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）是两种最常见的精神疾病。 健康障碍和高度共病。不幸的是，PTSD的发病率在美国和加拿大都要高得多。 退伍军人人口。更糟糕的是，患有创伤后应激障碍的退伍军人几乎是酒精问题的两倍 滥用和AUD。这两种疾病都被认为是由“异常学习”引起的， 调整最终导致持续药物滥用或恐惧行为的行为（例如认知灵活性受损）。 最近的证据进一步表明，恐惧和焦虑症的神经回路以及神经系统的神经回路， 吸毒成瘾有许多共同的特点。这两种疾病的一个突出特点是功能失调的顶部- 前额叶皮层（PFC）对行为的控制。前额叶介导的认知过程的改变 调节行为的基因可能导致了这些疾病的高并发症。具有特别的临床重要性， 与非共病相比，这种共病与显著更差的恢复预后相关 个体也有证据表明，PTSD症状是AUD发展的重要风险因素 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。本申请 将检查三个独立的目标，其中包含关于PTSD/AUD共病的新问题，并利用 最先进的技术来回答他们。我们认为，压力和酒精暴露的结合改变了许多 与疾病相关的因素包括药物使用、复发行为、认知缺陷和易受 未来的创伤这项提议的首要假设是，压力和酒精暴露会改变随后的 药物，认知，和压力相关的行为，通过在PFC的亚区域的神经递质机制。 为了验证这一点，我们将使用多方面的方法，包括行为药理学，光遗传学， 遥测研究创伤性应激源和慢性酒精暴露之间的相互作用，以确定 某些大脑机制，可能介导的行为变化。目标1将检查 压力和慢性暴露对酒精相关行为的影响，包括摄入、复发样行为， 灭绝记忆的巩固我们将利用最新的技术发展来监测一些 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 以确定是否压力引起的酒精行为的改变与心脏缺陷有关 心率变异性（HRV：反映应对能力的生理指标）。在这一目标和其他目标中， 将试图通过操纵来减轻或防止压力和酒精引起的行为缺陷 前额叶皮层中的多巴胺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中的炎症标记物。目标2将检查一个组件 PTSD/AUD在该领域尚未得到充分研究。这些是基于认知的任务， 测量临床人群中常见的行为，如正常决策过程的变化。 因此，我们将评估压力和慢性酒精对未来“危险”行为的影响，这些行为通常先于药物。 虐待和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 慢性酒精导致特定脑区神经炎症的显著增加。这一点至关重要 因为它提供了一个潜在的机制，在这个群体中观察到的行为效应。重要的是， 我们有数据表明，调节mGlu 5可以减少应激/酒精诱导的神经炎症， 为药物治疗提供了新的靶点。结合起来，这组实验奠定了基础， 从多个角度研究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.