Reduced Motivation in the BACHD Rat Model of Huntington Disease Is Dependent on the Choice of Food Deprivation Strategy

Abstract

Huntington disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models.

The BACHD Rat Model of Huntington Disease Shows Signs of Fronto-Striatal Dysfunction in Two Operant Conditioning Tests of Short-Term Memory

“…These findings are largely similar to what we have presented in previous publications [31], and what we have found in several studies that remain unpublished at this time. It should, however, be noted that in most of these studies the initial training steps were performed when the rats were 2–5 months old, and learning deficits might still be present in older animals.…”

“…The only exception was the longer pellet retrieval latencies seen among BACHD rats, which was present in both protocols. This phenotype has been found in almost all operant conditioning tests that have been run with the BACHD rats at our institute (seven longitudinal studies) and is described in previous publications [31]. Interestingly, similar phenotypes have been found in transgenic rats that carry a fragment of the HD-causing gene (TgHD rats) [34].…”

“…Alternatively, the impairments might be due to neuropathology caused by developmental deficits. Specifically, male BACHD rats have been found to be smaller than their WT littermates [31] and consistently have smaller brains (unpublished results). At this point, it is unclear if this developmental deficit only regards size or also functionality.…”

“…We have previously found that male BACHD rats are obese, but have comparable body weights to WT rats [31]. Interestingly, the transgenic rats still reliably consume less food than their WT littermates [30,31].…”

“…Interestingly, the transgenic rats still reliably consume less food than their WT littermates [30,31]. It is currently unclear to what extent these phenotypes affect the BACHD rats’ motivation to perform food-oriented tasks in general, although it has been shown that they are less motivated than WT rats to perform a progressive ratio task (a classical test of motivation) when standard food restriction protocols are used [31]. Because of this, we sought to evaluate the impact of motivation on the readouts from the protocols used in the current study.…”