Chronic effects of acute stress in rats

描述（由申请方提供）：本提案中的研究调查了急性应激对体重长期调节的慢性影响。连续3天每天暴露于3小时束缚的大鼠在应激当天体重减轻，在应激结束时体重增加，但不会恢复到其非应激对照组的体重。因此，反复的束缚提供了一个独特的模型，其中急性应激导致体重的慢性减轻。确定这种持续降低体重的机制将提供新的信息，体重的正常调节，并可能导致新的策略，成功地维持体重减轻超重的个人。虽然我们已经确定，体重减轻的开始是依赖于激活的中央促肾上腺皮质激素释放因子2型（CRF 2）受体相邻的第3和/或第4脑室，我们还没有确定持续的变化，在基础的神经化学或内分泌状态的动物在应激后的时期。然而，我们已经证明，给大鼠喂食高脂肪（40%千卡脂肪）饮食会通过诱导更大的体重减轻来夸大对应激的反应，并且观察到，暴露于重复约束应激的大鼠对随后的轻度应激表现出夸大的内分泌和食欲减退反应。我们推测，急性应激导致慢性高反应性的CRF系统的方面，都是应激反应，并参与调节能量稳态。CRF系统的高反应性可能会阻止应激大鼠体重的恢复。这些相同系统的敏感性也受到饮食组成的影响，以增加喂食高脂肪饮食的大鼠的应激反应。具体目标1将测试暴露于重复束缚应激的大鼠是否对随后的轻度应激表现出过度的神经化学、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将测试喂食高脂肪饮食是否会导致CRF系统的高反应性或应激后CRF活性下调的抑制，以澄清高脂肪喂食大鼠中应激反应性增加是否是由与暴露于重复束缚的大鼠相同的机制引起的。具体目标3将确定核在下丘脑和脑干是关键的压力引起的体重减轻。

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.