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

去甲肾上腺素能回路对前额神经元整体动力学和线索诱导的海洛因寻求的影响

• 批准号: 10574625
• 负责人: James M Otis
• 金额: $ 36.96万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574625
• 关键词: Axon; Behavior; Brain; Brain region; Calcium; Cells; Characteristics; Complex; Cue-induced relapse; Cues; Data; Development; Drug usage; Elements; Extinction; Foundations; Future; Gene Expression; Genetic; Heroin; Human; Image; Impairment; Individual; Jaw; Light; Literature; Measures; Mus; Neuromodulator; Neurons; Norepinephrine; Opiate Addiction; Opsin; Output; Patients; Pattern; Pharmaceutical Preparations; Population; Prefrontal Cortex; Publications; Relapse; Resolution; Rewards; Rodent; Self Administration; Stimulus; Structure; Substance Use Disorder; Sucrose; Testing; Time; beta-adrenergic receptor; calcium indicator; drug reward; drug seeking behavior; effective therapy; excitatory neuron; experimental study; heroin use; locus ceruleus structure; neuronal circuitry; neurotechnology; noradrenergic; novel; optogenetics; redshift; therapy development; treatment strategy; two-photon

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.

摘要/摘要 物质使用障碍 (SUD) 与背内侧前额叶皮层 (dmPFC) 异常相关，dmPFC 是一种 被药物预测线索激活并有助于寻找药物的大脑区域。最近的研究表明 dmPFC 内的非重叠细胞群，由基因表达或投影目标定义，显示出独特的 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中，也有相当多的细胞 发现细胞变异性表明需要更高的分辨率来了解独特的影响 dmPFC 神经元集合对行为的影响。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。 啮齿动物和人类持续吸毒后，dmPFC 的活性受到高度抑制，部分原因是 控制 dmPFC 输出神经元内在兴奋性的通道功能降低。考虑到 这种抑制的兴奋性，令人惊讶的是，药物相关线索的呈现可以唤起强烈的活动 在 SUD 患者的 dmPFC 中，该活动是未来复发的可靠预测因子。因此，快速转变 dmPFC 神经元的兴奋性可能发生在药物相关线索暴露期间，这种变化可能是 由神经调节剂去甲肾上腺素控制。为了支持这个想法，我在这里展示了化学遗传学抑制 dmPFC (LC dmPFC) 中蓝斑去甲肾上腺素能轴突的变化消除了提示诱导的海洛因恢复 寻求。此外，我确认下游 dmPFC 兴奋性输出神经元表现出双向可塑性 使用海洛因后，自我服用海洛因后变得活跃，但恢复正常活动 在提示诱发的复发期间。考虑到这些发现，我在这里研究以下假设：去甲肾上腺素能 LC dmPFC 神经元在药物预测线索呈现期间变得活跃（目标 1），即去甲肾上腺素能 dmPFC 的活性对于线索诱导的药物寻找和放大下游 dmPFC 的活性至关重要 神经元集合（目标 2），并且选择 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）。总的来说，这些实验将表征活动动态和功能 在提示诱导海洛因寻找过程中精确定义的 dmPFC 电路元件。这些研究的结果是 对于制定使 dmPFC 活动正常化并减少复发脆弱性的策略至关重要 患有 SUD 的患者。