Dissecting the Role of Prefrontal Circuitry in Basolateral Amygdala Physiology and Regulation of Anxiety Following Chronic Ethanol Exposure and Withdrawal

项目摘要 酒精戒断期间焦虑增加是酒精依赖的一个中心特征， 据报道，这是酒精依赖者复发的常见潜在原因， 他们的治疗。酒精依赖的动物模型同样显示出在治疗期间增加的焦虑样行为。 酒精戒断，这表明他们是一个有效的翻译模型。外侧/基底外侧杏仁核（BLA）具有 被认为是调节许多情绪行为的神经回路的关键组成部分， 包括焦虑我们的实验室最近表明，长期接触乙醇和戒断会产生 BLA中的不同突触改变是输入和时间特异性的。例如，多巴胺能传入神经 沿着内侧BLA边界到达终纹（ST）内表达了突触前形式的可塑性 在酒精暴露的早期发展，而输入通过外囊（EC）到达沿着 BLA的外侧边界在酒精暴露后表达突触后增强。这些数据表明 ST段输入的这种初始突触前易化可能对行为和生理的发展至关重要。 在长期乙醇暴露过程中形成的特征。然而，很少有人知道如何具体 来自不同上游大脑区域的输入受到慢性乙醇暴露的影响，或者这些输入如何可能 独立影响戒酒期间的焦虑。在目前的NRSA提案中，我们将研究 来自内侧前额叶皮层（mPFC）和无颗粒岛叶皮层（AI）的BLA输入， 通过这两条解剖学上不同的途径到达BLA。因此，本培训提案的总体目标是 了解mPFC和/或AI对BLA的输入是否经历类似或独特的突触改变 慢性乙醇暴露/戒断后，以及它们是否是表达 戒断引起的焦虑样行为我们的中心假设是ST段的早期突触前易化- 来自mPFC输入的BLA对于随后的神经生理和行为后果是必要的， 慢性酒精暴露和戒断。我们将通过两个具体目标来解决这个假设。在目标1中， 我们将使用DREADD技术在慢性乙醇过程中的不同时间操纵这些BLA输入， 暴露并使用各种焦虑测定，包括高架十字迷宫和明/暗盒。我们 假设是在慢性乙醇暴露期间mPFC-BLA输入早期易化介导戒断- 引起类似焦虑的行为使用这些相同的动物，在目标2中，我们将使用全细胞膜片钳 电生理学和光遗传学来表征前和后之间的时间生理学关系。 慢性乙醇暴露和戒断后ST-和EC-BLA突触的突触后增强。 对特定脑区的识别可能会为更有效的治疗带来潜在的新靶点。 临床环境中酒精戒断引起的焦虑。

PROJECT SUMMARY Increased anxiety during alcohol withdrawal is a central characteristic of alcohol dependence and has been reported as a common, underlying cause of relapse in those with alcohol dependence, which is a critical barrier to their treatment. Animal models of alcohol dependence likewise show increased anxiety-like behaviors during alcohol withdrawal, suggesting they are a valid translational model. The lateral/basolateral amygdala (BLA) has been identified as a critical component of the neural circuitry that regulates many emotional behaviors, including anxiety. Our laboratory has recently shown that chronic ethanol exposure and withdrawal produce distinct synaptic alterations in the BLA that are input- and timing-specific. For example, glutamatergic afferents arriving within the stria terminalis (ST) along the medial BLA boundary express a presynaptic form of plasticity that develops early during alcohol exposure, whereas inputs arriving via the external capsule (EC) along the lateral boarder of the BLA express postsynaptic potentiation later in alcohol exposure. These data suggest that this initial presynaptic facilitation of ST inputs may be crucial for development of the behavioral and physiologic characteristics that develop during prolonged ethanol exposure. However, little is known about how specific inputs from distinct upstream brain regions are affected by chronic ethanol exposure or how these might independently influence anxiety during alcohol withdrawal. In the current NRSA proposal, we will examine inputs to the BLA from the medial prefrontal cortex (mPFC) and the agranular insular cortex (AI), which project to the BLA via these two anatomically distinct pathways. Thus, the overall goal of this training proposal is to understand whether the mPFC and/or AI inputs to the BLA undergo similar or unique synaptic alterations following chronic ethanol exposure/withdrawal, and whether they are necessary for the expression of withdrawal-induced anxiety-like behavior. Our central hypothesis is that early presynaptic facilitation of the ST- BLA from mPFC inputs is necessary for the subsequent neurophysiologic and behavioral consequences of chronic ethanol exposure and withdrawal. We will address this hypothesis through two Specific Aims. In Aim 1, we will use DREADD technology to manipulate these BLA inputs at different times during chronic ethanol exposure and use a variety of anxiety assays including the elevated plus maze and light/dark box. Our hypothesis is that early facilitation of mPFC-BLA inputs during chronic ethanol exposure mediate withdrawal- induced anxiety-like behavior. Using these same animals, in Aim 2, we will employ whole-cell patch clamp electrophysiology and optogenetics to characterize the temporal physiological relationships between pre- and postsynaptic potentiation of ST- and EC-BLA synapses following chronic ethanol exposure and withdrawal. The identification of specific brain regions might lead to potential novel targets for more effective treatments of alcohol withdrawal-induced anxiety in the clinical setting.