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。将儿童虐待与不安全的饮食和长期行为联系起来的核心角色异常。（MU-Apoid受体或MOR）与不安全的依恋，情绪失调和异常有关威胁要测试这一前提，我们开发了一个复杂的创伤的鼠标模型。概括了儿童虐待的几个关键特征，包括存在多个逆境，分散的虐待产妇护理，不安全的依恋，孕产妇缓冲受损，线程检测增加，和异常的社会探索。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。农业的激活会触发超声发声的发射 - 相当于婴儿哭泣并征求大坝的注意力和关怀。距离与农业的交织大脑中的β-内啡肽。大坝激活POMC神经元，而它们的消融增加了因此，婴儿小鼠的发声。在与母亲的互动期间触发。我们假设童年时期这种复杂的创伤 - 由小鼠中的UPS建模 - 损害了Theerer的能力激活POMC神经元以减少AGRP神经元的MOR信号传导。激活Agrons和持续性困扰，进一步侵蚀了母体缓冲，安全性和 UPS以后生活中的社交和评估威胁的能力。移动幼崽和切片电生理学来表征UPS OND AGRP神经元的影响激活及其对AGRP神经元中MOR信号的影响。 POMC神经元和MOR信号传导使孕产妇的隶属关系/缓冲和威胁检测/社会行为 AIM 3中的青春期将测试AGRP神经元持续激活的程度负责暴露于UPS的小鼠中的行为异常。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。