Reversing Cocaine-induced Impairments in the NAc with Controllable Stressors

用可控压力源逆转可卡因引起的 NAc 损伤

• 批准号: 10619282
• 负责人: Michael Saddoris
• 金额: $ 1.74万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10619282
• 关键词: Adolescence; Adult; Affect; Animal Model; Animals; Appointment; Behavior; Behavior Control; Behavioral; Brain; Cocaine; Consumption; Cues; Development; Drug Modelings; Drug abuse; Drug usage; Elements; Extinction (Psychology); Food; Fright; Functional disorder; Grant; Housing; Impairment; Individual; Intoxication; Investigation; Lead; Learning; Life; Mediating; Motivation; Neurons; Parents; Pharmaceutical Preparations; Phase; Population; Prefrontal Cortex; Process; Rattus; Rewards; Shock; Stress; Substance Use Disorder; Time; Weaning; Work; addiction; base; compulsion; early life stress; experience; experimental study; human model; pup; relating to nervous system; resilience; stressor; translational model

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.

项目概要 虽然吸毒是一种极为普遍的现象，但绝大多数消费是自愿且良好的 由用户控制。也就是说，大多数人能够以一定量开始和结束中毒期 对吸毒事件的行为控制，而无需寻求和升级进一步的药物 使用。然而，对于一小部分人来说，这种对毒品寻求的行为控制的丧失可能会导致 物质使用障碍（SUD）和成瘾。药物滥用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，这未能解释绝大多数的发展 生命早期和青春期大脑中发生的变化。因此，我们在这里建议翻译 人类 SUD 模型应纳入重要的发展要素，以了解个体如何 变得特别容易受到不再受行为控制的失调药物使用的影响。我们有 最近表明，早期生活压力（在产后第一周获得优质床上用品的机会有限；“ELS”） 幼鼠会引发与恐惧消失相关的前额叶（PFC）功能的持续变化。基于 根据这些观察结果，当前提案通过调查是否存在类似的情况来扩展母版 R01 的目标 ELS 经验会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，当大鼠逃离电击时，PFC 中的神经元表现出更大的激活。 与接受相同（但不可控）电击的带轭动物相比，可控应激源（ES）。尤其， IS 组的动物对先前奖励性食物相关线索的阶段性活动明显少于 ES 大鼠经历此经历后，表明 ES 期间 PFC 激活可以预防 IS 介导的 动力下降。基于这一点和我们之前的工作，我们在这里建议 ELS 破坏了正确的 PFC 在发育过程中成熟，并且这些功能障碍持续到成年期。因此，我们进一步 假设具有 ELS 经验的动物将无法从 ES 相关的复原力中适当受益， 这将对个人调节压力、吸毒和其他形式的能力产生严重影响 的行为控制。为了实现这一目标，我们将分配大鼠在正常条件下饲养，或在 PND1-7 的垫料 ELS 有限，然后改用普通舍，直至断奶。然后老鼠将学习（预 压力）巴甫洛夫条件方法（PCA）任务，然后是使用 ES 的压力源可控性会话， IS 或无压力家庭笼 (HC) 控制，最后是压力后 PCA 课程。我们将录制单个单元 PFC 的前边缘 (PL) 和下边缘 (IL) 部分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 有助于提高可控性、跨情境弹性以及 ELS 如何改变这些过程。赞助的 候选人将受益于掌握这些独立的行为和神经方法，并建立一个 他的博士候选人论文和随后的博士后任命的清晰轨迹。