Affective Consequences of Chemotherapy

 描述(申请人提供)：乳腺癌是女性中最常见的癌症；在美国，每8名女性中就有1名在一生中被诊断出患有这种疾病。检测和治疗的进步大大提高了乳腺癌患者的5年生存率。然而，在这群幸存者中，抑郁和焦虑的发生率大约是一般人口中女性的3-5倍。尽管这一显著增加，乳腺癌患者抑郁和焦虑的病因仍不清楚。在小鼠身上，我们已经能够确定化疗引起的神经炎症和情感行为变化之间的因果联系。这项建议的第一个目标是确定切除的肿瘤是否启动了对化疗的炎症反应，并确定在多种化疗过程中神经炎症和情感行为是如何变化的。这项提议的第二个目标是，确定被假设为导致化疗后抑郁和焦虑发展的个体差异的因素，特别是压力和社会孤立，是否通过增加化疗的促炎后果来实现。我们的初步数据显示，在接受化疗的小鼠中，压力暴露和社会隔离分别显著增加了抑郁样行为和焦虑样行为。Aim 2中的实验将确定化疗引起的抑郁样行为的加重是否通过皮质类固醇介导的神经炎症增加的机制实现，以及阻断糖皮质激素对应激的反应是否减少了化疗的神经炎症和情感后果。AIM 3中的实验将确定关联性社会互动是否为化疗引起的神经炎症和情感变化提供了缓冲。这项拟议的研究是对这一假说的首次实验测试，该假说是对化疗引起的神经炎症的调节改变发展为抑郁和焦虑的风险的假设。这项拟议研究的长期目标是通过缓解抑郁和焦虑来改善癌症患者的心理和身体健康，以及他们的生活质量。实现这一目标的重要第一步是提高对生物学过程的理解，通过这些生物学过程，环境因素影响对化疗相关情感障碍的易感性。

 DESCRIPTION (provided by applicant): Breast cancer is the most frequently diagnosed cancer in women; 1 in 8 women in the United States will be diagnosed with this disease during their lifetime. Advances in detection and treatment have substantially increased the 5-year survival rate for breast cancer patients. However, among this population of survivors, the incidences of depression and anxiety are approximately 3-5 times higher than among women in the general population. Despite this striking increase, the etiology of depression and anxiety among breast cancer patients remains unknown. In mice, we have been able to establish a causal link between chemotherapy-induced neuroinflammation and changes in affective behavior. The first goal of this proposal is to determine whether having a tumor that has been resected primes the inflammatory response to chemotherapy and to determine how neuroinflammation and affective behavior change over the course of multiple chemotherapy treatments. The second goal of this proposal is to determine whether factors that are hypothesized to contribute to individual differences in susceptibility to the development of depression and anxiety after chemotherapy, specifically stress and social isolation, do so by increasing the proinflammatory consequences of chemotherapy. Our preliminary data indicate that stress exposure and social isolation significantly increase depressive-like behavior and anxiety-like behavior, respectively, among mice treated with chemotherapy. The experiments in Aim 2 will determine whether the chemotherapy-induced exacerbation of depressive-like behavior is achieved through a mechanism involving corticosteroid mediated increases in neuroinflammation, and whether blocking the glucocorticoid response to stress reduces the neuroinflammatory and affective consequences of chemotherapy. The experiments in Aim 3 will determine whether affiliative social interaction provides a buffer against chemotherapy-induced neuroinflammation, and affective changes. The proposed research represents the first experimental test of the hypothesis that modulation of chemotherapy-induced neuroinflammation alters the risk of developing depression and anxiety. The long-range goal of the proposed research is to improve the mental and physical health of cancer patients, as well as their quality of life, through the alleviation of depression and anxiety. The important first stp in achieving this goal is improved understanding of the biological processes through which environmental factors influence susceptibility to chemotherapy-related affective disorders.