The glucocorticoid receptor as a mechanism of top-down control of cue-motivated behavior

糖皮质激素受体作为线索驱动行为自上而下控制的机制

基本信息

批准号：
10360678
负责人：
Shelly Beth Flagel
金额：
$ 23.4万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360678
关键词：
Abstinence Address Affect Afferent Neurons Attenuated Behavior Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Cocaine Dependence Complex Corpus striatum structure Cues Dopamine Emotional Event Exhibits Exposure to Extinction (Psychology)Foundations Functional disorder Future Genes Genetic Polymorphism Glucocorticoid Receptor Glucocorticoids Glutamates Goals Grant Hyperactivity Impulsivity Incentives Individual Individual Differences Intake Lead Learning Mediating Memory Mental disorders Motivation Neurons Nucleus Accumbens Outcomes Research Pharmaceutical Preparations Physiology Play Predisposition Process Property Psychological reinforcement Rattus Relapse Reporting Research Rewards Role Site Stimulus Stress Substance abuse problem Technology Testing Viral Vector Work addiction addiction liability attentional control base biological adaptation to stress brain behavior cocaine self-administration cocaine use combinatorial drug of abuse drug seeking behavior endophenotype incentive salience knock-down maladaptive behavior motivated behavior neural circuit neurobehavioral neuromechanism novel receptor receptor function response stressor tool trait

项目摘要

PROJECT SUMMARY/ABSTRACT The glucocorticoid receptor (GR) is best known for its role in mediating the stress response. Thus, it is not surprising that this receptor has been implicated in the pathophysiology of several psychiatric disorders. Recently, a number of reports have emerged identifying GR-related polymorphisms associated with susceptibility to cocaine use and addiction. Indeed, it has been known for decades that glucocorticoids, via GR, interact with dopamine to produce individual differences in response to drugs of abuse. The mechanism by which this occurs, however, remains to be determined. Importantly, while stress can facilitate dopamine- glucocorticoid interactions, it is not necessary. That is, an individual may be inherently “wired”, or primed for these interactions to occur, rendering them more susceptible to addiction, even in the absence of stress. The overarching goal of the proposed work is to identify one such priming mechanism. Some individuals may be particularly prone to addiction because they have a tendency to attribute drug cues with excessive incentive motivational value. For these individual exposure to cues (e.g. paraphernalia) previously associated with drug- taking may precipitate relapse, despite a desire to remain abstinent. In rats, we have shown that those with an increase propensity for incentive learning have insufficient “top-down” cortical control, concurrent with hyperactive subcortical mechanisms. In conjunction, these rats are more impulsive, have deficits in attentional control and are more likely to exhibit cue-induced reinstatement of drug-seeking behavior (i.e. relapse). The neurobehavioral endophenotype captured by the propensity to attribute incentive salience to reward cues, therefore, is reminiscent of individuals with addiction. The central hypothesis to be tested here is that GR function in a “top-down” cortico-striatal circuit plays a critical role in determining this addiction-related endophenotype. We will take advantage of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas 9-mediated gene-editing technology to selectively manipulate GR in glutamatergic afferents projecting from the prelimbic cortex (PrL) to the nucleus accumbens core (NAcC) - a circuit that we believe has little to do with stress responsivity and more to do with mediating responses to reward-associated cues. We hypothesize that knockdown of GR selectively in this cortico-striatal circuit will attenuate 1) the propensity to attribute incentive motivational value to a reward cue, and 2) cue-induced reinstatement of cocaine-seeking behavior. This exploratory grant has the potential to uncover a novel neural mechanism that contributes to the propensity for relapse. Regardless of the outcome, this research will set a foundation for future studies to further investigate the role of GR in addiction-related behaviors with great neuroanatomical precision.

项目概要/摘要糖皮质激素受体（GR）以其介导应激反应的作用而闻名，但事实并非如此。令人惊讶的是，这种受体与多种精神疾病的病理生理学有关。最近，出现了一些报告，鉴定了与 GR 相关的多态性事实上，几十年来人们都知道糖皮质激素通过 GR，与多巴胺相互作用，产生对滥用药物反应的个体差异。然而，重要的是，压力会促进多巴胺的产生，但这种情况的发生仍有待确定。糖皮质激素相互作用，这是没有必要的，也就是说，一个人可能天生就“有线”，或者准备好了。这些相互作用的发生，使他们更容易上瘾，即使在没有压力的情况下也是如此。拟议工作的总体目标是确定一种这样的启动机制。特别容易上瘾，因为他们倾向于将药物线索归因于过度的激励对于这些个体暴露于先前与毒品相关的线索（例如用具）而言。尽管在大鼠中希望保持戒断，但服用可能会导致复发。增加激励学习的倾向，“自上而下”的皮质控制不足，同时皮质下机制过度活跃，这些老鼠更加冲动，注意力缺陷。控制，更有可能表现出线索诱导的寻药行为恢复（即复发）。通过将激励显着性归因于奖励线索的倾向来捕获神经行为内表型，因此，让人想起成瘾者。这里要检验的中心假设是 GR。 “自上而下”的皮质纹状体回路中的功能在确定这种与成瘾相关的过程中起着至关重要的作用我们将利用 CRISPR（成簇规则间隔短回文）。 Repeats)/Cas 9介导的基因编辑技术选择性操纵谷氨酸传入神经中的GR 从前边缘皮质 (PrL) 投射到伏核核心 (NAcC) - 我们认为有一个回路与压力反应关系不大，更多地与调节对奖励相关线索的反应有关。 1）倾向将激励动机价值归因于奖励提示，以及 2) 提示诱导的可卡因寻求恢复这项探索性资助有可能发现一种有助于行为的新颖神经机制。无论结果如何，这项研究都将为未来的研究奠定基础。以极高的神经解剖学精度进一步研究 GR 在成瘾相关行为中的作用。