Stress-Induced Alterations in Amygdala-LC Interactions

描述(由申请人提供)：压力是药物滥用开始和复发的一个主要因素。在过去的资助期间，研究了压力对杏仁核-蓝斑(LC)系统的影响，以及在长期应激暴露后这种反应是如何改变的。在这次重新提交中，这将扩展到受LC影响的系统，以及它们可能如何影响药物滥用。压力和药物滥用有许多共同的特征，包括在靶结构中释放多巴胺(DA)和去甲肾上腺素(NE)的能力，以及与环境的强烈联系。出于这个原因，这项工作特别关注一个区域：海马体腹侧下丘(VSub)。VSub主要参与上下文相关的过程，越来越多的证据表明它在调节应激反应中起着至关重要的作用。此外，我们还表明，vSub通过控制群体活动(即自发放电的DA神经元的比例)来对DA神经元的活动进行有效的控制，这设置了系统对相性事件做出反应时的“增益”。我们的初步数据表明，vSub诱导的DA神经元群体活动的激活可能是苯丙胺行为敏化的基础。因此，应激或重复治疗对苯丙胺的敏化导致DA神经元群体活性的增加，这可以通过vSub的失活来绕过。此外，杏仁核和NE系统都为vSub神经元的放电提供了强大的激活。我们的中心假设是，苯丙胺治疗和应激都发挥着共同的作用，即vSub介导的DA神经元群体活动的激活，这是药物敏化的基础。我们将使用vSub和腹侧被盖DA神经元的活体记录，使用行为和微透析措施来确认敏化反应。我们将沿着以下具体目标来探讨这一点：1)检查急性应激源或伤害性刺激是否激活vSub，以及这是否依赖于NE和BLA传入；这将表明已知的导致敏化的刺激是否也激活vSub。2)检测急性应激源对DA神经元活性和苯丙胺行为反应的影响，以及这是否通过vSub介导；这将评估vSub在应激诱导的DA神经元群体活动增加中的作用。3)研究急性和重复安非他明对DA神经元活动的影响；这将评估由vSub驱动的DA神经元群体放电增加是否也有助于安非他明诱导的敏化。4)研究慢性应激如何改变DA神经元的放电和苯丙胺敏化；这将扩展我们之前关于慢性应激期间杏仁核-NE系统变化的结果，以及这如何影响敏化。敏化在吸毒中的作用尚不清楚，但大量数据表明，心理刺激剂敏化在对吸毒行为的渴望和复发中发挥着核心作用。通过更好地了解应激暴露的神经生物学后果，我们希望揭示边缘系统中发生的神经适应性变化，这些变化使个人容易发生吸毒行为，并导致复发。压力在人类进行吸毒行为和复发的倾向中起着重要作用，众所周知，压力会增加安非他明等药物在动物身上的回报特性。压力和苯丙胺对大脑中的神经递质多巴胺都有共同的作用。在这个项目中，我们测试了暴露在安非他明和压力下的大脑中产生的共同适应性变化，以更好地了解是什么导致人们对药物上瘾和复发，并指导开发更有效的长期药物滥用治疗方法。

DESCRIPTION (provided by applicant): Stress is a major factor in the onset and relapse to drug abuse. Over the past funding period, the effects of stress on the amygdala-locus coeruleus (LC) system, and how the response is altered after chronic stress exposure, was examined. In this resubmission, this will be extended to systems affected by the LC, and how they may impact drug abuse. Stress and drug abuse share a number of features in common, including the ability to release dopamine (DA) and norepinephrine (NE) in target structures, and a strong association with context. For this reason, this work focuses on one area in particular: the ventral subiculum (vSub) of the hippocampus. The vSub is centrally involved in context dependent processes, and increasing evidence points to its crucial role in regulating stress responsivity. Furthermore, we have shown that the vSub exerts potent control over DA neuron activity by controlling the population activity (i.e., proportion of DA neurons firing spontaneously), which sets the "gain" of the system when it responds to phasic events. Our preliminary data suggest that vSub-induced activation of DA neuron population activity may underlie behavioral sensitization to amphetamine. Thus, sensitization to amphetamine by stress or by repeated treatment leads to an increase in DA neuron population activity that can be circumvented by inactivation of the vSub. Moreover, both the amygdala and the NE system provide a strong activation of vSub neuron firing. Our central hypothesis is that both amphetamine treatment and stress exert a common action, i.e., vSub-mediated activation of DA neuron population activity, which underlies drug sensitization. We will pursue this using in vivo recordings in the vSub and from ventral tegmental DA neurons, using behavioral and microdialysis measures to confirm sensitized responses. We will explore this along the following specific aims: 1) Examine whether acute stressors or noxious stimuli activate the vSub, and whether this is dependent on NE and BLA afferents; this will show if stimuli known to lead to sensitization also activate the vSub. 2) Examine the effects of acute stressors on DA neuron activity and behavioral response to amphetamine, and if this is mediated via the vSub; this will evaluate the role of the vSub in stress-induced increase in DA neuron population activity. 3) Examine the effects of acute versus repeated amphetamine on DA neuron activity; this will evaluate whether increased DA neuron population firing as driven by the vSub also contributes to amphetamine-induced sensitization. 4) Examine how chronic stress alters DA neuron firing and amphetamine sensitization; this will extend our previous results on alterations in the amygdala-NE system during chronic stress, and how this impacts sensitization. The role of sensitization in drug taking is not clear; however, substantial data suggest that psychostimulant sensitization plays a central role in craving and relapse to drug-taking behavior. By gaining a better understanding of the neurobiological consequences of stress exposure, we hope to uncover the neuroadaptive changes that take place within the limbic system that predispose an individual to drug-taking behavior and contribute to relapse. Stress plays a major role in the propensity of humans to engage in drug-taking behavior and to suffer relapse, and is known to increase the rewarding properties of drugs such as amphetamine in animals. Both stress and amphetamine have common actions on the neurotransmitter dopamine in the brain. In this project, we test for common adaptive changes that are produced in a brain exposed to amphetamine and stress in order to better understand what causes people to become addicted and relapse to drug taking behavior, and to guide development of more effective long-term treatments for drug abuse.