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.

项目摘要 虽然吸毒是一种极为普遍的现象，但绝大多数消费都是自愿的，而且很好 由用户控制。也就是说，大多数人能够以一定的数量开始和结束中毒期 对那些吸收毒品发作的行为控制，而无需强迫寻找并升级进一步的药物 使用。但是，对于一小部分人口，对毒品寻求毒品的行为控制丧失可能会导致 药物使用障碍（SUD）和成瘾。药物滥用的动物模型压倒性地使用成人发作药物 将其作为调查的起点，这没有考虑到绝大多数发展 在早期和青少年期间大脑中发生的变化。因此，我们在这里提出翻译 人类SUD的模型应结合发展的重要要素，以了解个人如何 变得特别容易受到不再在行为控制下的药物使用失调。我们有 最近表明，早期的生活压力（在生命的第一个后期获得优质床上用品的机会有限；“ Els”） 大鼠幼崽会沉淀与恐惧扩展有关的前额叶（PFC）功能的持续变化。基于 在这些观察结果上，当前的提案通过研究是否类似，扩大了父r01的目标 ELS经验会影响大鼠在压力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，当大鼠逃脱了一次冲击时，PFC中的神经元显示出更大的激活 与受到相同（但无法控制的）休克的Yok动物相比，可控的应激源（ES）。尤其， IS组中的动物对以前奖励食物相关的提示显示出明显少的阶段性活性 经过这种经历后的ES大鼠，表明ES期间的PFC激活可以预防IS介导 动机下降。基于此和我们的先前工作，我们在这里提出了ELS破坏适当的建议 PFC在开发过程中的成熟，并且这些功能障碍持续到成年。因此，我们进一步 假设具有ELS经验的动物将无法从与ES相关的弹性中适当受益， 这将对个人调节压力，吸毒和其他形式的能力产生关键的影响 行为控制。为此，我们将分配老鼠在正常条件下或在下面饲养 PND1-7的床上用品EL有限，然后切换到普通外壳直至断奶。然后，老鼠会学习一个（预先 - 压力）Pavlovian条件方法（PCA）任务，然后进行应力源可控性会话，任何ES， 是或无重理的归宿（HC）控制，然后最终应施加压力PCA会话。我们将记录单个单元 在所有人期间，PFC的前BIC（PL）和Infralimbic（IL）部分中的神经活动和局部田间电势 任务的三个阶段。这将使我们始终访问理解实时计算 这有助于可控性，跨阳性弹性以及ELS如何改变这些过程。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 明确为他的博士学位论文和随后的博士后任命而明确。