Opioid-induced dysregulation of cortico-striatal circuits

项目总结/摘要 阿片类药物是疼痛管理的支柱，尽管存在依赖性，成瘾性和 认知障碍，即使是按照指示服用。然而，阿片类药物成瘾的神经基础 仍然相对不足的研究，从而限制了我们对神经和相关的理解。 阿片类药物成瘾的心理基础决策能力减弱，毅力强， 获得毒品的动机被广泛认为是成瘾的核心方面。这些行为只表现在 暴露于药物的一小部分-突出了个体差异的显著程度，需要 确定传达风险或复原力的大部分未知因素。前额叶回路功能减退 作为发生这种转变的主要机制，然而，关于性质的证据，子电路 基因座，缺乏这种功能减退的发展。我们公布的数据发现，自我管理（SA）的 强效阿片类药物瑞芬太尼（Rem）可促进前边缘皮层（PrL）的进行性活动减退状态 锥体神经元的认知灵活性受损的基础，这种现象发生在一个更快的 女性的时间轴。试点数据表明，成瘾性与持续性药物寻求增加一致， 吸毒的动机在女性中更为突出。我们预测这些变化是由于 在PL-核心电路中，由于导频数据表明活动减退在PrL-核心PN中更为突出， 可塑性与下游核心介质突触强度的性别和细胞类型特异性适应一致 基于多巴胺I型（D1）与II型（D2）受体的表达的多刺神经元（MSN）。这项建议 将结合联合收割机回路特异性的可塑性体外测量、体内Ca 2+成像和化学遗传学， SA模型，允许纵向评估个体差异的发展动机和 持续性药物寻求和临床相关的操作模型，以评估认知灵活性（策略 移位）以识别从突触到功能再到行为的变化。本提案的目标1将进一步调查 使用通路特异性离体电生理学在PrL核心电路内的暴露依赖性变化。 交叉化学遗传学操作将评估这一电路的灵活性和药物寻求的贡献 以及功能障碍是否是灵活性缺陷和毅力/动机变化的基础。aim 2将使用 Ca 2+成像检查阿片可塑性对PrL-Core信息的相应破坏作用 与决策相关的处理和测量基础状态和活动的纵向变化 编码阿片类药物服用与进行性SA。目的3将鉴定PrL-核心D1-和D2-的突触修饰。 MSN突触。双侧化学发生靶向将决定PrL-至-D1-MSN和PrL-至-D1-MSN的贡献。 到D2-MSN回路的灵活性和纵向决定是否有助于阿片类药物服用和行为转变 随着时间拟议的研究将提供新的见解，逐步发展的功能变化， 行为，有可能根据性别和成瘾阶段提供更有针对性的治疗。

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.