Reversing Cocaine-induced Impairments in the NAc with Controllable Stressors

项目总结 虽然吸毒是一种极其普遍的现象，但绝大多数的消费都是自愿的，而且是健康的。 由用户控制。也就是说，大多数人能够以一定的量开始和结束醉酒期 对那些吸毒事件的行为控制，而没有寻找和升级进一步毒品的强迫 使用。然而，对于一小部分人来说，失去对毒品寻求的行为控制可能会导致 物质使用障碍(SUD)和成瘾。滥用药物的动物模型绝大多数使用成人起效药物 作为他们调查的起点，这未能占到绝大多数的发展 大脑在生命早期和青春期发生的变化。因此，我们在此建议翻译 人类可持续发展的模型应包含发展的重要元素，以了解个体如何 变得特别容易受到不再受行为控制的不规范药物使用的影响。我们有 最近表明，早期生活压力(在出生后第一周内获得优质床上用品的机会有限；“ELS”) 小鼠的前额叶(PFC)功能与恐惧消退有关。基座 根据这些观察，目前的提案通过调查是否类似于 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。我们的实验室 现在已经证明，当大鼠从休克中逃脱时，PFC中的神经元显示出更大的激活 可控应激源(ES)与受到相同(但不可控)电击的带轭动物相比。值得注意的是， 与之前奖励食物相关的线索相比，IS组中的动物表现出明显更少的时相活动 ES大鼠经历了这一过程后，提示在ES过程中激活PFC可以保护其免受IS的介导 动力减弱。基于这一点和我们之前的工作，我们在这里提出ELS扰乱了适当的 PFC在发育过程中的成熟，这些功能障碍会持续到成年。因此，我们进一步 假设有ELS经验的动物将无法适当地受益于ES相关的复原力， 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 行为控制的能力。为了做到这一点，我们将分配饲养的老鼠在正常条件下，或在 限制PND1-7的卧床ELs，然后切换到正常的住房，直到断奶。然后，老鼠将学习一种(前- 应激)巴甫洛夫条件化方法(PCA)任务，随后与任一ES进行应激源可控性会议， IS或非应激归巢(HC)控制，最后是后应激PCA会议。我们将记录单个单元 前额叶(PFC)前部(PL)和下缘部(IL)的神经活动和局部场电位 这项任务分为三个阶段。这将给予我们前所未有的机会来理解实时计算 这有助于可控性、跨情景弹性以及ELS如何改变这些过程。赞助商 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 他的博士候选人论文和随后的博士后任命轨迹清晰。

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.