The influence of noradrenergic circuitry on prefrontal neuronal ensemble dynamics and cue-induced heroin seeking

摘要/摘要 物质使用障碍(SUD)与背内侧前额叶皮质(DmPFC)的异常有关，a 被毒品预测线索激活并有助于寻找毒品的大脑区域。最近的研究表明， 由基因表达或投射靶点定义的dmPFC内的非重叠细胞群显示独特 在寻求奖励期间的活动概况。有趣的是，即使在这些确定的细胞群体中，也有相当多的细胞- 对像元的可变性的发现表明，需要更高的分辨率来理解Unique的影响 DmPFC神经元对行为的影响。总体而言，独特的dmPFC神经元整体活动的影响 寻求毒品的模式尚不清楚。 在啮齿动物和人类持续使用药物后，dmPFC的活性受到高度抑制，部分原因是 这与控制dmPFC输出神经元内在兴奋性的通道功能降低有关。考虑 这抑制了兴奋性，令人惊讶的是，与药物相关的线索的呈现可以唤起强烈的活动 在SUD患者的dmPFC中，这种活动是未来复发的可靠预测因子。因此，一个快速的转变 在药物相关线索暴露期间，dmPFC神经元的兴奋性可能发生变化，这一变化可能是 由神经调节剂去甲肾上腺素控制。为了支持这一观点，我在这里展示了化学发生抑制 DmPFC蓝斑去甲肾上腺素能轴突(LC DmPFC)阻断线索诱导的海洛因戒断 寻找。此外，我还证实了dmpfc下游兴奋性输出神经元具有双向可塑性。 吸食海洛因后，自我用药后变得活动不足，但恢复正常活动 在线索诱导的复发过程中。考虑到这些发现，我在这里调查去甲肾上腺素能 LC dmPFC神经元在呈现药物预测线索(目标1)时变得活跃，即去甲肾上腺素能 DmPFC的活性对线索诱导的药物寻找和下游dmPFC的活性放大至关重要。 神经元集合(目标2)，以及在选定的dmPFC神经元集合中的活动调节线索诱导的药物 寻求行为(目标3)。总体而言，这些实验将表征活动动力学和功能 在线索诱导海洛因寻找过程中精确定义的dmPFC电路元件。这些研究的发现是 对于制定可使dmPFC活动正常化并减少复发脆弱性的战略至关重要 患有SUD的患者。

SUMMARY/ABSTRACT Substance use disorder (SUD) is associated with abnormalities in the dorsomedial prefrontal cortex (dmPFC), a brain region that is activated by drug-predictive cues and contributes to drug seeking. Recent studies show that non-overlapping cell populations within dmPFC, defined by gene expression or projection target, display unique activity profiles during reward seeking. Interestingly, even within these defined cell populations considerable cell- to-cell variability is found suggesting that greater resolution is needed to understand the influence of unique dmPFC neuronal ensembles on behavior. Overall, the influence of unique dmPFC neuronal ensemble activity patterns on drug seeking is unclear. Activity in the dmPFC is highly suppressed following persistent drug use in rodents and humans, in part due to the reduced function of channels that control the intrinsic excitability of dmPFC output neurons. Considering this suppressed excitability, it is surprising that the presentation of drug-associated cues can evoke robust activity in dmPFC of patients with SUD, with that activity being a reliable predictor of future relapse. Thus, a rapid shift in the excitability of dmPFC neurons likely occurs during drug-associated cue exposure, a change that may be controlled by the neuromodulator noradrenaline. In support of this idea, here I show that chemogenetic inhibition of locus coeruleus noradrenergic axons in dmPFC (LC dmPFC) abolishes cue-induced reinstatement of heroin seeking. Furthermore, I confirm that downstream dmPFC excitatory output neurons display bidirectional plasticity following heroin use, becoming hypoactive following heroin self-administration but recovering normal activity during cue-induced relapse. Considering these findings, here I investigate the hypotheses that noradrenergic LC dmPFC neurons become active during the presentation of drug-predictive cues (Aim 1), that noradrenergic activity in dmPFC is critical for cue-induced drug seeking and for amplifying activity in downstream dmPFC neuronal ensembles (Aim 2), and that activity in select dmPFC neuronal ensembles modulates cue-induced drug seeking behavior (Aim 3). Overall, these experiments will characterize the activity dynamics and function of precisely defined dmPFC circuit elements during cue-induced heroin seeking. Findings from these studies are critical for the development of strategies that could normalize dmPFC activity and reduce relapse vulnerability in patients suffering from SUD.