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：
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
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/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

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.

项目摘要儿童虐待与不安全的依恋，情绪失调和异常威胁有关检测。在这里，我们提出脑β-内啡肽信号通路的异常失调会发挥将儿童虐待与不安全的依恋和长期行为联系起来的核心角色异常。这一想法得到了表明主要β-内啡肽接收器失调的工作支持（MU-Apoid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。 UPS 概括了儿童虐待的几个关键特征，包括存在多个逆境，破碎的滥用材料护理，不安全的依恋，材料缓冲受损，威胁检测增加，和异常的社会探索。我们还发现下丘脑中表达agouti-的神经元相关肽（AGRP）响应婴儿小鼠的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发声的发射 - 相当于婴儿哭泣 - 并巩固了大坝的注意力和关心。那就是，AGRP神经元在婴儿期间充当婴儿的警报系统困扰。与AGRP神经元交织在一起的是proopiomelanocortin（POMC）神经元，这是主要来源大脑中的β-内啡肽。我们发现，婴儿小鼠的POMC神经元与与大坝。 POMC神经元的激活被抑制，虽然其消融增加，但超声波的发射婴儿小鼠的发声。那就是POMC神经元充当婴儿的缓冲/安全系统在与母亲互动期间触发。基于提案中详细介绍的这些观察结果，我们假设童年时期的这种复杂的创伤（由小鼠的UPS模型）影响了母亲的能力激活POMC神经元导致AGRP神经元中MOR信号传导降低。这反过来导致延长激活AGRP神经元和持续的困扰，从而进一步侵蚀物质缓冲，安全依恋和 UPS小鼠在以后生活中进行社交和评估威胁的能力。 AIM 1的工作将在现场使用纤维光度法移动幼崽和切片电生理学以表征UPS对POMC和AGRP神经元的影响激活及其对AGRP神经元中MOR信号的影响。 AIM 2的工作将决定 POMC神经元和MOR信号传导对孕产妇的会员/缓冲和威胁检测/社会行为产生青少年。 AIM 3中的工作将测试婴儿AGRP神经元持续激活的程度是负责暴露于UPS的小鼠中看到的行为异常。成功完成这项工作将提供有关童年计划中复杂创伤异常的机制的新见解依恋，增强威胁检测并损害社会行为。