Ethanol & Anxiety: Cellular Mechanisms

酒精滥用会引起行为和神经生物学功能的显著变化。在行为 持续滥用的关键表现是焦虑和寻求奖励的严重增加 行为。这些结果是密切相关的，并共同推动随后的乙醇滥用。的 外侧/基底外侧杏仁核在调节焦虑和奖赏寻求中起着关键作用。最近 对未使用过药物的动物的条件反射行为的研究表明，隔离但混合的种群 基底外侧杏仁核主神经元独立参与“奖赏”和“厌恶”相关 电路.重要的是，这种分离也反映在突触水平上，奖励或厌恶影响着 这些神经元以回路特异性和相互排斥的方式连接到这些群体上。但在 尽管在幼稚条件下存在这种功能分离，但奖赏寻求和“厌恶”通常是共同的。 在有药物经验的动物中表达。而且，我们已经证明，依赖性，如乙醇暴露强烈 以非分离的方式改变BLA突触功能。奖励的并列-/ BLA内的情感回路控制，以及慢性乙醇对参与这些神经元的影响。 电路，表明可能的细胞机制驱动巧合的奖励寻求和负面影响， 酒精依赖后。这导致了当前应用程序的中心假设， 不同BLA输入的合作突触可塑性控制着奖赏寻求和 慢性酒精暴露后的负面情绪状态。为了验证这一假设，我们提出了三个具体的 目标。目标1将检验长期饮酒的工作假设，与自然条件行为不同， 促进独立于其投射靶的主神经元处的BLA突触功能。我们将整合 逆行追踪和电生理方法来测量突触功能和内在的 不同的“valenced”BLA神经元参与不同的“奖励”和“厌恶”电路的特性。 目标2将检验工作假设，即慢性乙醇的突触前易化是必要的， 足以在不同的突触处发展突触后可塑性。我们这'乙醇诱导 通过整合光遗传学、化学遗传学和体外电生理学， 测定定义的输入（前边缘和无颗粒岛叶皮质）之间的功能耦合，和2）破坏它们的 功能性互动最后，对于目标3，我们将检验乙醇对细胞生长的调节障碍这一工作假设。 BLA-PrL突触通过整合控制慢性乙醇后的负性情感和奖赏寻求 化学遗传学与依赖性相关的酒精饮酒和焦虑样行为。拟议的工作是 这在技术上是创新的，意义重大，因为它利用了最先进的基于电路的方法， 直接定义调节酒精依赖性负面影响和奖励的神经生物学机制， 寻求酒精滥用和成瘾的特征。

Ethanol abuse produces marked changes in behavior and neurobiological function. Among the behavioral manifestations critical for continued abuse are the profound increases in anxiety-like and reward-seeking behaviors. These outcomes are intimately related and together drive subsequent ethanol abuse. The lateral/basolateral amygdala plays a critical role in the regulation of both anxiety and reward-seeking. Recent work with conditioned behaviors in drug naïve animals suggests that segregated but intermingled populations basolateral amygdala principal neurons independently participate within `reward'- and `aversion'-related circuits. Importantly, this segregation is also reflected at the synaptic level with reward or aversion influencing glutamatergic synapses onto these populations in a circuit-specific and mutually exclusive manner. Yet, in spite of this functional segregation in the naïve condition, reward-seeking and `aversion' are typically are co- expressed in drug-experienced animals. And, we have shown that dependence-like ethanol exposure robustly alters BLA synaptic function in what appears to be a non-segregated fashion. The juxtaposition of reward-/ affective-circuit control within the BLA, and the effects of chronic ethanol across neurons participating in these circuits, suggests possible cellular mechanisms driving coincidental reward-seeking and negative affect following alcohol dependence. This leads to the CENTRAL HYPOTHESIS of the current application that cooperative synaptic plasticity at distinct BLA inputs controls the interaction between reward-seeking and negative affective states that follow chronic ethanol exposure. To test this hypothesis, we propose three specific aims. Aim 1 will test the working hypothesis that chronic ethanol, unlike naturally conditioned behaviors, facilitates BLA synaptic function at principal neurons independent of their projection target. We will integrate retrograde tracing and electrophysiological approaches to measure both synaptic function and intrinsic properties of differentially `valenced' BLA neurons participating within distinct `reward' and `aversion' circuits. Aim 2 will test the working hypothesis that presynaptic facilitation by chronic ethanol is necessary and sufficient for the development of postsynaptic plasticity at distinct synapses. We this `ethanol-induced heterosynaptic cooperation' by integrating optogenetics, chemogentics, and in vitro electrophysiology to 1) assay functional coupling between defined inputs (prelimbic and agranular insular cortex) and 2) disrupt their functional interaction. Finally, for Aim 3, we will test the working hypothesis that ethanol dysregulation of BLA-PrL synapses governs both negative affect and reward seeking following chronic ethanol by integrating chemogenetics with dependence-related ethanol drinking and anxiety-like behavior. The proposed work is both technically innovative and significant because it utilizes state-of-the-art circuit-based approaches to directly define neurobiological mechanisms regulating both ethanol-dependent negative affect and reward- seeking which characterize alcohol abuse and addiction.