IGFI and Depression

描述(申请人提供)：在人类中，积极的情感状态与抑郁的恢复力以及全球健康水平的提高和死亡率的降低有关。目前可用的抗抑郁药物不能治疗与抑郁相关的积极情绪下降的症状。以积极的情感状态为目标，与抑郁症的复原力相关，是一种有吸引力的替代治疗方法。大鼠享乐性50 kHz超声发声(享乐性USVs)是一种公认的积极情感状态的测量方法。使用这个模型，我们已经确定胰岛素样生长因子-I在功能上参与了积极情绪诱导的抑郁症的复原力。在人类中，胰岛素样生长因子I(IGFI)被证明既能增加积极情绪，又能减少抑郁和焦虑症状，但外周副作用(低血糖)限制了其临床应用。拟议的研究将进一步检验IGFI对抑郁的复原力的功能作用。在这些拟议的实验中，(I)将确定IGFI诱导的积极情绪和抗抑郁作用的最佳大脑区域，(Ii)将使用多种动物测量积极情绪和抑郁的方法来检查IGFI诱导的弹性，以及(Iii)将确定胰岛素样生长因子结合蛋白2(IGFBP-2)作为治疗抑郁症的治疗潜力。研究积极情绪及其与抑郁症复原力的关系是一种独特的方法，可能会导致新型抗抑郁药物的发明。 公共卫生相关性：抑郁症影响了超过10%的成年人口，预计到2020年将成为第二大死亡原因。不到30%的抑郁症患者对目前可用的抗抑郁药物有反应，这些药物主要通过减少负面情绪起作用。在这项应用中，将研究IGFI诱导的积极情绪和对抑郁的弹性的机制，目的是提供机制洞察力，以及 为抑郁症的治疗创造了一条新的治疗发展途径。

DESCRIPTION (provided by applicant): In humans, positive affective states are associated with resilience to depression as well as increased global health and decreased mortality. Currently available antidepressants fail to treat the symptom of decreased positive affect associated with depression. Targeting positive affective states associated with resilience to depression is an attractive alternative treatment approach. Rat hedonic 50-kHz ultrasonic vocalizations (hedonic USVs) are a well established measure of positive affective states. Using this model, we have identified Insulin-like Growth Factor-I as functionally involved in positive- affect-induced resilience to depression. In humans, Insulin-like Growth Factor I (IGFI) has been shown to both increase positive affect and reduce symptoms of depression and anxiety, but peripheral side effects (hypoglycemia) limits its clinical utility. The proposed studies will furthr examine the functional role of IGFI resilience to depression. In these proposed experiments, (i) the optimal brain region for IGFI-induced positive affect and antidepressant effects will be determined, (ii) IGFI-induced resilience will be examined using multiple animal measure of positive affect and depression, and (iii) the therapeutic potential of Insulin-like growth factor binding protein 2 (IGFBP-2) as a treatment for depression will be determined. Studying positive affect and how it relates to resilience to depression is a unique approach that may lead to the creation of novel antidepressants. PUBLIC HEALTH RELEVANCE: Depression affects over 10% of the adult population and is projected to become the second leading cause of death by 2020. Less than 30% of depressed patients respond to currently available antidepressants which work primarily by decreasing negative emotions. In this application, the mechanism of IGFI-induced positive affect and resilience to depression will be studied with the goal of providing mechanistic insight, as well as creating a novel therapeutic development pathway, for the treatment of depression.