mGlu5 modulation prevents and attenuates deficits in a model of PTSD/AUD comorbidity

创伤后应激障碍(PTSD)和酒精使用障碍(AUD)是最常见的两种精神疾病 健康紊乱，并高度并存。不幸的是，创伤后应激障碍的发病率在 退伍军人群体。更糟糕的是，患有创伤后应激障碍的退伍军人患酒精问题的可能性几乎是前者的两倍 虐待和澳元。这两种障碍都被认为是由于“异常学习”导致的能力缺陷引起的。 调整最终导致持续滥用药物或恐惧行为的行为(如认知灵活性受损)。 最近的证据进一步表明，恐惧和焦虑症的神经回路以及 吸毒成瘾有许多共同特征。这两种疾病的一个显著特征是顶叶功能障碍- 前额叶皮质(PFC)对行为的下行控制。前额叶调节的认知过程的改变 调节行为可能是导致这些疾病的高共病的原因之一。具有特殊的临床重要性， 与非共病相比，这种合并症与显著更差的康复预后有关。 个人。也有证据表明，创伤后应激障碍症状是发展为澳门氏症的重要风险因素。 这反过来又会干扰创伤后应激障碍的治疗，并导致功能障碍的增加。此应用程序 将研究三个独立的目标，其中包含关于创伤后应激障碍/AUD共病的新问题，并利用 回答这些问题的艺术技巧。我们认为，压力和酒精暴露的结合会改变许多 与疾病相关的因素包括药物使用、复发行为、认知缺陷和易感性 未来的创伤。这一建议的主要假设是，压力和酒精暴露会改变随后的 药物、认知和应激相关行为通过PFC亚区的谷氨酸能机制。至 测试，我们将使用多方面的方法，结合行为药理学，光遗传学，和 遥测调查创伤应激源和慢性酒精暴露之间的相互作用以识别 某些大脑机制可能会调节由此导致的行为变化。目标1将检查以下结果 压力和慢性暴露对酒精相关行为的影响，包括摄入、旧病复发行为和 对灭绝记忆的巩固。我们将利用技术的最新发展来监控一些 在老鼠身上进行的测量与人类研究中经常使用的相同。无线电遥测传感器将被植入 确定应激诱导的酒精行为改变是否与心脏功能障碍有关的大鼠 心率变异性(HRV：反映应对能力的生理指标)。在这个目标和剩下的目标中， 将试图通过操纵来减轻或防止压力和酒精诱导的行为缺陷 PFC中的谷氨酸能信号及其向其他大脑区域的投射。最后，为了更好地理解 涉及的神经机制我们将测量PFC中的炎症因子。AIM 2将检查一个组件 创伤后应激障碍/澳门氏症的风险没有在实地得到充分的调查。这些是基于认知的任务， 测量临床人群中常见的行为，如正常决策过程中的变化。 因此，我们将评估压力和长期饮酒对未来通常在吸毒之前的“危险”行为的影响。 滥用与创伤后应激障碍的发展。在目标3中，我们将确定如何暴露于压力和压力的组合 长期饮酒会导致特定大脑区域的神经炎症显著增加。这一点很关键 因为它为在这个群体中观察到的行为影响提供了一种潜在的机制。重要的是 我们有数据表明，调节mGlu5可以减少应激/酒精诱导的神经炎症，这 为药物治疗提供了一个新的靶点。当组合在一起时，这组实验奠定了基础 从多个角度审视PTSD/AUD，突出潜在的神经机制，并开发新的 治疗方案。

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are two of the most common mental health disorders and are highly comorbid. Unfortunately, the incidence rate of PTSD is significantly greater in the Veteran population. Even worse, Veterans with PTSD are almost twice as likely to develop issues with alcohol abuse and AUD. Both disorders are thought to arise from “aberrant learning” resulting in deficits in the ability to adjust behavior (e.g. impaired cognitive flexibility) that ultimately drives continued drug abuse or fear behavior. Recent evidence further suggests that the neurocircuitry of fear and anxiety disorders and the neurocircuitry of drug addiction have many common characteristics. A prominent feature of both disorders is dysfunctional top- down control of behavior by the prefrontal cortex (PFC). Alterations in prefrontal-mediated cognitive processes that regulate behavior likely contribute to the high comorbidity of the disorders. Of particular clinical importance, this comorbidity is associated with significantly worse prognosis of recovery when compared to non-comorbid individuals. There is also evidence that PTSD symptoms are a significant risk factor for development of AUD that, in turn, interfere with PTSD treatment and contributes to increased functional impairment. This application will examine three separate aims that contain novel questions about PTSD/AUD comorbidity and utilize state-of- the-art techniques to answer them. We propose that the combination of stress and alcohol exposure alters many factors associated with the disorder including drug use, relapse behavior, cognitive deficits, and vulnerability to future traumas. The overarching hypothesis of this proposal is that stress and alcohol exposure alter subsequent drug, cognitive, and stress-related behaviors through glutamatergic mechanisms in subregions of the PFC. To test this, we will use a multi-faceted approach that incorporates behavioral pharmacology, optogenetics, and telemetry to investigate the interactions between a traumatic stressor and chronic alcohol exposure to identify certain brain mechanisms that may mediate the resulting changes in behavior. Aim 1 will examine the result of stress and chronic exposure on alcohol-related behaviors including intake, relapse-like behavior, and consolidation of extinction memories. We will use recent developments in technology to monitor some of the same measurements in rats that are often used in human studies. Radiotelemetry sensors will be implanted in the rats to determine whether stress-induced alterations in alcohol behaviors are associated with deficits in heart rate variability (HRV: a physiological measure that reflects coping ability). In this aim, and the remaining aims, will attempt to either attenuate or prevent stress- and alcohol-induced behavioral deficits through manipulation of glutamatergic signaling in the PFC and its projections to other brain regions. Finally, to better understand the neural mechanisms involved we will measure inflammatory makers in the PFC. Aim 2 will examine a component of PTSD/AUD that has not been investigated sufficiently in the field. These are cognitive-based tasks that measure behaviors often seen in the clinical population such as changes in normal decision-making processes. Thus, we will assess the impact of stress and chronic alcohol on future “risky” behaviors that often precede drug abuse and the development of PTSD. In Aim 3 we will determine how exposure to the combination of stress and chronic alcohol leads to significant increases in neuroinflammation in specific brain regions. This is critical because it provides a potential mechanism for the behavioral effects observed in this population. Importantly, we have data showing that modulation of mGlu5 can reduce stress/alcohol-induced neuroinflammation and this provides a novel target for drug treatment. When combined, this set of experiments lays the foundation to examine PTSD/AUD from multiple perspectives, highlight potential neural mechanisms, and develop novel treatment options.