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

Abstract

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.

Early Alterations in Operant Performance and Prominent Huntingtin Aggregation in a Congenic F344 Rat Line of the Classical CAGn51trunc Model of Huntington Disease

“…Such notion is also in line with an increased light phase RER value observed at 3 months of age. Consequently, we cannot completely rule out an impact of metabolic differences on the animals' performance in food-rewarded tests, an issue that has been discussed in detail for the BACHD rat model (Clemensson et al, 2017 ). However, we did not observe significant metabolic differences in 6-month-old F344tgHD transgenic rats compared to wild-type controls, while impulsivity traits were still present in the progressive ratio and consecutive DRL task, so we conclude that our transgenic rats display an early impairment of inhibitory control not likely to be confounded by differential effects of food restriction.…”

Environment-dependent striatal gene expression in the BACHD rat model for Huntington disease

“…Here, we however sought to minimize disturbances of the animals through behavioural testing and handling as they may confound gene expression changes 62 . Moreover, only part of the behavioural phenotypes described for BACHD rats have been examined at such early age 29 – 32 , 63 , 64 . Follow-up studies that consider later time points will enable investigations whether behavioural and physiological characteristics in the BACHD rat model depend on environmental factors.…”

Age‐related alteration of emotional regulation in the BACHD rat model of Huntington disease

“…BACHD rats were shown to be less motivated to perform a progressive ratio test and to consume less food compared to their wild type littermates, even though their body weight were similar . It is possible however that the reduced consumption rate found in the BACHD rats may be due to motor impairments rather than differences in hunger or motivation . Another cause could be the development of apathy with age in HD, related to cognitive deterioration and functional decline intrinsic to the evolution and progression of the disease .…”