小鼠体内的恶病质使卡路里限制引起的认知灵活性的改善变得迟钝。

IF 7.6 2区 医学 Q1 IMMUNOLOGY
Kyna Conn, Laura K Milton, Alyssa Teoh, Priscila T Levi, Kelly L Walton, Zane B Andrews, Claire J Foldi, Sarah H Lockie
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引用次数: 0

摘要

大约50- 80% %的癌症患者患有恶病质,这是一种代谢综合征,涉及炎症、食欲减退、肌肉和脂肪消耗。癌症患者的另一常见合并症是认知障碍,临床证据表明恶病质的发生与更严重的认知症状有关。考虑到研究人类癌症患者认知功能变化的困难,我们开始研究胰腺癌(胰腺导管腺癌;PDAC)恶病质小鼠模型的认知表现的关键方面,使用笼内操作装置(喂养实验装置版本3;FED3)和反转学习任务。在操作性逆转任务中的表现与两个没有癌症的对照组进行比较:自由进食,假注射磷酸盐缓冲盐水(PBS),热量限制(CR)到原来体重的90-95 %,以控制恶病质小鼠减少食物摄入和体重减轻。我们的PDAC模型重现了恶病质的特征,包括厌食、体重减轻、肌肉萎缩和炎症。CR小鼠在逆转任务中的表现明显优于PDAC和PBS小鼠,实现了更多的逆转和更大的颗粒回收。PBS组与PDAC组间无差异。这些结果表明,癌症期间发生的体重和食欲下降与卡路里限制导致的体重下降在大脑中的处理方式不同,PDAC小鼠没有经历与体重下降一致的食物动机驱动的增加。为了模拟PDAC组的不适,我们给CR小鼠注射了LiCl。低剂量(150 mM)的LiCl不影响应答,然而,高剂量(300 mM)的LiCl显著减少了活性针刺和颗粒回收的数量。这表明疾病引起的奖励贬值,一个可能影响PDAC组在这项任务中表现不佳的因素。我们还使用一系列基于迷宫的测试来检查PBS组和PDAC组的探索性和焦虑样行为。我们发现,在高架加迷宫、开阔场地或光/暗箱中,各组之间的表现没有显著差异,这表明在这种恶病质模型中,基线焦虑样症状没有升高。这些结果发生在促恶病质因子GDF15、激活素A和激活素B水平显著升高的情况下,表明这些TGF-β家族肽的水平升高并不足以在这些测试中产生行为改变。我们的研究结果为胰腺癌患者疾病状态对认知灵活性的特定影响提供了证据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cachexia in mice blunts improved cognitive flexibility induced by calorie restriction.

Approximately 50-80 % of cancer patients suffer from cachexia, a metabolic syndrome involving inflammation, appetite loss, and muscle and fat wasting. Another common co-morbidity of cancer patients is cognitive impairment, and clinical evidence suggests the incidence of cachexia is linked to more severe cognitive symptoms. Given the difficulty of studying changes in cognitive function in human cancer patients, we set out to examine key aspects of cognitive performance in a mouse model of pancreatic cancer (pancreatic ductal adenocarcinoma; PDAC) cachexia, using an in-cage operant device (Feeding Experimental Device version 3; FED3) and a reversal learning task. Performance on the operant reversal task was compared to two control groups without cancer: ad libitum fed, sham injected with phosphate buffered saline (PBS), calorie restricted (CR) to 90-95 % of original body weight to control for reduced food intake and weight loss in cachexia mice. Our PDAC model recapitulated features of cachexia, including anorexia, weight loss, muscle wastage and inflammation. CR mice performed significantly better on the reversal task than both PDAC and PBS mice, achieving significantly more reversals and greater pellet retrieval. There was no difference between PBS and PDAC groups. These results suggest that the weight and appetite loss that occurs during cancer is processed by the brain differently to weight loss that occurs as a result of calorie restriction, with PDAC mice not experiencing an increase in motivational drive for food in line with their falling body weight. To mimic the malaise experienced by the PDAC group, we dosed CR mice with LiCl. Low dose (150 mM) LiCl did not affect responding, however, high dose (300 mM) LiCl significantly reduced both number of active pokes and pellet retrieval. This indicates a sickness-induced devaluation of reward, a factor that may impact poor performance of this task in the PDAC group. We additionally examined exploratory and anxiety-like behaviour in PBS and PDAC groups using a battery of maze-based tests. We saw no significant differences in performance between groups in the elevated plus maze, open field or light/dark box, suggesting no elevations in baseline anxiety-like symptoms in this cachexia model. These results occurred in the face of significantly elevated levels of the pro-cachexia factors GDF15, Activin A and Activin B, indicating that elevated levels of these TGF-β family peptides are not sufficient to produce behavioural changes in these tests. Our results provide evidence for a specific impact of sickness state on cognitive flexibility during pancreatic cancer.

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来源期刊
CiteScore
29.60
自引率
2.00%
发文量
290
审稿时长
28 days
期刊介绍: Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.
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