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.

总结/摘要 物质使用障碍（SUD）与背内侧前额叶皮层（dmPFC）异常有关， 这是一个由药物预测线索激活并有助于寻找药物的大脑区域。近年来研究表明 dmPFC内的非重叠细胞群（由基因表达或投射靶点定义）显示出独特的 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中， 细胞的变异性表明，需要更大的分辨率来了解独特的影响， dmPFC神经元集合对行为的影响。总之，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 降低了控制dmPFC输出神经元内在兴奋性的通道的功能。考虑 这种被抑制的兴奋性，令人惊讶的是，药物相关线索的呈现可以引起强烈的活动， 在SUD患者的dmPFC中，该活性是未来复发的可靠预测因子。因此， dmPFC神经元的兴奋性可能发生在药物相关的线索暴露期间，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一观点，我在这里指出， 蓝斑去甲肾上腺素能神经轴突在dmPFC（LC dmPFC）中的作用消除了线索诱导的海洛因复吸 寻找此外，我证实下游dmPFC兴奋性输出神经元显示双向可塑性 海洛因使用后，海洛因自我给药后活动减退，但恢复正常活动 在线索诱发的复发中。考虑到这些发现，在这里，我调查的假设，去甲肾上腺素能 LC dmPFC神经元在呈现药物预测线索（Aim 1）时变得活跃，去甲肾上腺素能神经元在呈现药物预测线索（Aim 1）时变得活跃。 dmPFC中的活性对于线索诱导的药物寻找和放大下游dmPFC中的活性至关重要 神经元系综（目的2），并在选定dmPFC神经元系综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 精确定义的dmPFC电路元件在线索诱导海洛因寻求。这些研究的结果是 对于制定可以使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。