Chronic effects of acute stress

急性应激的慢性影响

• 批准号: 7036544
• 负责人: Ruth B Harris
• 金额: $ 25.87万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036544
• 关键词: behavior test; bioenergetics; biological models; brain mapping; brain stem; caloric dietary content; corticosterone; corticotropin releasing factor; dexamethasone; dietary lipid; environmental stressor; hormone inhibitor; hormone receptor; hormone regulation /control mechanism; hypothalamus; injection /infusion; laboratory mouse; laboratory rat; norepinephrine; nutrition related tag; receptor expression; restraint; stimulus interval; stress; weight loss

DESCRIPTION (provided by applicant): Studies in this proposal investigate the chronic effects of acute stress on long-term regulation of body weight. Rats exposed to 3 hours of restraint on each of 3 consecutive days lose weight on the days of stress and gain weight when stress ends, but do not return to the weight of their non-stressed controls. Thus, repeated restraint provides a unique model in which acute stress results in a chronic reduction in body weight. Identification of mechanisms responsible for this sustained reduction in body weight will provide new information on the normal regulation of body weight and may lead to novel strategies for successful maintenance of weight loss in overweight individuals. Although we have determined that initiation of weight loss is dependent upon activation of central corticotropin releasing factor Type 2 (CRF2) receptors adjacent to the 3rd and/or 4th ventricle, we have not identified sustained changes in the basal neurochemical or endocrine status of the animals during the post-stress period. We have, however, shown that feeding rats a high-fat (40 percent kcal fat) diet exaggerates the response to stress by inducing a greater weight loss and have observed that rats that have been exposed to repeated restraint stress show an exaggerated endocrine and hypophagic response to a subsequent mild stress. We hypothesize that acute stress causes a chronic hyper-reactivity of aspects of the CRF system that are both stress-responsive and are involved in the regulation of energy homeostasis. Hyper-reactivity of the CRF system may prevent recovery of body weight in stressed rats. The sensitivity of these same systems also is influenced by diet composition to increase stress responsiveness in rats fed a high-fat diet. Specific Aim 1 will test whether rats that have been exposed to repeated restraint stress exhibit an exaggerated neurochemical, energetic and behavioral response to a subsequent mild stress, which would be indicative of an increased reactivity of the CRF system. Specific Aim 2 will test whether feeding a high-fat diet results in a hyper-responsiveness of the CRF system or a suppression of the post-stress down-regulation of CRF activity, to clarify whether increased stress responsiveness is caused by the same mechanisms in high-fat fed rats as in rats that have been exposed to repeated restraint. Specific Aim 3 will identify nuclei in the hypothalamus and brainstem that are critical for stress-induced weight loss.

描述（由申请人提供）：本提案中的研究调查了急性压力对体重长期调节的慢性影响。连续 3 天每天受到 3 小时束缚的大鼠在有压力的日子里体重减轻，并在压力结束时体重增加，但不会恢复到无压力对照组的体重。因此，反复限制提供了一种独特的模型，其中急性压力导致体重慢性减轻。确定导致体重持续减轻的机制将提供有关体重正常调节的新信息，并可能导致超重个体成功维持体重减轻的新策略。尽管我们已经确定体重减轻的开始取决于邻近第三和/或第四心室的中枢促肾上腺皮质激素释放因子2型（CRF2）受体的激活，但我们尚未发现动物在应激后时期基础神经化学或内分泌状态的持续变化。然而，我们已经证明，给老鼠喂食高脂肪（40％千卡脂肪）饮食会导致更大的体重减轻，从而夸大对压力的反应，并且观察到，反复受到束缚压力的老鼠对随后的轻微压力表现出夸大的内分泌和食欲减退反应。我们假设急性应激会导致 CRF 系统各方面的慢性过度反应，这些方面既具有应激反应性，又参与能量稳态的调节。 CRF 系统的过度反应可能会阻碍应激大鼠体重的恢复。这些相同系统的敏感性也受到饮食成分的影响，以增加高脂肪饮食大鼠的应激反应能力。具体目标 1 将测试反复受到束缚应激的大鼠是否对随后的轻度应激表现出夸张的神经化学、精力和行为反应，这表明 CRF 系统的反应性增加。具体目标 2 将测试喂养高脂肪饮食是否会导致 CRF 系统过度反应或抑制应激后 CRF 活性的下调，以阐明高脂肪喂养大鼠的应激反应性增加是否是由与反复受到限制的大鼠相同的机制引起的。具体目标 3 将识别下丘脑和脑干中对压力引起的体重减轻至关重要的核团。