Affective Consequences of Chemotherapy

 描述（由申请人提供）：乳腺癌是女性中最常诊断的癌症;在美国，每8名女性中就有1名在其一生中被诊断患有这种疾病。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，在这些幸存者中，抑郁症和焦虑症的发病率比一般人口中的妇女高出约3-5倍。尽管这一惊人的增长，乳腺癌患者中抑郁和焦虑的病因仍然未知。在小鼠中，我们已经能够建立化疗诱导的神经炎症和情感行为变化之间的因果关系。该提案的第一个目标是确定已切除的肿瘤是否引发对化疗的炎症反应，并确定神经炎症和情感行为在多次化疗治疗过程中如何变化。该提案的第二个目标是确定假设有助于化疗后抑郁和焦虑发展易感性个体差异的因素，特别是压力和社会隔离，是否通过增加化疗的促炎后果来实现。我们的初步数据表明，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。目标2中的实验将确定化疗诱导的抑郁样行为的恶化是否通过涉及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化疗的神经炎症和情感后果。目标3中的实验将确定亲和的社会互动是否提供了对化疗诱导的神经炎症和情感变化的缓冲。这项研究代表了第一个实验测试的假设，化疗诱导的神经炎症的调制改变抑郁症和焦虑症的风险。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身心健康以及生活质量。实现这一目标的第一个重要stp是提高对环境因素影响化疗相关情感障碍易感性的生物学过程的理解。

 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.