Effects of chemotherapeutic agents on learning and memory in mice

描述（由申请人提供）：癌症化疗导致大量患者认知能力受损（称为“化疗雾”、“化疗脑”或“化疗相关认知功能障碍”）的观点被患者和医疗保健提供者广泛接受。涉及许多其他因素，如潜在的病理，慢性疾病的存在，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（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充足的机会。因此，为了准确评估化疗药物可能的认知效果，独立于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，称为自塑造。自动成形过程是一种快速、客观、可靠的测量方法，可以衡量药物是否会影响习得反应的习得、巩固、检索、消退、自发恢复和再习得。具体来说，我们将在不同的时间点用多剂量环磷酰胺、阿霉素、5-氟尿嘧啶、甲氨蝶呤、他莫昔芬和多西他赛治疗雄性和雌性小鼠，以测量在自动成形过程中对习得、巩固、检索、消退、自发恢复、再习得和状态依赖学习的影响，以及在渐进比例过程中对动机的影响。这些药物将分别进行测试，更重要的是，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中急性和反复施用。我们假设，在不改变液体强化剂的动机方面的剂量下，急性或反复暴露于单一或联合化疗药物会在更严重依赖海马功能（巩固、检索和再获取）的学习过程中产生更大的衰退，而不是较少依赖海马功能（获取和消失）的学习过程。同样，我们预测，与获得消退学习相比，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缺陷，特别是在雌性小鼠的巩固和恢复方面。综上所述，这些实验将首次全面考察一系列化疗药物及其组合在小鼠简单认知模型中的行为效果。公共卫生相关性：本申请中提出的研究将在临床前小鼠模型中评估六种常用化疗药物单独使用和联合使用对破坏学习和记忆能力的影响。如果某些药物/组合比其他药物产生更多的副作用，临床医生可以对患者的治疗做出明智的选择，并改善癌症幸存者及其家人的生活质量。

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. PUBLIC HEALTH RELEVANCE: The studies proposed in the present application will assess the effects of six commonly used chemotherapy agents alone and in combination for the capacity to disrupt learning and memory in a preclinical mouse model. If certain drugs/combinations produce more adverse effects than others do, clinicians can make informed choices about their patients' therapy and improve the quality of life for cancer survivors and their families.