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.

现在达成共识，早期生活疼痛和压力是随后情绪变化的风险因素，情绪和感官系统。然而，在新生儿的背景下继续发生痛苦的事件重症监护病房（NICU）和其他可预防的设置。同样，各种不太控制的压力诸如次优育儿条件之类的情况也导致随后的功能障碍。但是，新生儿广告导致后来焦虑，抑郁和感觉超敏反应的机制保持不清楚。由于早期创伤的后果往往会在儿童晚期或早期出现为了设计新颖的治疗和成功的干预措施，青少年敏感至关重要新生儿事件在发育过程中的不同时间对行为和大脑功能的影响。为了更好地了解早期生活疼痛和压力如何影响较晚的大脑功能和行为，该建议使用创伤的“双重打击”模型，以检验新生儿创伤改变发育轨迹的假设杏仁核，随后的下丘脑 - 肾上腺垂体轴功能，包括皮质营养素释放因子（CRF）和皮质酮（CORT）。特别是，我们相信新生儿创伤改变了杏仁核和下丘脑中的CRF信号传导。暴露于“激活创伤”生命后期，表达了焦虑或抑郁表型。此外，对杏仁核会改变降低疼痛系统，从而导致触觉超敏反应，并倾向于疼痛。在当前的实验中，新生大鼠将暴露于侵入性脚跟刺，炎症性损伤或在生命的第一周，无毒理的处理。恐惧条件和体感功能将是在多个年龄段评估，包括幼儿，青少年和成年。一旦行为影响已建立，我们将研究杏仁核和下丘脑CRF和Cort在这些作用中的作用。这将通过测量CRF和Cort表达以及接收器分布来实现。这会然后是使用局部和系统药理学破坏这些信号的实验。我们期待新生儿疼痛将导致随后的恐惧调节和感觉功能的改变。而且，杏仁核中CRF/CORT水平和接收器分布的变化将考虑到观察到的行为改变。尽管以前的工作表明，早期的广告可能会影响随后的 HPA轴功能，这些变化与随后的行为改变之间的联系可能导致行为功能障碍尚未确定。总体而言，这些实验将检查早期生活创伤，并深入了解保护人类健康的潜在干预措施。