Further investigation of phenotypes and confounding factors of progressive ratio performance and feeding behavior in the BACHD rat model of Huntington disease

Huntington disease is an inherited neurodegenerative disorder characterized by motor, cognitive, psychiatric and metabolic symptoms. We recently published a study describing that the BACHD rat model of HD shows an obesity phenotype, which might affect their motivation to perform food-based behavioral tests. Further, we argued that using a food restriction protocol based on matching BACHD and wild type rats’ food consumption rates might resolve these motivational differences. In the current study, we followed up on these ideas in a longitudinal study of the rats’ performance in a progressive ratio test. We also investigated the phenotype of reduced food consumption rate, which is typically seen in food-restricted BACHD rats, in greater detail. In line with our previous study, the BACHD rats were less motivated to perform the progressive ratio test compared to their wild type littermates, although the phenotype was no longer present when the rats’ food consumption rates had been matched. However, video analysis of food consumption tests suggested that the reduced consumption rate found in the BACHD rats was not entirely based on differences in hunger, but likely involved motoric impairments. Thus, restriction protocols based on food consumption rates are not appropriate when working with BACHD rats. As an alternative, we suggest that studies where BACHD rats are used should investigate how the readouts of interest are affected by motivational differences, and use appropriate control tests to avoid misleading results. In addition, we show that BACHD rats display distinct behavioral changes in their progressive ratio performance, which might be indicative of striatal dysfunction.亨廷顿舞蹈症（Huntington disease, HD）是一种遗传性神经退行性疾病，以运动、认知、精神及代谢症状为典型特征。我们近期发表的一项研究表明，HD的BACHD大鼠模型（BACHD rat model）存在肥胖表型，该表型可能会影响其完成基于食物的行为学测试的动机。此外，我们论证认为，采用匹配BACHD大鼠与野生型大鼠（wild type rats）摄食量的食物限制方案，或可消除二者的动机差异。在本研究中，我们通过纵向研究追踪了上述思路，检测大鼠在渐进比率测试（progressive ratio test）中的行为表现，并对食物限制的BACHD大鼠中常见的摄食量降低表型展开了更细致的探究。与此前的研究结果一致，相较于野生型同窝大鼠，BACHD大鼠完成渐进比率测试的动机显著更弱，但当二者摄食量匹配后，该表型便不再显现。然而，对摄食量测试的视频分析显示，BACHD大鼠的摄食量降低并非完全由饥饿差异导致，还可能与运动功能受损有关。因此，在使用BACHD大鼠开展实验时，基于摄食量的食物限制方案并不适用。作为替代方案，我们建议使用BACHD大鼠的研究应先考察目标检测指标如何受动机差异影响，并采用恰当的对照测试以避免误导性结果。此外，本研究还发现，BACHD大鼠在渐进比率测试中的行为表现存在独特变化，该变化或可作为纹状体功能障碍（striatal dysfunction）的指示指标。