Dysregulation of the opioid system in early life adversity

早年逆境中阿片类药物系统的失调

• 批准号: 10698168
• 负责人: Marcelo Dietrich
• 金额: $ 81.93万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698168
• 关键词: Abbreviations; Ablation; Adolescence; Adolescent; Animal Model; Attention; Beds; Behavior; Behavioral; Brain; Buffers; Caring; Child Abuse and Neglect; Childhood; Cognitive; Complex; Crying; Cues; Detection; Distress; Early-life trauma; Electrophysiology (science); Endorphin Receptors; Etiology; Exposure to; Fiber; Genetic; Human; Hypothalamic structure; Impairment; Impulsivity; Individual; Infant; Life; Link; Medical; Methods; Modeling; Mothers; Multiple Trauma; Mus; Neurons; Opioid; Opioid agonist; Peptides; Photometry; Play; Population; Pro-Opiomelanocortin; Process; Receptor Signaling; Risk; Role; Safety; Secure; Signal Pathway; Slice; Social Behavior; Socialization; Source; Substance Use Disorder; System; Testing; Trauma; Ultrasonics; Work; beta-Endorphin; early life adversity; early life stress; emotion dysregulation; in vivo; insight; maternal separation; mouse model; mu opioid receptors; nonhuman primate; novel; offspring; pediatric trauma; programs; pup; receptor; receptor-mediated signaling; response; social; stress reduction; tool; vocalization

PROJECT SUMMARY Childhood maltreatment is associated with insecure attachment, emotional dysregulation, and abnormal threat detection. Here we propose that abnormal dysregulation of the brain beta-endorphin signaling pathway plays a central role linking childhood maltreatment with insecure attachment and with long-term behavioral abnormalities. This idea is supported by work showing that dysregulation of the main beta-endorphin receptor (mu-opioid receptor, or MOR) is associated with insecure attachment, emotional dysregulation, and abnormal threat detection. To test this premise, we developed a mouse model of complex trauma, abbreviated UPS. UPS recapitulates several key features of childhood maltreatment including the presence of multiple adversities, fragmented abusive maternal care, insecure attachment, impaired maternal buffering, increased threat detection, and abnormal social exploration. We also discovered that neurons in the hypothalamus expressing the agouti- related peptide (Agrp) are rapidly activated in response to unpredictable maternal separation in infant mice. Activation of Agrp neurons triggers the emission of ultrasonic vocalizations—the equivalent of the infant cry— and solicited dam’s attention and care. Thus, Agrp neurons function as an alarm system for the infant during distress. Intertwined with Agrp neurons are proopiomelanocortin (POMC) neurons, which are the main source of beta-endorphin in the brain. We found that POMC neurons of infant mice are rapidly activated by reunion with the dam. Activation of POMC neurons suppressed, while their ablation increased, the emission of ultrasonic vocalizations in infant mice. Thus, POMC neurons function as a buffering/safety system for the infant that is triggered during interactions with the mother. Based on these and other observations detailed in the proposal, we hypothesize that complex trauma in childhood—modeled by UPS in mice—impairs the ability of the mother to activate POMC neurons leading to reduced MOR signaling in Agrp neurons. This in turn causes prolonged activation of Agrp neurons and sustained distress that further erodes maternal buffering, secure attachment, and the ability of UPS mice to socialize and assess threat later in life. Work in Aim 1 will use fiber photometry in live moving pups and slice electrophysiology to characterize the effects of UPS on POMC and Agrp neuronal activation and its impact on MOR signaling in Agrp neurons. Work in Aim 2 will determine the contribution that POMC neurons and MOR signaling make to maternal affiliation/buffering and threat detection/social behavior in adolescence. Work in Aim 3 will test the extent to which sustained activation of Agrp neurons in infants is responsible for the behavioral abnormalities seen in mice exposed to UPS. Successful completion of this work will provide new insights into the mechanisms by which complex trauma in childhood programs abnormal attachment, enhances threat detection, and impairs social behavior.

项目总结 儿童期虐待与不安全的依恋、情绪失调和异常威胁有关 侦测。在这里，我们认为大脑β-内啡肽信号通路的异常失调在 将儿童期虐待与不安全的依恋和长期行为联系起来的中心角色 异常现象。这一观点得到了一项研究的支持，该研究表明，主要的β-内啡肽受体的失调 (MU-阿片受体，或MOR)与不安全的依恋、情绪失调和异常有关 威胁检测。为了验证这一前提，我们开发了一种复杂创伤的小鼠模型，简称UPS。UPS 概括了儿童期虐待的几个主要特征，包括多重逆境的存在， 支离破碎的虐待产妇护理，没有安全感的依恋，产妇缓冲受损，威胁检测增加， 以及不正常的社会探索。我们还发现，下丘脑中表达刺激物的神经元- 相关肽(AgRP)在幼鼠对不可预测的母体分离做出反应时被迅速激活。 AgRP神经元的激活触发了超声波发声--相当于婴儿的哭声-- 并请求大坝的关注和关心。因此，AgRP神经元在婴儿发育过程中起警报系统的作用 苦恼。与AgRP神经元交织在一起的是前阿片黑素皮质素(POMC)神经元，它是 大脑中的β-内啡肽。我们发现幼年小鼠的POMC神经元通过与 水坝。POMC神经元的激活受到抑制，而其消融增加，超声发射 幼鼠的发声。因此，POMC神经元为婴儿发挥缓冲/安全系统的作用，即 在与母亲的互动中被触发。根据提案中详细说明的这些和其他意见， 我们假设儿童时期的复杂创伤--由UPS在小鼠身上模拟--会损害母亲的能力 激活POMC神经元，导致AgRP神经元内MOR信号减少。这反过来又会导致延长 AgRP神经元的激活和持续的窘迫进一步侵蚀了母体的缓冲、安全依恋和 UPS小鼠在以后的生活中进行社交和评估威胁的能力。在目标1中工作将在现场使用光纤光度测量 运动幼鼠和脑片电生理学研究UPS对POMC和AgRP神经元的影响 AgRP神经元的激活及其对MOR信号的影响。目标2的工作将决定 POMC神经元和MOR信号在母系联系/缓冲和威胁检测/社会行为中起作用 青春期。目标3的工作将测试婴儿体内AgRP神经元持续激活的程度 对暴露在UPS中的小鼠的行为异常负责。圆满完成这项工作 将为儿童计划中的复杂创伤异常的机制提供新的见解 依恋，增强威胁检测，并损害社交行为。