Hippocampal-dependent neural immune interactions regulate heroin-conditioned immunomodulation

海马依赖性神经免疫相互作用调节海洛因条件免疫调节

• 批准号: 9759468
• 负责人: Jacqueline Elizabeth Paniccia
• 金额: $ 3.67万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759468
• 关键词: Animal Model; Astrocytes; Attenuated; Complex; Computer software; Conditioned Reflex; Confocal Microscopy; Coupled; Cues; Data; Disease; Dorsal; Drug usage; Exposure to; Fostering; Glial Fibrillary Acidic Protein; Goals; Heroin; Heroin Abuse; Hippocampus (Brain); Histologic; Immune; Immune response; Immunity; Immunohistochemistry; In Situ Hybridization; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Knowledge; Label; Laboratories; Learning; Link; Measures; Mediating; Memory; Messenger RNA; Methods; Modeling; Neurobiology; Neuroimmune; Neuroimmunomodulation; Opioid; Peripheral; Pharmaceutical Preparations; Physiological; Procedures; Process; Proteins; Publishing; Reporting; Research; Role; Signal Transduction; Stimulus; Techniques; Testing; Tissues; Training; Work; addiction; career; conditioning; cytokine; designer receptors exclusively activated by designer drugs; drug quality; experience; experimental study; heroin use; immune function; immunoregulation; in vivo; innovation; interdisciplinary approach; mRNA Expression; paired stimuli; protein expression; receptor; relating to nervous system; response; skills; tool; training opportunity

Project Summary/Abstract Negative consequences of heroin use are not limited to those produced by the addictive qualities of the drug. Heroin and other opioids negatively alter host immunity, leaving users more susceptible to diseases commonly associated with heroin abuse. These immunomodulatory effects can become conditioned to environmental stimuli following repeated context-heroin pairings. The presentation of heroin-conditioned stimuli is sufficient to elicit pronounced suppression of peripheral pro-inflammatory measures in the absence of heroin itself. Through well-controlled animal models, our laboratory has demonstrated that heroin-conditioned immunomodulation is a classically conditioned response and follows the principles of learning. Consistently, the context-heroin association is governed through dorsal hippocampal (DH) processes. Within the DH, we have discovered that intact neuroimmune signaling is required for the heroin-conditioned peripheral immune response to occur. We have elegantly shown that both DH interleukin-1β (IL-1β) and its active receptor, IL-1 receptor type 1 (IL-1R1), critically mediate the expression of heroin-conditioned immunomodulation. To further investigate hippocampal neuroimmune involvement in this conditioned response, we employed state-of-the-art chemogenetic tools to selectively manipulate DH astroglial signaling in vivo. Stimulation of astroglial Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs) during the exposure to heroin-conditioned stimuli disrupted conditioned suppression of peripheral immune measures. Thus, separately, DH IL-1 signaling and astroglial activity are necessary during presentation of heroin-paired cues to elicit the conditioned immune response. However, it is presently unknown if there is a mechanistic relationship between DH astroglial activity and IL-1 signaling in this Pavlovian response. There is evidence to suggest hippocampal astroglia support mechanisms of learning and memory through both IL-1β and IL-1R1. The current proposal is a targeted approach to investigate the relationship between DH astroglia and IL-1 signaling in heroin-conditioned immunomodulation. The specific aims test the overarching hypothesis that DH astroglia are a critical component of the IL-1 signaling necessary for heroin-conditioned immunomodulation. Aim 1 will examine astroglial-specific alterations in IL-1β and IL-1R1 mRNA and protein as a consequence of exposure to heroin-conditioned stimuli. Aim 2 will employ chemogenetic tools to selectively stimulate DH astroglial Gi-signaling during presentation of these heroin-paired cues to determine if this in vivo manipulation attenuates the IL-1β and IL-1R1 expression required for heroin- conditioned immunomodulation to occur. Collectively, the purposed experiments will enhance our understanding of critical neuroimmune mechanisms governing heroin-conditioned responses and will provide a valuable training opportunity to foster independence of my scientific career.

项目总结/摘要 使用海洛因的消极后果并不局限于毒品的致瘾性质所产生的后果。 海洛因和其他阿片类药物会对宿主免疫力产生负面影响，使使用者更容易感染疾病， 与海洛因滥用有关这些免疫调节作用可以成为条件的环境 重复情境-海洛因配对后的刺激。海洛因条件刺激的呈现足以 在海洛因本身不存在的情况下引起外周促炎性措施的明显抑制。通过 在良好控制的动物模型中，我们的实验室已经证明，海洛因条件性免疫调节是一种 经典的条件反射，并遵循学习的原则。Consistently，上下文-海洛因 关联通过背侧海马（DH）过程控制。在卫生署内部，我们发现， 完整的神经免疫信号传导是海洛因调节的外周免疫应答发生所必需的。我们 已经清楚地表明，DH白细胞介素-1 β（IL-1β）及其活性受体，IL-1受体1型（IL-1 R1）， 关键介导海洛因条件免疫调节的表达。为了进一步研究海马 神经免疫参与这种条件反应，我们采用了最先进的化学遗传学工具， 在体内选择性地操纵DH星形胶质细胞信号传导。刺激星形胶质细胞Gi偶联设计受体 在暴露于海洛因条件刺激期间， 外周免疫措施的条件性抑制。因此，单独地，DH IL-1信号传导和星形胶质细胞 活性在呈现海洛因配对线索以引发条件性免疫应答期间是必需的。 然而，目前尚不清楚DH星形胶质细胞活性与IL-1之间是否存在机制关系 在这个巴甫洛夫反应中发出信号。有证据表明海马星形胶质细胞支持机制 通过IL-1β和IL-1 R1来促进学习和记忆。目前的建议是一种有针对性的办法， 探讨海洛因条件性免疫调节中DH星形胶质细胞与IL-1信号的关系。 具体的目的是检验总体假设，即DH星形胶质细胞是IL-1信号传导的关键组分。 这是海洛因免疫调节所必需的。目的1将检测星形胶质细胞特异性IL-1β的改变， 和IL-1 R1 mRNA和蛋白作为暴露于海洛因条件刺激的结果。目标2将采用 化学遗传学工具，以选择性地刺激DH星形胶质细胞的Gi-信号转导过程中提出这些海洛因配对 确定这种体内操作是否减弱海洛因所需的IL-1β和IL-1 R1表达的线索。 条件免疫调节发生。总的来说，这些有目的的实验将增强我们对 关键的神经免疫机制管理海洛因条件反射，并将提供一个有价值的培训 这是一个培养我科学事业独立性的机会。