表明PAE可以改变 MPFC功能，增加BLA可塑性，降低杏仁核KOR水平(与所见相反的效果 成年后接触乙醇)，是否适度的PAE水平更有可能出现在怀孕 女性影响这些目标以及这些变化之间的相互作用(S)在极易受到伤害的期间 青春期的发育阶段尚不清楚。我们最近确定了一个中度PAE模型的特征 在妊娠第12天单次暴露于蒸发乙醇，在此期间 杏仁核开始出现，这会在青春期的后代中产生更多类似社交焦虑的行为。 基于此，我们假设适度的G12 PAE通过以下途径增加青春期的焦虑样行为 MPFC、、BLA突触可塑性增强，Dyn/Kor功能降低。为了检验我们的假设，目标1将 体外实验检测适度的G12PAE对mPFC、、BLA突触可塑性的影响 光遗传和电生理工具。目标2将测试适度的G12 PAE对KOR调制的影响 结合分子、电生理和体内实验研究mPFC--Bla突触可塑性 光遗传学与行为药理学相结合。这些创新的研究将检验新奇和独特的 围绕中度PAE的长期影响的假说，并描述了特定于 焦虑样行为方面的缺陷。

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.