Evaluation of inflammation in the locus coeruleus during physical withdrawal symptoms and cognitive development in a rat model of neonatal opioid withdrawal syndrome (NOWS)

新生儿阿片戒断综合征 (NOWS) 大鼠模型身体戒断症状和认知发展过程中蓝斑炎症的评估

• 批准号: 10750776
• 负责人: Sara Lynn Mills-Huffnagle
• 金额: $ 3.7万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750776
• 关键词: Address; Adult; Amygdaloid structure; Animal Model; Attention; Attenuated; Behavioral; Birth; Brain; Brain Stem; Brain region; Characteristics; Child; Clinical; Cognition; Cognitive; Cognitive deficits; Compensation; Corpus striatum structure; Cost of Illness; Diagnosis; Disease; Evaluation; Exposure to; Female of child bearing age; Foundations; Future; Genetic Induction; Heroin; Heroin Dependence; Hippocampus; Hyperactivity; Immunohistochemistry; Infant; Inflammation; Inflammatory; Intellectual impairment; Intervention; Learning; Life; Long-Term Effects; Longitudinal Studies; Measures; Medial; Medical Care Costs; Memory; Memory impairment; Microglia; Minocycline; Modeling; Molecular; Molecular Target; Motor Activity; Mutation; Naloxone; Neonatal; Neonatal Abstinence Syndrome; Neuroglia; Neurons; Neuropeptides; Neurotransmitters; Norepinephrine; Operative Surgical Procedures; Opioid; Pennsylvania; Phenotype; Population; Pre-Clinical Model; Pregnancy; Pregnant Women; Proteins; Publishing; Rattus; Regulation; Research; Rewards; Rodent Model; Role; Saline; Source; Symptoms; Syndrome; System; TLR4 gene; Techniques; Testing; Training; Translational Research; Ultrasonics; United States; Up-Regulation; Weaning; Withdrawal; Withdrawal Symptom; Work; career; chemokine; clinically relevant; cognitive development; cognitive function; cognitive testing; cohort; cost; cytokine; education cost; emerging adult; endogenous opioids; experience; experimental study; in utero; indexing; inflammatory marker; inhibitor; insight; interest; locus ceruleus structure; mu opioid receptors; multiplex assay; neonatal brain development; neonate; novel; opioid exposure; opioid use; opioid use disorder; opioid withdrawal; physical symptom; postnatal; pre-clinical; preadolescence; pup; stem; targeted treatment; treatment strategy; vocalization

Abstract In the past decade, opioid use disorders have significantly increased in pregnant women and women of childbearing age. In parallel, we have seen a drastic rise in neonatal opioid withdrawal syndrome (NOWS). Despite having well-defined, short-term phenotypic symptoms for NOWS, molecular effects and long-term consequences are incomprehensible. This is of particular concern given that opioid exposure alone, as well as withdrawal, can induce inflammation in the brain, and recent work has shown an increase in pro-inflammatory cytokines and chemokines, which may be promoted by reactive glia as a result of in utero opioid exposure. Moreover, cognitive functioning and memory deficits have been observed in preclinical models of in utero opioid exposure, and intellectual impairments and increased attention disorders have been observed in clinical populations previously diagnosed with NOWS. While much of the research has focused on inflammation and in utero opioid exposure in brain regions associated with reward and cognition, less is known about the brain regions associated with withdrawal symptoms in NOWS, and how this may relate to cognitive function later in life. Understanding the pro-inflammatory effects of in utero opioid exposure and withdrawal may allow for novel targets for the treatment of NOWS, and better understanding of long-term consequences. Therefore, by using an established rat model of NOWS that has previously shown an upregulation of inflammatory markers due to in utero opioid exposure, we will investigate inflammation in a withdrawal-associated brain region, the locus coeruleus, and determine effects on behavioral indices of withdrawal and subsequent cognitive function. More specifically, in a rat model of NOWS, we will utilize immunohistochemistry, qPCR, and multiplex assays to evaluate inflammatory markers including reactive glial cells, toll-like receptor 4 expression, and levels of pro- inflammatory cytokines and associated neuropeptides, and their respective associations with quantified behavioral withdrawal symptoms. In addition, we will test the specific role of reactive glia on physical withdrawal symptoms in the rat neonate by systemically administering the glia-inhibiting agent, minocycline. We will assess the resultant cognitive function at PN21 and PN60, when rats are considered preadolescent and early adulthood, respectively. We will test spatial learning and memory in heroin- or saline-exposed rat pups who experienced precipitated withdrawal at PN10. Additional experiments will also include the use of neonatal, systemic minocycline administration to mitigate cognitive deficits previously observed in preclinical and clinical populations of NOWS. Together, these experiments will allow us to better understand the effects of inflammation on physical withdrawal symptoms, as well as the relationship between physical withdrawal symptoms and subsequent cognitive function, as a result of in utero opioid exposure and precipitated withdrawal, thereby establishing novel targets for the treatment of NOWS and laying the foundation for future studies evaluating its long-term consequences.

抽象的 在过去的十年中，阿片类药物使用障碍在孕妇和妇女的妇女中显着增加 生育年龄。同时，我们看到新生儿阿片类药物戒断综合征（现在）的急剧上升。 尽管现在有明确定义的短期表型症状，但分子效应和长期效果 后果是难以理解的。鉴于仅阿片类药物的暴露以及 戒断，可能诱发大脑的炎症，最近的工作显示促炎的增加 细胞因子和趋化因子，可以通过反应性神经胶质细胞来促进子宫阿片类药物。 此外，在子宫内的临床前模型中已经观察到认知功能和记忆缺陷 在临床上观察到了阿片类药物的暴露，智力障碍和注意力障碍的增加 人群以前被诊断为现有。尽管许多研究都集中在炎症和 子宫阿片类药物在与奖励和认知相关的大脑区域中暴露，对大脑的了解少 与现在的戒断症状相关的区域，以及以后与认知功能有关的区域 生活。了解子宫阿片类药物暴露和戒断的促炎作用可能允许新颖 现在治疗现在的目标，并更好地理解长期后果。因此，通过使用 既定的现在的大鼠模型，以前已经显示出由于 在子宫阿片类药物暴露中，我们将调查与戒断相关的大脑区域中的炎症 凝结，并确定对戒断和随后的认知功能行为指数的影响。更多的 具体而言，在现在的大鼠模型中，我们将利用免疫组织化学，qPCR和多重测定 评估包括反应性神经胶质细胞，Toll样受体4表达以及促炎性标志物的水平 炎性细胞因子和相关的神经肽，及其各自的关联 行为戒断症状。此外，我们将测试反应性神经胶质在物理上的特定作用 大鼠新生儿的戒断症状是通过系统地施用抑制神经胶质剂Minocycline的。 当大鼠被视为preadelectent时，我们将评估PN21和PN60的最终认知功能 和成年早期。我们将在海洛因或盐水暴露的老鼠中测试空间学习和记忆 在PN10中经历了沉淀戒断的幼崽。其他实验还将包括使用 新生儿，全身米诺环素给药以减轻先前在临床前观察到的认知缺陷 和现在的临床人群。这些实验一起将使我们能够更好地理解 身体戒断症状的炎症以及身体戒断之间的关系 症状和随后的认知功能，由于子宫阿片类药物暴露和沉淀 提取，从而建立新的目标来治疗现在，并为未来奠定基础 研究评估其长期后果的研究。