Reversing Cocaine-induced Impairments in the NAc with Controllable Stressors

项目摘要 虽然吸毒是一种极为普遍的现象，但绝大多数消费是自愿的， 由用户控制。也就是说，大多数人都能够开始和结束中毒期与一定量的 行为控制这些药物服用事件没有强迫寻找和升级进一步的药物 使用.然而，对于一小部分人来说，这种对药物寻求的行为控制的丧失可能导致 物质使用障碍（SUD）和成瘾。药物滥用的动物模型绝大多数使用成人发作药物 作为他们调查的起点，这未能解释绝大多数发展中国家的情况。 在生命早期和青春期大脑发生的变化。因此，我们在这里建议， 人类SUD模型应纳入发展的重要因素，以了解个人如何 变得特别容易受到不再受行为控制的药物使用失调的影响。我们有 最近表明，早期生活压力（出生后第一周内获得优质床上用品的机会有限;“ELS”）， 幼鼠的前额叶（PFC）功能发生了持续的变化，这些变化与恐惧的消失有关。基于 根据这些观察结果，目前的建议通过调查是否存在类似的问题， ELS经验影响大鼠在应激源可控性任务中获得行为控制的能力。我们实验室 现在已经证明，当大鼠逃避电击时，PFC中的神经元表现出更大的激活， 可控的应激源（ES）相比，轭动物接受相同的（但无法控制的）休克。值得注意的是， IS组的动物对先前奖励食物相关线索的阶段性活动明显少于 ES大鼠在此经历后，表明ES期间PFC激活可以保护IS介导的 减少动机。基于这一点和我们以前的工作，我们在这里提出，ELS破坏了适当的 PFC在发育过程中的成熟，这些功能障碍持续到成年期。因此，我们进一步 假设具有ELS经历的动物将不能适当地从ES相关的恢复力中受益， 这将对个人调节压力，药物使用和其他形式的能力产生严重影响 行为控制。为了实现这一点，我们将分配大鼠在正常条件下饲养，或在 PND 1 -7的有限寝具ELS，然后转换为正常饲养直至断奶。然后，老鼠将学习（前， 压力）巴甫洛夫条件接近（PCA）任务，然后是一个压力可控性会话与ES， IS或无压力的家庭护理（HC）控制，然后最后压力后PCA会议。我们将记录单个单元 在PFC的边缘前（PL）和边缘下（IL）部分期间的神经活动和局部场电位 任务的三个阶段。这将使我们能够前所未有地了解实时计算 这有助于可控性，跨情境弹性，以及ELS如何改变这些过程。受赞助 候选人将受益于掌握这些行为和神经方法的独立性，并建立一个 为他的博士候选人论文和随后的博士后任命明确的轨迹。

PROJECT SUMMARY While drug use is an extremely common phenomenon, the vast majority of consumption is voluntary and well controlled by the user. That is, most individuals are able to initiate and end intoxication periods with some amount of behavioral control over those drug taking episodes without a compulsion to seek out and escalate further drug use. However, for a small portion of the population, this loss of behavioral control over drug seek can result in substance use disorder (SUD) and addiction. Animal models of drug abuse overwhelmingly use adult onset drug taking as a starting point in their investigations, which fails to account for the great majority of developmental changes that occur in the brain during early life and adolescence. As such, we propose here that a translational model of human SUD should incorporate important elements of development to understand how individuals may become particularly susceptible to dysregulated drug use that is no longer under of behavioral control. We have recently shown that early life stress (limited access to quality bedding in the first post-natal week of life; “ELS”) in rat pups precipitates persistent changes in prefrontal (PFC) functions that are related to extinction of fear. Based on these observations, the current proposal extends the aims of the parent R01 by investigating whether similar ELS experience affects the ability for rats to acquire behavioral control in a stressor controllability task. Our lab has now demonstrated that neurons in the PFC show greater activation when rats are escaping shock from a controllable stressor (ES) compared to yoked animals receiving an identical (but uncontrollable) shock. Notably, animals in the IS group show significantly less phasic activity to previously-rewarding food-associated cues than ES rats after this experience, suggesting that PFC activation during ES can protect against IS-mediated decrements in motivation. Based on this and our prior work, we here propose that ELS disrupts the proper maturation of the PFC during development, and that these dysfunctions persist into adulthood. As such, we further hypothesize that animals with ELS experience will be unable to appropriately benefit from ES-related resilience, which would have critical consequences on the ability for individuals to regulate stress, drug use, and other forms of behavioral control. To accomplish this, we will assign rats to be raised either in normal conditions, or under limited bedding ELS for PND1-7, and then switched to normal housing until weaning. Rats will then learn a (pre- stress) Pavlovian Conditioned Approach (PCA) task, followed by a stressor controllability session with either ES, IS or unstressed homecage (HC) control, and then finally post-stress PCA sessions. We will record single unit neural activity and local field potentials during in prelimbic (PL) and infralimbic (IL) portions of the PFC during all three phases of the task. This will grant us unprecedented access to understanding the real-time computations that contribute to controllability, trans-situational resilience, and how ELS alters these processes. The sponsored candidate will benefit from mastering these behavioral and neural approaches to independence, and establish a clear trajectory for his doctoral candidacy thesis and subsequent postdoctoral appointment.