Dissecting the role of amygdalo-striatal circuits in the regulation of stress and cocaine comorbidity in rats

总结/摘要 一般来说，创伤后应激障碍（PTSD）和物质使用障碍（SUD）是分开检查的 在临床前研究中，虽然它们可以同时发生在患者中。因此，有必要观察 这两种疾病紧密结合在一起，以更好地了解这种并发症的机制， 对神经生理学的影响。成瘾的主要问题之一是当患者 暴露于环境线索或其他可能引发与成瘾相关记忆的因素。目前， 与高复发状态相关的因素之一是压力。暴露于压力或创伤性事件中， 会导致创伤后应激障碍此外，PTSD患者表现出更高的SUD率。两个重要的大脑 参与这些疾病发展的结构是基底外侧杏仁核（BLA）和核 （NAc）. BLA涉及恐惧记忆和PTSD的发展，而NAc是 奖励回路，并在SUD的进展中起着重要作用。该NAc被细分为两个主要部分 区域：核心和外壳。研究表明，核心驱动可卡因寻求行为，而外壳 调节灭绝减少可卡因成瘾行为重要的是，BLA-NAc突触的抑制 导致整体药物寻求行为的减少，但慢性应激对这些突触的影响仍然存在。 未知目的是剖析BLA调节复合动物NAc的机制 PTSD和SUD模型。这将有助于更好地了解一种疾病如何影响另一种疾病。中央 假设慢性应激将诱导BLA-NAc核和壳的神经生理学变化 突触，这将与增加可卡因寻求行为相关。为了解决这个问题，该团队建议 目的1：确定慢性应激对大鼠大脑皮层突触神经生理学的影响， 基底外侧杏仁核和杏仁核。目标2：确定光学效应 慢性可卡因成瘾大鼠BLA-NAc壳核突触的激活与可卡因觅药行为无关 可卡因暴露前的压力总的目标是了解慢性压力是如何诱导 啮齿类动物的神经生理学变化与可卡因前的可卡因寻找行为变化相关 exposure.长期的目标是了解大脑的机制和适应所造成的 创伤性事件导致PTSD的发展和获得SUD的易感性。

SUMMARY/ABSTRACT Generally, post traumatic stress disorder (PTSD) and substance use disorder (SUD) are examined seperately in preclinical studies, although they can occur simultaneously in patients. Therefore, it is necessary to observe these two disorders closely together to better understand the mechanisms that underlie this comorbidity and the effects on the neurophysiology. One of the main problems in addiction is the high relapse rate when the patient is exposed to environmental cues or other factors that can trigger memories associated with addiction. Presently, one of the factors associated with a high relapse state is stress. Exposure to a stressful or traumatic events can lead to the development of PTSD. Moreover, PTSD patients exhibit higher rates of SUD. Two important brain structures involved in the development of these disorders are the basolateral amygdala (BLA) and the nucleus accumbens ( NAc). The BLA concerns the development of fear memories and PTSD, while the NAc is part of the reward circuitry and plays an important role in the progression of SUD. This NAc is sub-divided in two main regions: the core and the shell. Studies have shown that the core drives cocaine-seeking behavior while the shell modulates extinction, decreasing cocaine-seeking behavior. Importantly, the inhibition of BLA-NAc synapses leads to a decrease in overall drug seeking behavior, but the effects of chronic stress on these synapses are still unknown. The objective is to dissect the mechanism by which BLA modulates the NAc in a combined animal model of PTSD and SUD. This will help to better understand how one disorder influences the other. The central hypothesis is that chronic stress will induce neurophysiological changes to the BLA-NAc core and shell synapses, which will correlate with increased cocaine-seeking behaviors. To address this, the team proposed the following aims: Aim 1: Determine the effects of chronic stress on the neurophysiology of synapses of the basolateral amygdala and nucleus accumbens prior to cocaine exposure. Aim 2: Determine the effects of optical activation of BLA-NAc shell and core synapses independently on cocaine-seeking behavior in rats with chronic stress prior to cocaine exposure. The overall goal is to understand how the chronic stress induced neurophysiological changes in a rodent correlate with cocaine seeking-behavior changes prior to cocaine exposure. The long-term goal is to understand the mechanisms and adaptations of the brain caused by a traumatic event that leads to the development of PTSD and the susceptibility of acquiring SUD.