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

项目总结/摘要 糖皮质激素受体（GR）是最有名的介导应激反应的作用。因而是不可 令人惊讶的是，这种受体与几种精神疾病的病理生理学有关。 最近，一些报告已经出现，确定GR相关的多态性与 易受可卡因使用和成瘾的影响。事实上，几十年来人们已经知道糖皮质激素通过GR， 与多巴胺相互作用，产生对滥用药物的反应的个体差异。的机制 然而，这种情况发生的原因仍有待确定。重要的是，虽然压力可以促进多巴胺- 糖皮质激素的相互作用，这是没有必要的。也就是说，一个人可能是天生的“有线”，或准备为 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。的 所提出的工作的总体目标是确定一种这样的启动机制。有些人可能是 特别容易上瘾，因为他们倾向于将药物线索归因于过度激励 激励价值对于这些个体暴露于先前与药物相关的线索（例如，用具）， 服用可能会加速复发，尽管希望保持禁欲。在大鼠中，我们已经表明， 激励性学习倾向增加具有不足的“自上而下”的皮层控制，同时 过度活跃的皮层下机制同时，这些老鼠更冲动，注意力不足， 控制和更有可能表现出线索诱导的药物寻求行为的恢复（即复吸）。的 神经行为内在表型，由将激励显著性归因于奖励线索的倾向所捕获， 因此，这让人联想到有毒瘾的人。这里要检验的中心假设是， 在“自上而下”的皮质-纹状体回路中， 内表型我们将利用CRISPR（定期间隔的短回文） Repeats）/Cas9介导的基因编辑技术选择性地操纵多巴胺能传入中的GR 从前边缘皮层（PrL）投射到核神经元核心（NAcC）-我们认为这是一个电路， 这与压力反应能力关系不大，而更多地与对奖励相关线索的中介反应有关。我们 假设在该皮质-纹状体回路中选择性地敲低GR将减弱1） 将激励动机价值归因于奖励线索，以及2）线索诱导的可卡因寻求恢复 行为这项探索性的资助有可能揭示一种新的神经机制，有助于 复发倾向无论结果如何，这项研究将为未来的研究奠定基础， 进一步研究GR在成瘾相关行为中的作用，具有很高的神经解剖学精度。

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.