Effects of chemotherapeutic agents on learning and memory in mice

描述(申请人提供)：癌症化疗会导致相当多患者的认知能力受损(称为“化疗迷雾”、“化疗脑”或“化疗相关的认知功能障碍”)这一观点被患者和医疗保健提供者广泛接受。还涉及许多其他因素，如潜在的病理、慢性病的存在，以及在人体试验中难以消除的心理因素。此外，在治疗过程中，许多患者(如果不是大多数患者)接受几种药物的“鸡尾酒”组合，为药物相互作用提供了大量机会。因此，为了准确地评估化疗药物可能的认知影响，而不是与临床研究相关的并发症，我们建议直接在小鼠学习和记忆模型中测试化疗药物，称为自动整形。自动整形程序是一种快速、客观和可靠的方法，可以衡量药物是否会影响获得性反应的获得、巩固、恢复、消退、自发恢复和再获得。具体地说，我们将在不同的时间点用不同剂量的环磷酰胺、阿霉素、5-氟尿嘧啶、甲氨蝶呤、三苯氧胺和多西紫杉醇治疗雄性和雌性小鼠，以测量在自动整形过程中对获得、巩固、恢复、消失、自发恢复、再获得和状态依赖学习的影响，以及在累进比率过程中对动机的影响。这些药物将被单独测试，重要的是，将使用数学上严格的联合作用分析，以不同的组合进行测试。此外，化疗药物及其组合将在雄性和雌性小鼠身上进行急性和重复给药。我们假设，急性或反复暴露于单一或联合化疗药物将在学习过程中产生更大的减少，这些学习过程更依赖于海马体功能(巩固、恢复和重新获得)，而不是那些不那么依赖海马体功能(获得和消失)的学习过程，剂量不会改变液体增强剂的动机方面。同样，我们预测，与消退学习的获得相比，化疗药物对消退学习的恢复(自发恢复)的影响更大。我们还预测了与抗雌激素药物他莫昔芬和其他化疗药物的协同作用不足，特别是在雌性小鼠的巩固和恢复方面。综上所述，这些实验将在一个简单的小鼠认知模型中首次全面检查一系列化疗药物及其组合的行为影响。

DESCRIPTION (provided by applicant): The belief that cancer chemotherapy causes impairment of cognitive ability (termed 'chemo-fog', 'chemo- brain', or 'chemotherapy-related cognitive dysfunction') in a significant number of patients is widely accepted by patients and healthcare providers. A host of other factors are involved, such as the underlying pathology, the presence of a chronic disease, and psychological factors that are difficult to eliminate in human trials. In addition, during the course of treatment many, if not the majority, of patients receive a 'cocktail' combination of several drugs, providing abundant opportunity for drug interactions. Therefore, to accurately assess the possible cognitive effects of chemotherapeutic agents independent of the complications associated with clinical studies, we propose to directly test chemotherapeutic agents in a mouse model of learning and memory called autoshaping. The autoshaping procedure is a rapid, objective, and reliable measure of whether a drug will affect acquisition, consolidation, retrieval, extinction, spontaneous recovery, and reacquisition of a learned response. Specifically, we will treat male and female mice with multiple doses of cyclophosphamide, doxorubicin, 5-fluorouracil, methotrexate, tamoxifen, and docetaxel at various time points to measure effects on acquisition, consolidation, retrieval, extinction, spontaneous recovery, reacquisition, and state-dependent learning in the autoshaping procedure and on motivation in the progressive ratio procedure. The drugs will be tested individually and, importantly, in varying combinations using the mathematically rigorous 'joint-action analysis.' In addition, the chemotherapeutic agents and their combinations will be administered both acutely and repeatedly in male and female mice. We hypothesize that acute or repeated exposure to single or combined chemotherapeutic agents will produce greater decrements in the learning processes more heavily reliant on hippocampal functioning (consolidation, retrieval, and reacquisition) than those less reliant on hippocampal functioning (acquisition and extinction) at doses that do not alter the motivational aspects of the liquid reinforcer. Similarly, we predict that the retrieval of extinction learning (spontaneous recovery) will be affected to a greater degree by the chemotherapeutic agents than the acquisition of extinction learning. We also predict synergistic deficits with the antiestrogen tamoxifen and the other chemotherapeutic agents especially on consolidation and retrieval in female mice. Taken together, these experiments will provide the first comprehensive examination of the behavioral effects of a range of chemotherapeutic agents and their combinations in a simple, cognitive model in mice.