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

• 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
• 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

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变化的危险因素， 情绪和感觉系统然而，在新生儿的情况下，疼痛事件继续发生。 重症监护病房（NICU）和其他可预防的环境。同样，各种不太可控的压力 不理想的养育条件等情况也会导致随后的功能障碍。但 新生儿逆境导致后期焦虑、抑郁和感觉过敏的机制 仍然不清楚。由于早期生活创伤的后果往往出现在童年晚期或早期， 为了设计新的治疗方法和成功的干预措施，关键是要检查 新生儿事件在发育过程中不同时期对行为和脑功能的影响。为了 为了更好地了解早期生活中的痛苦和压力如何影响后来的大脑功能和行为，该提案使用 一个“双重打击”的创伤模型，以检验新生儿创伤改变发育轨迹的假设 杏仁核，以及随后的下丘脑-肾上腺-垂体轴功能，包括 促肾上腺皮质激素释放因子（CRF）和皮质酮（CORT）。特别是，我们认为， 创伤改变了杏仁核和下丘脑中的CRF信号。当暴露于“激活”时， 在以后的生活中，焦虑或抑郁表型被表达。此外，修改 杏仁核将改变下行疼痛系统，导致触觉过敏和倾向于 痛苦在目前的实验中，新生大鼠将暴露于侵入性足跟针刺、炎症损伤或 在出生后的第一周进行无害处理。恐惧条件反射和躯体感觉功能 在多个年龄段进行评估，包括幼儿期、青少年期和成年期。一旦行为效应 我们将研究杏仁核和下丘脑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实现。这将 然后进行实验，使用局部和全身药理学来破坏这些信号。我们预计 新生儿疼痛会导致随后的恐惧条件反射和感觉功能的改变。此外，委员会认为， CRF/CORT水平和杏仁核中受体分布的变化将解释所观察到的 行为改变尽管先前的研究表明，早期生活中的逆境会影响随后的生活， HPA轴功能，这些变化和随后的行为改变之间的联系，可能导致 行为功能障碍还没有得到很好的证实。总的来说，这些实验将研究 早期生活创伤，并提供对保护人类福祉的潜在干预措施的见解。