Neonatal Trauma Alters Subsequent Fear and Sensory Function via Changes in Limbic CRF and CORT

新生儿创伤通过边缘系统 CRF 和 CORT 的变化改变随后的恐惧和感觉功能

基本信息

批准号：
9304414
负责人：
Michael A Burman
金额：
$ 42.58万
依托单位：
UNIVERSITY OF NEW ENGLAND
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-21 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304414
关键词：
11 year old Adolescence Adolescent Adult Affect Affective Afferent Pathways Age Age of Onset Agreement Amygdaloid structure Anesthesia procedures Animal Experiments Anxiety Anxiety Disorders Behavior Behavioral Belief Brain Caring Child Child Rearing Childhood Clinical Cognitive Corticosterone Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Data Development Disease model Early-life trauma Emotional Event Face Freezing Fright Functional disorder Heel Human Hypersensitivity Hypothalamic structure Immunohistochemistry Incidence Inflammatory Injection of therapeutic agent Injury Intervention Lead Learning Life Limbic System Link Literature Long-Term Effects Measures Mediating Medical Mental Depression Mental Health Modeling Moods Nature Neonatal Neonatal Intensive Care Units Neurobiology Newborn Infant Odors Pain Pain Threshold Painless Pathway interactions Pharmacology Phase Phenotype Phobias Pituitary-Adrenal System Play Post-Traumatic Stress Disorders Predisposition Procedures Psychological Models Rattus Reflex action Reporting Risk Risk Factors Role Sensory Signal Transduction Source Stress Stressful Event Structure System Tactile Testing Time Trauma Work base behavioral study conditioned fear depressive symptoms design early adolescence early childhood experimental study hypothalamic-pituitary-adrenal axis insight maternal separation mature animal neonate novel predictive modeling receptor receptor density receptor expression sensory system somatosensory successful intervention

项目摘要

There is now agreement that early life pain and stress are risk factors for subsequent changes in emotional, mood and sensory systems. Nevertheless, painful events continue to occur in the context of neonatal intensive care units (NICU) and other preventable settings. Similarly, a variety of less controllable stressful situations, such as suboptimal parenting conditions, also contribute to subsequent dysfunction. However, the mechanisms by which neonatal adversity leads to later anxiety, depression and sensory hypersensitivity remain unclear. As the consequences of early life trauma tend to emerge during late childhood or early adolescence, in order to design novel treatments and successful interventions, it is critical to examine the effects of neonatal events on behavioral and brain function at various times during development. In order to better understand how early life pain and stress can affect later brain function and behavior, this proposal uses a “double-hit” model of trauma to test the hypothesis that neonatal trauma alters the developmental trajectory of the amygdala, and subsequently hypothalamic-adrenal-pituitary axis function, including the role of corticotrophin releasing factor (CRF) and corticosterone (CORT). In particular, we believe that neonatal trauma alters CRF signaling in the amygdala and perhaps hypothalamus. When exposed to an “activating trauma” later in life, the anxiogenic or depressive phenotype is expressed. Furthermore, alterations to the amygdala will alter the descending pain system leading to tactile hypersensitivity and a predisposition towards pain. In the current experiments, neonatal rats will be exposed to invasive heel pricks, inflammatory injury or non-noxious handling over the first week of life. Fear conditioning and somatosensory function will then be assessed at multiple ages including early childhood, adolescence and adulthood. Once the behavioral effects are established, we will examine the role of amygdalar and hypothalamic CRF and CORT in these effects. This will be accomplished by measuring CRF and CORT expression, as well as receptor distribution. This will be followed by experiments that disrupt these signals using local and systemic pharmacology. We anticipate that neonatal pain will lead to alterations in subsequent fear conditioning and sensory function. Moreover, changes in CRF/CORT levels and receptor distribution in the amygdala will account for the observed behavioral changes. Although previous work has demonstrated that early life adversity can affect subsequent HPA axis function, the link between those changes and subsequent behavioral alterations that may lead to behavioral dysfunction is not well established. Overall, these experiments will examine the consequences of early-life trauma and offer insight into potential interventions protecting human well being.

现在人们一致认为，早期生活的痛苦和压力是随后情绪、情绪变化的危险因素。然而，新生儿的痛苦事件继续发生。同样，重症监护病房 (NICU) 和其他可预防的环境也存在各种难以控制的压力。诸如养育条件不佳之类的情况也会导致随后的功能障碍。新生儿逆境导致日后焦虑、抑郁和感觉过敏的机制目前尚不清楚，因为早期生活创伤的后果往往在童年晚期或早期出现。青春期，为了设计新的治疗方法和成功的干预措施，至关重要的是检查新生儿事件对发育过程中不同时期的行为和大脑功能的影响。该提案使用了更好地了解早期生活的痛苦和压力如何影响以后的大脑功能和行为创伤的“双重打击”模型，用于检验新生儿创伤改变发育轨迹的假设杏仁核的作用，以及随后的下丘脑-肾上腺-垂体轴功能，包括我们特别认为新生儿促肾上腺皮质激素释放因子（CRF）和皮质酮（CORT）。当受到“激活”时，创伤会改变杏仁核甚至下丘脑中的 CRF 信号。在以后的生活中，“创伤”会表现出焦虑或抑郁表型。杏仁核会改变下行疼痛系统，导致触觉过敏和倾向于在目前的实验中，新生大鼠将遭受侵入性足跟刺伤、炎症损伤或疼痛。在生命的第一周内，恐惧调节和体感功能将得到无害处理。在多个年龄段进行评估，包括幼儿期、青春期和成年期的行为影响。确定后，我们将检查杏仁核和下丘脑 CRF 和 CORT 在这些效应中的作用。这将通过测量 CRF 和 CORT 表达以及受体分布来完成。随后进行使用局部和全身药理学破坏这些信号的实验。新生儿疼痛会导致随后的恐惧调节和感觉功能的改变。 CRF/CORT 水平和杏仁核受体分布的变化将解释观察到的情况尽管之前的研究已经证明，早年的逆境会影响以后的生活。 HPA 轴功能，这些变化与随后可能导致的行为改变之间的联系总体而言，行为功能障碍尚未得到充分证实，这些实验将检查行为功能障碍的后果。早期生命创伤，并提供对保护人类福祉的潜在干预措施的见解。