权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Neural systems controlling the inhibition of heroin seeking

控制海洛因寻求抑制的神经系统

基本信息

批准号：
10676200
负责人：
RYAN T LALUMIERE
金额：
$ 42.38万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10676200
关键词：
Address Amygdaloid structure Anterior Behavior Behavior Control Behavioral Paradigm Brain region Complex Consumption Custom Data Development Electrophysiology (science)Epidemic Extinction Face Foundations Future Genetic Goals Heroin Heroin Dependence Heterogeneity Impairment Implant Individual Knowledge Laboratories Mediating Modeling Neurons Nucleus Accumbens Opiate Addiction Opioid Output Pathway interactions Pharmaceutical Preparations Population Prefrontal Cortex Rattus Relapse Research Rodent Rodent Model Role Self Administration Site Structure System Testing Training United States Veins Work cocaine seeking design drug of abuse drug seeking behavior effective therapy examination questions experimental study genetic approach genetic manipulation heroin use learning extinction multi-electrode arrays neural neural circuit neurophysiology optogenetics programs public health relevance

项目摘要

Relapse to heroin use remains a significant challenge in the treatment of heroin addiction, yet our understanding of those neural systems that enable individuals to inhibit heroin 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 heroin-seeking behavior, using rat models of heroin seeking. Previous work with cocaine seeking has suggested that the infralimbic cortex is involved in the extinction and inhibition of cocaine seeking. Yet, the role of this prefrontal region in opioid seeking has been unclear, as studies have produced findings indicating that the infralimbic promotes and inhibits opioid seeking. As increasing evidence suggests that different projections from prefrontal regions can mediate distinct functions, we have hypothesized that the ability of the infralimbic to either promote or inhibit heroin seeking is related to the specific projections from this region to the nucleus accumbens shell (NAshell) vs. the amygdala. In addition, we have recently developed preliminary data suggesting that the anterior portion of the insular cortex (rostral agranular insular cortex, RAIC) inhibits heroin seeking. However, other studies with other drugs of abuse indicate that the RAIC also appears to promote drug-seeking behavior. Thus, it seems likely that, as with the IL, the key to understanding the role of the RAIC in heroin seeking depends on targeting different projections. Indeed, like the infralimbic, the RAIC projects to the amygdala, a region that prior studies have found to be involved in promoting reinstatement to heroin seeking. However, the RAIC also provides an input to the infralimbic itself, thus providing a mechanism for how the RAIC may influence and interact with the infralimbic during the extinction and inhibition of heroin seeking. The proposed studies, therefore, will examine these circuits during heroin seeking and will include approaches that have not, to our knowledge, been used in studies of heroin seeking. In particular, our studies will examine the neurophysiological correlates of heroin seeking in the RAIC and IL via ensemble recordings in both regions simultaneously. The findings from this work will likely reveal neuronal subpopulations in both regions related to the extinction and/or inhibition of heroin seeking. Moreover, our proposed work will use optogenetic and chemogenetic manipulations of the specific projections from the infralimbic to the NAshell and amygdala and from the RAIC to the infralimbic cortex and amygdala. Specifically, these manipulations will allow us to interrogate the role of each pathway in the encoding of the extinction learning and the reinstatement of heroin seeking. As a result, this proposal will provide converging lines of evidence regarding this circuitry and the inhibition of heroin seeking. The findings from the studies will furnish critical new basic knowledge of the neural systems underlying the suppression of heroin seeking that will potentially lead to the development of more effective treatments that strengthen such systems in heroin- addicted individuals.

海洛因复吸仍然是治疗海洛因成瘾的一个重大挑战，但我们的对那些使个人能够抑制海洛因寻找和复发的神经系统的理解可怜。我们实验室的长期目标是识别神经回路和这些回路中的变化使用海洛因寻找的大鼠模型，为抑制海洛因寻找行为奠定了基础。以前使用的工作寻找可卡因表明，下缘皮质参与了可卡因的消退和抑制寻找。然而，前额叶区域在寻找阿片类药物方面的作用还不清楚，因为研究已经产生了研究结果表明，下缘促进和抑制阿片类药物寻求。越来越多的证据表明前额叶区域的不同投射可以调节不同的功能，我们假设下丘脑促进或抑制海洛因寻找的能力与这一区域的特定投射有关。伏隔核壳(NAShell)区域与杏仁核。此外，我们最近开发了一种初步数据表明，岛叶皮质的前部(嘴无颗粒岛叶皮质， (RAIC)抑制海洛因寻找。然而，其他关于滥用药物的研究表明，RAIC也似乎促进了寻求毒品的行为。因此，很可能，就像IL一样，理解 RAIC在寻找海洛因方面的作用取决于目标不同的预测。的确，就像低音部， RAIC投射到杏仁核，先前的研究发现该区域参与促进恢复吸食海洛因的行为。然而，RAIC也向下缘本身提供输入，因此提供了一种机制，说明在物种灭绝期间，RAIC如何影响下缘生物并与之相互作用和抑制海洛因寻觅。因此，拟议的研究将检查海洛因过程中的这些回路。寻求，并将包括据我们所知在海洛因寻找研究中未使用过的方法。特别是，我们的研究将在RAIC和IL中检查寻求海洛因的神经生理学关联通过同时在两个地区进行的合奏录音。这项工作的发现可能会揭示神经元这两个地区的亚群都与寻求海洛因的灭绝和/或抑制有关。而且，我们的拟议的工作将使用光遗传和化学遗传操作来自下缘至NAShell和杏仁核，以及从RAIC到下缘皮质和杏仁核。具体来说，这些操作将允许我们询问每一条途径在编码灭绝中的作用学习和恢复海洛因寻觅。因此，这项提议将提供关于这个回路和抑制海洛因寻找的证据。研究的结果将提供关于抑制海洛因寻觅的神经系统的关键新基础知识可能会导致更有效的治疗方法的开发，以加强海洛因的这种系统- 上瘾的人。