Chronic effects of acute stress in rats

描述(由申请人提供)：本提案中的研究调查了急性应激对长期体重调节的慢性影响。连续3天每天束缚3小时的大鼠在应激期间体重减轻，应激结束后体重增加，但没有恢复到非应激对照组的体重。因此，反复束缚提供了一种独特的模式，在这种模式下，急性应激会导致体重的慢性减轻。识别导致体重持续下降的机制将提供有关正常体重调节的新信息，并可能导致成功维持超重个体体重减轻的新策略。虽然我们已经确定体重减轻的开始依赖于邻近第三和/或第四脑室的中枢促肾上腺皮质激素释放因子2型(CRF2)受体的激活，但我们没有发现动物在应激后阶段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，喂给老鼠高脂肪(40%卡路里脂肪)饮食会通过诱导更大的体重减轻来夸大对压力的反应，并观察到反复暴露在约束压力下的大鼠对随后的温和压力表现出夸大的内分泌和低吞噬反应。我们假设，急性应激导致CRF系统各方面的慢性高反应性，这些方面既是应激反应的，又参与了能量稳态的调节。CRF系统的高反应性可能会阻止应激大鼠体重的恢复。这些系统的敏感性也受到饮食结构的影响，以提高喂食高脂饮食的大鼠的应激反应。特定目标1将测试暴露在反复束缚应激下的大鼠是否对随后的轻度应激表现出夸大的神经化学、能量和行为反应，这将表明CRF系统的反应性增加。具体目标2将测试喂食高脂饮食是否会导致CRF系统的高反应性或抑制应激后CRF活性的下调，以阐明高脂饮食大鼠的应激反应增强是否与反复受到束缚的大鼠相同的机制所致。具体目标3将确定下丘脑和脑干中对压力诱导的体重减轻至关重要的核团。

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.