Neural systems mediating the extinction and inhibition of cocaine seeking

介导可卡因寻求的灭绝和抑制的神经系统

• 批准号: 10215464
• 负责人: RYAN T LALUMIERE
• 金额: $ 44.29万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10215464
• 关键词: Amygdaloid structure; Behavior; Behavioral; Brain region; Cell Nucleus; Cocaine; Cocaine Dependence; Consumption; Custom; Data; Development; Drug usage; Elements; Etiology; Extinction (Psychology); Face; Failure; Frequencies; Future; Goals; Heterogeneity; Hippocampus (Brain); Human; Impairment; Implant; Individual; Knowledge; Laboratories; Lead; Medial; Mediating; Modeling; Neural Pathways; Neurons; Neurosciences; Nucleus Accumbens; Output; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Play; Prefrontal Cortex; Process; Rattus; Relapse; Research; Rodent; Role; Site; Structure; Structure of paraventricular nucleus of thalamus; System; Testing; Thalamic structure; Training; Work; base; cocaine self-administration; cocaine use; craving; design; effective therapy; experimental study; insight; learning extinction; multi-electrode arrays; neural circuit; novel strategies; optogenetics; public health relevance; relating to nervous system

Relapse to cocaine use remains a significant challenge in the treatment of cocaine addiction, yet our understanding of those neural systems that enable individuals to inhibit cocaine seeking and relapse remains poor. The long-term goal of our laboratory is to identify the neural circuits and the changes in those circuits that underlie the inhibition of cocaine-seeking behavior, using rat models of cocaine seeking. The current proposal builds upon the findings we have obtained in recent years as well as new approaches we have developed in our laboratory. In our studies, rats undergo cocaine self-administration, extinction training and reinstatement testing of their cocaine seeking. We have found that the infralimbic cortex is a central component of the systems involved in the extinction and inhibition of cocaine-seeking behavior. Activity in the infralimbic cortex is necessary for the normal encoding of the extinction learning as well as extinction expression. For example, infralimbic activation inhibits cocaine seeking following extinction training. However, the larger circuit in which the infralimbic cortex performs these functions remains unclear. In particular, as evidence suggests functional heterogeneity within the infralimbic cortex in terms of its role in cocaine seeking, understanding the larger circuitry may provide insight into these issues. The proposed work will focus on the specific pathways projecting into and out of the infralimbic that account for its role in extinction and inhibition of cocaine seeking. The work will include approaches that have not, to our knowledge, been used in studies of cocaine seeking and, therefore, will enable notable progress in our knowledge of these systems. In particular, our studies will use multi-site recordings of neural activity during cocaine seeking to understand how a network of brain regions coordinates behavior. Moreover, the proposed studies will use optogenetic approaches to examine how different pathways mediate different aspects of the extinction and inhibition of cocaine seeking. The findings from this work will reveal those specific pathways and network activity related to the IL with regard to the extinction/inhibition of cocaine seeking. Furthermore, the proposed work will both 1) examine changes in IL-based circuits as a consequence of cocaine self-administration and extinction and 2) manipulate these circuits to determine how they functionally control the inhibition of cocaine seeking. The findings from the studies will furnish critical new basic knowledge of the neural systems underlying the suppression of cocaine seeking that will potentially lead to the development of more effective treatments that strengthen such systems in cocaine-addicted individuals.

可卡因复吸仍然是治疗可卡因成瘾的一个重大挑战，但我们的研究表明， 对那些使个体能够抑制可卡因寻求和复发的神经系统的理解仍然存在 扶贫我们实验室的长期目标是识别神经回路以及这些回路中的变化， 使用可卡因寻求的大鼠模型，说明可卡因寻求行为的抑制。现时的建议 建立在我们近年来获得的发现以及我们在 我们的实验室在我们的研究中，大鼠经历可卡因自我管理，灭绝训练和恢复 测试他们对可卡因的需求我们已经发现，边缘下皮层是大脑皮层的中心组成部分， 系统参与的灭绝和抑制可卡因寻求行为。边缘下皮层的活动 这是灭绝学习和灭绝表达的正常编码所必需的。比如说， 边缘下激活抑制消退训练后的可卡因寻求。然而，更大的电路，其中 边缘下皮质执行这些功能仍然不清楚。特别是，有证据表明， 边缘下皮层在可卡因寻求中的作用方面的异质性，了解更大的 电路可以提供对这些问题的洞察。拟议的工作将侧重于具体途径 投射进和投射出边缘下区，这解释了它在消除和抑制可卡因寻求中的作用。 据我们所知，这项工作将包括尚未用于可卡因寻求研究的方法。 因此，这将使我们对这些系统的了解取得显著进展。特别是，我们的研究将 使用可卡因期间的神经活动的多点记录，寻求了解大脑网络如何 区域协调行为。此外，拟议的研究将使用光遗传学方法来检查 不同的途径如何介导可卡因寻求的消退和抑制的不同方面。的 这项工作的结果将揭示与IL相关的特定途径和网络活动， 可卡因寻求的消失/抑制。此外，拟议的工作将：（1）审查 IL为基础的电路作为可卡因自我管理和灭绝的结果，2）操纵这些 电路，以确定它们如何在功能上控制可卡因寻求的抑制。的调查结果 这些研究将为可卡因抑制的神经系统提供重要的新的基础知识 寻求这一点可能会导致开发出更有效的治疗方法， 可卡因成瘾的人。