Opioid-induced dysregulation of cortico-striatal circuits

阿片类药物引起的皮质纹状体回路失调

• 批准号: 10595258
• 负责人: Matthew Carl Hearing
• 金额: $ 37.18万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595258
• 关键词: Attention; Behavior; Behavioral; Brain region; Cognitive; Contralateral; Corpus striatum structure; Data; Decision Making; Dependence; Development; Dopamine; Drug Modelings; Drug usage; Electrophysiology (science); Exposure to; Female; Functional disorder; Genetic; Image; Impaired cognition; Impairment; Incidence; Individual; Intervention; Label; Measures; Medial; Modeling; Modification; Motivation; Nature; Neurologic; Neurons; Opiate Addiction; Opioid; Output; Pain management; Pathway interactions; Pattern; Pharmaceutical Preparations; Physiological; Physiology; Pilot Projects; Play; Prefrontal Cortex; Preventive measure; Publishing; Regulation; Reporting; Risk; Role; Self Administration; Slice; Synapses; Techniques; Testing; Time; Transgenic Mice; Viral; Woman; addiction; biological sex; cell type; clinically relevant; cognitive function; drug seeking behavior; flexibility; frontal lobe; functional adaptation; genetic manipulation; glutamatergic signaling; heroin use; hippocampal pyramidal neuron; in vivo; individual variation; individualized medicine; information processing; insight; male; neural; neuroadaptation; neuromechanism; neuronal circuitry; novel; opioid use; opioid use disorder; optogenetics; prescription opioid misuse; psychologic; receptor; remifentanil; resilience; sex; timeline

Project Summary/Abstract Opioid-based drugs are mainstays for pain management despite the risk of dependence, addiction, and cognitive impairments, even when taken as directed. Yet, the neurological underpinnings of opioid addiction remain relatively under-investigated, thereby limiting our understanding of the neural and associated psychological basis of addiction to opioids. Impaired decision-making, strong perseverance and an extraordinary motivation to obtain drug are widely seen as core aspects of addiction. These behaviors are expressed only by a fraction of those exposed to the drug – highlighting a significant degree of individual variability and a need to identify largely unknown factors that convey risk or resilience. Hypofunction of prefrontal circuits has emerged as a primary mechanism by which this transition occurs, however evidence regarding the nature, sub-circuit(s) locus, and development of this hypofunction is lacking. Our published data find that self-administration (SA) of the potent opioid, remifentanil (Rem), promotes a progressive hypoactive state in prelimbic cortex (PrL) pyramidal neurons that underlies impairments in cognitive flexibility, and that this phenomenon occurs on a faster timeline in females. Pilot data indicate inflexibility aligns with increased perseverative drug seeking and motivation for drug that is more prominent in females. We predict these changes emerge as a result of changes in PL-Core circuits, as pilot data indicate that hypoactivity is more prominent in PrL-Core PN and that this plasticity aligns with sex- and cell-type specific adaptations in synaptic strength at downstream Core medium spiny neurons (MSNs) based on expression of dopamine type I (D1) versus type II (D2) receptors. This proposal will combine circuit-specific ex vivo measures of plasticity, in vivo Ca2+ imaging, and chemogenetics with a novel SA model that permits longitudinal assessment of individual variability in the development of motivated and perseverative drug-seeking and a clinically relevant operant model to assess cognitive flexibility (strategy shifting) to identify changes from synapse to function to behavior. Aim1 of this proposal will further investigate exposure dependent changes within PrL-Core circuits using pathway-specific ex vivo electrophysiology. Intersectional chemogenetic manipulations will assess the contribution of this circuit flexibility and drug seeking and whether dysfunction underlies deficits in flexibility and changes in perseverance/motivation. Aim2 will use Ca2+ imaging to examine the corresponding disruptive effects of opioid plasticity on PrL-Core information processing associated with decision making and measure longitudinal changes in basal states and activity encoding opioid taking with progressive SA. Aim 3 will identify synaptic modifications at PrL-Core D1- and D2- MSN synapses. Contralateral chemogenetic targeting will determine contributions of PrL-to-D1-MSN and PrL- to-D2-MSN circuits in flexibility and longitudinally determine if contributions to opioid taking and behavior shifts over time. Proposed studies will provide novel insight into progressively developing changes in function and behavior, with the potential to inform more tailored treatments based on sex and stage of addiction.

项目摘要/摘要 基于阿片类药物的药物是疼痛管理任务的支柱，依赖，成瘾和 即使按照指示服用，认知障碍也是如此。然而，阿片类药物成瘾的神经系统基础 保持相对投资，从而限制我们对神经和相关的理解 成瘾的心理基础。决策，强大的毅力和非凡的障碍 获得药物的动机被广泛视为成瘾的核心方面。这些行为仅由 暴露于该药物的人中的一小部分 - 强调了很大程度的个人可变性，并且需要 确定传达风险或弹性的很大未知因素。前额叶电路的功能不全 作为这种过渡的主要机制，无论涉及性质的证据，子电路） 缺乏基因座和这种功能障碍的发展。我们发布的数据发现，自我管理（SA） 有效的阿片类药物Remifentanil（REM）促进了预临时皮层（PRL）中的进行性降低状态 认知灵活性损害的基础的金字塔神经元，这种现象发生在更快的速度上 女性的时间表。指示僵化性与寻求持久性药物增加和 在女性中更突出的药物动机。我们预测由于变化而出现这些变化 在PL核电路中，作为飞行员数据，表明在PRL核PN中低连贯性更为突出 可塑性与在下游核心介质处的性别和细胞型特异性适应 基于多巴胺I型（D1）与II型（D2）受体的表达的棘神经元（MSN）。这个建议 将结合特定电路特异性的体内塑性，体内Ca2+成像和化学遗传学的测量 SA模型允许对融合和融合发展的个体变异性进行纵向评估 持久性毒品寻求药物和临床相关的操作模型，以评估认知灵活性（策略 移动）以识别从突触到功能到行为的变化。该提案的AIM1将进一步调查 使用特异性的离体电生理学，PRL核电路内的暴露依赖性变化。 交叉化学发生操作将评估该电路灵活性和寻求药物的贡献 以及功能障碍是否依赖于灵活性和毅力/动机的变化。 AIM2将使用 CA2+成像以检查阿片可塑性对PRL核信息信息的相应破坏性影响 与基本状态和活动的决策和测量纵向变化相关的处理 用渐进式SA编码阿片类药物。 AIM 3将在PRL核D1和D2-上识别突触修饰 MSN突触。对侧化学遗传靶向将确定PRL到D1-MSN和PRL-的贡献 to-d2-msn电路的灵活性和纵向确定对阿片类药物的贡献和行为转移的贡献是否贡献 随着时间的推移。拟议的研究将为逐步发展功能变化和 行为，有可能根据性别和成瘾阶段为更量身定制的治疗提供信息。