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

现在人们一致认为，早期的生活痛苦和压力是随后情绪变化的风险因素， 情绪和感觉系统。然而，在新生儿的情况下，痛苦的事件继续发生 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 一些情况，如不理想的育儿条件，也会导致随后的功能障碍。然而， 新生儿逆境导致以后焦虑、抑郁和感觉过敏的机制 目前仍不清楚。因为早期生活创伤的后果往往出现在童年后期或早期 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 不同发育时期新生儿事件对行为和脑功能的影响为了 为了更好地理解早年的痛苦和压力如何影响后来的大脑功能和行为，这项建议使用了 一种“双击式”创伤模型来检验新生儿创伤改变发育轨迹的假说 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，我们认为新生儿 创伤改变了杏仁核和下丘脑中的CRF信号。当暴露在“激活”状态下时 创伤“在生命的后期，会表现出引起焦虑或抑郁的表型。此外，对 杏仁核将改变下行疼痛系统，导致触觉过敏和易感 疼痛。在目前的实验中，新生大鼠将暴露于侵入性脚跟刺痛、炎性损伤或 在生命的第一周内进行无害的处理。恐惧的条件反射和躯体感觉功能 在多个年龄段进行评估，包括儿童早期、青春期和成年期。一旦行为影响 我们将研究杏仁核、下丘脑CRF和皮质醇在这些效应中的作用。 这将通过测量CRF和CORT的表达以及受体的分布来实现。这将是 随后进行使用局部和系统药理学干扰这些信号的实验。我们期待着 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， CRF/CORT水平和杏仁核受体分布的变化将解释观察到的 行为上的改变。尽管先前的研究表明，早年生活中的逆境会影响以后的生活 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 行为障碍并没有得到很好的证实。总体而言，这些实验将检验 并提供对保护人类福祉的潜在干预措施的洞察。

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.