Interactions Between Chronic Alcohol Exposure and Fear Memories

 描述(由申请人提供)：尽管酒精使用障碍(AUD)和创伤后应激障碍(PTSD)之间的共患率很高，但我们对这些障碍如何相互作用导致行为和认知严重缺陷的了解存在很大差距。具体地说，关于创伤后应激障碍背后的神经机制如何驱动随后的酒精使用的研究很少。相反，酗酒对创伤后应激障碍相关恐惧记忆的影响并不为人所知。临床和临床前的研究结果都表明，酗酒和创伤后应激障碍之间存在复杂的行为交互作用。例如，暴露在与创伤后应激障碍相关的线索中会增加促进酗酒的焦虑，而这种反复的酗酒会导致创伤后应激障碍记忆的增强，使他们对治疗更具抵抗力。这种模式导致了一个破坏性的循环，包括创伤后应激障碍诱导的酒精消费，加强了创伤后应激障碍的记忆，这反过来又促进了酒精滥用的升级，最终导致了AUD。AUD/PTSD共病的建立导致神经生物学变化，导致认知缺陷，进一步维持酒精滥用和对恐惧线索的夸大反应。此外，关于与AUD/PTSD共发生有关的性别差异的潜在机制还知之甚少。临床结果表明，女性创伤后应激障碍的患病率是男性的两倍，患有创伤后应激障碍的男性和女性饮酒的动机不同。通过使用已建立的动物模型，我们的初步数据表明，恐惧条件化后暴露在慢性间歇性乙醇(CIE)中会导致恐惧相关行为消失的缺陷，对恐惧线索的反应增加酒精摄入量，以及认知灵活性的缺陷。此外，我们还表明，mGluR5的调节可以减轻CIE诱导的恐惧消退学习缺陷，这表明谷氨酸能机制在这些过程中发挥了作用。我们设计了一套全面的研究来测试这一假设的总体假设，即CIE/恐惧条件反射的组合改变了涉及学习、灭绝和记忆重新巩固的特定神经回路。拟议的研究涉及包括行为药理学和光遗传学在内的多方面方法来检验以下假设：目的1)CIE暴露改变恐惧记忆的消退，而恐惧记忆通过PFC和杏仁核中mGluR5的增强而减弱；目的2)在AUD/PTSD模型中，重复暴露于恐惧线索会削弱PFC功能，导致酒精摄入量增加；目的3)在再巩固过程中破坏恐惧记忆可以减轻CIE导致的恐惧消退缺陷；目的4)CIE/恐惧条件反射的组合导致调节灵活行为的执行功能缺陷。这些研究的结果将有助于更好地理解AUD和PTSD之间复杂相互作用的神经机制，这些相互作用导致显著的行为和认知缺陷。它们还将提供潜在的治疗靶点，有助于开发更有效的治疗AUD/PTSD共病的方法。

 DESCRIPTION (provided by applicant): Despite the high rates of comorbidity between alcohol use disorder (AUD) and post traumatic stress disorder (PTSD) there is a substantial gap in our knowledge concerning how these disorders interact to cause significant deficits in behavior and cognition. Specifically, there has been little investigation into how the neural mechanisms underlying PTSD drive subsequent alcohol use. Conversely, the impact of alcohol abuse on PTSD-related fear memories is not well known. Both clinical and pre-clinical findings show a complex behavioral interaction between alcohol abuse and PTSD. For example, exposure to PTSD-related cues increases anxiety that promotes alcohol abuse, while this repeated alcohol abuse leads to an enhancement of PTSD memories making them more resistant to treatment. This pattern results in a damaging cycle that consists of PTSD-induced alcohol consumption that strengthens PTSD memories, which, in turn, promote escalated alcohol abuse ultimately leading to an AUD. The establishment of AUD/PTSD comorbidity leads to neurobiological changes resulting in cognitive deficits that further sustain alcohol abuse and exaggerated responses to fear cues. Furthermore, there is little known about mechanisms underlying sex differences associated with co-occurring AUD/PTSD. Clinical findings indicate that the prevalence of PTSD is twice as high in women as in men and the motives to use alcohol differ between men and women with PTSD. With the use of established animal models, our preliminary data demonstrate that exposure to chronic intermittent ethanol (CIE) after fear conditioning leads to deficits in the extinction of fear-related behaviors, increased alcohol consumption in response to fear cues, and deficits in cognitive flexibility. In addition, we show that modulation of mGluR5 attenuates CIE-induced deficits in fear extinction learning suggesting that glutamatergic mechanisms play a role in these processes. We have designed a comprehensive set of studies to test the overarching hypothesis of this proposal that the combination of CIE/Fear conditioning alters specific neurocircuitry involved in learning, extinction, and memory reconsolidation. The proposed studies involve a multifaceted approach including behavioral pharmacology and optogenetics to test the following hypotheses: Aim 1) CIE exposure alters fear memory extinction that is attenuated through mGluR5 potentiation in regions of the PFC and amygdala; Aim 2) Repeated exposure to fear cues diminishes PFC function leading to increased alcohol intake in a model of AUD/PTSD; Aim 3) Disruption of a fear memory during reconsolidation can attenuate CIE-induced deficits in fear extinction; Aim 4) The combination of CIE/Fear conditioning leads to deficits in executive function that mediate flexible behavior. Findings from these studies will contribute to a better understanding of the neural mechanisms underlying the complex interactions between AUD and PTSD that contribute to significant behavioral and cognitive deficits. They will also provide potential therapeutic targets that will aide in the development of more effective treatments for AUD/PTSD comorbidity.