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: 10587155
• 负责人: Marcelo Dietrich
• 金额: $ 83.6万
• 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/10587155
• 关键词: Ablation; Adolescence; Adolescent; Animal Model; Attention; Behavior; Behavioral; Brain; Buffers; Caring; Child Abuse and Neglect; Childhood; Cognitive; Complex; Cues; Detection; Distress; Early-life trauma; Electrophysiology (science); Emotional; Endorphin Receptors; Etiology; Exposure to; Fiber; 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; Stress; System; Testing; Trauma; Ultrasonics; Work; base; beta-Endorphin; early life adversity; early life stress; emotion dysregulation; in vivo; insight; maternal separation; mouse model; mu opioid receptors; novel; offspring; pediatric trauma; programs; pup; receptor; receptor-mediated signaling; response; social; substance use; 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.

项目摘要 儿童期虐待与不安全依恋、情绪失调和异常威胁有关 侦测在这里，我们提出，大脑β-内啡肽信号通路的异常失调发挥了重要作用。 儿童期虐待与不安全依恋和长期行为之间的联系 异常这一观点得到了研究的支持，研究表明，主要的β-内啡肽受体的失调， （μ-阿片受体，或莫尔）与不安全的依恋，情绪失调，和异常 威胁检测为了验证这一假设，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，包括多种逆境的存在， 支离破碎的虐待性孕产妇护理，不安全的依恋，孕产妇缓冲受损，威胁检测增加， 和不正常的社会探索我们还发现，下丘脑中表达agglutinin的神经元- 相关肽（Agrp）在幼年小鼠中响应于不可预测的母体分离而被迅速激活。 Agrp神经元的激活触发了超声波发声的发射-相当于婴儿的哭声- 并请求大坝的关注和关怀。因此，Agrp神经元在婴儿发育过程中起着报警系统的作用。 痛苦与Agrp神经元相互干扰的是阿黑皮素原（POMC）神经元，其是Agrp神经元的主要来源。 大脑中的β-内啡肽我们发现，婴儿小鼠的POMC神经元被迅速激活， 大坝POMC神经元的激活抑制了超声波的发射，而它们的消融增加了超声波的发射。 幼鼠的发声。因此，POMC神经元充当婴儿的缓冲/安全系统， 在与母亲的互动中被触发。根据这些意见和提案中详述的其他意见， 我们假设儿童期的复杂创伤--以UPS为模型的小鼠--损害了母亲的能力， 激活POMC神经元，导致Agrp神经元中莫尔信号传导减少。这反过来又导致了长期的 Agrp神经元的激活和持续的痛苦，进一步侵蚀了母性缓冲，安全依恋， UPS小鼠在以后的生活中社交和评估威胁的能力。目标1中的工作将在现场使用光纤测光 移动幼崽和切片电生理学来表征UPS对POMC和Agrp神经元的影响 激活及其对Agrp神经元中莫尔信号传导的影响。目标2的工作将决定 POMC神经元和莫尔信号传导对母亲的联系/缓冲和威胁检测/社会行为的影响 青春期目标3中的工作将测试婴儿Agrp神经元的持续激活在多大程度上是 导致暴露于UPS的小鼠出现行为异常。圆满完成这项工作 将为儿童期复杂创伤程序异常的机制提供新的见解 依恋，增强威胁检测，并损害社会行为。