Dysregulation of the opioid system in early life adversity

早年逆境中阿片类药物系统的失调

基本信息

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
项目类别：
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

项目摘要

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.

项目概要童年虐待与不安全依恋、情绪失调和异常威胁有关在此，我们提出大脑β-内啡肽信号通路的异常调节发挥着重要作用。将儿童期虐待与不安全依恋和长期行为联系起来的核心作用这一观点得到了主要β-内啡肽受体失调的研究的支持。（mu-阿片受体，或 MOR）与不安全依恋、情绪失调和异常相关为了测试这个前提，我们开发了一种复杂创伤的小鼠模型，缩写为 UPS。概括了儿童虐待的几个关键特征，包括存在多种逆境，支离破碎的虐待性孕产妇护理、不安全依恋、孕产妇缓冲受损、威胁检测增加、我们还发现下丘脑中表达刺鼠的神经元相关肽（Agrp）会因婴儿小鼠不可预测的母体分离而迅速激活。 Agrp 神经元的激活会触发超声波发声的发射——相当于婴儿的哭声—— 并引起母亲的注意和照顾，因此，Agrp 神经元在婴儿的发育过程中起到了警报系统的作用。与 Agrp 神经元交织在一起的是阿黑皮素原 (POMC) 神经元，它们是痛苦的主要来源。我们发现，幼年小鼠的 POMC 神经元在与大脑团聚时会迅速激活。 POMC 神经元的激活受到抑制，而其消融则增加，超声波的发射。因此，POMC 神经元对婴儿来说起着缓冲/安全系统的作用。根据这些以及提案中详细说明的其他观察结果，在与母亲的互动中触发。我们以小鼠 UPS 为模型，追踪了童年时期的复杂创伤，这种创伤损害了母亲的能力激活 POMC 神经元，导致 Agrp 神经元中的 MOR 信号减少，这反过来又会导致时间延长。 Agrp 神经元的激活和持续的痛苦进一步削弱了母体的缓冲、安全依恋和 UPS 小鼠在以后的生活中社交和评估威胁的能力将在现场使用光纤光度测量。移动幼崽和切片电生理学来表征 UPS 对 POMC 和 Agrp 神经元的影响目标 2 中的工作将确定 Agrp 神经元中的激活及其对 MOR 信号传导的影响。 POMC 神经元和 MOR 信号传导有助于母亲的归属/缓冲和威胁检测/社会行为目标 3 的工作将测试婴儿期 Agrp 神经元持续激活的程度。成功完成这项工作的原因是暴露于 UPS 的小鼠中出现了行为异常。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。