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.

A three-base-pair deletion in the human TOR1A gene is causative for the most common form of primary dystonia: the early-onset dystonia type 1 (DYT1 dystonia). The pathophysiological consequences of this mutation are still unknown. To study the pathology of the mutant torsinA (TOR1A) protein, we have generated a transgenic rat line that overexpresses the human mutant protein under the control of the human TOR1A promoter. This new animal model was phenotyped with several approaches, including behavioral tests and neuropathological analyses. Motor phenotype, cellular and ultrastructural key features of torsinA pathology were found in this new transgenic rat line, supporting that it can be used as a model system for investigating the disease’s development. Analyses of mutant TOR1A protein expression in various brain regions also showed a dynamic expression pattern and a reversible nuclear envelope pathology. These findings suggest the differential vulnerabilities of distinct neuronal subpopulations. Furthermore, the reversibility of the nuclear envelope pathology might be a therapeutic target to treat the disease.

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BackgroundThe BACHD rat overexpresses a bacterial artificial chromosome (BAC) with the full length human mutant huntingtin (mHTT) with 97 alternating CAA/CAG repeats, which are the sole cause of disease onset. BACHD rats display mHTT aggregates and nuclear accumulation of mHTT throughout the brain and develop behavioural and neuropathological- and metabolic abnormalities, growth deficits, mitochondrial dysfunction as well as obesity and a lack of body weight loss that are not typical for human HD.AimsThe aim of this study was to investigate different metabolic properties and possible mitochondrial deficits in primary neurons of BACHD rats.MethodsBACHD rat pups were dissected at embryonic day 19 and primary neurons of the hypothalamus, striatum and cortex were cultivated and used for following assays:MTT- and LDH-assays and IGF-1 levels for general health and growth.MitoTracker measurements and JC-1-assay to assess the mitochondrial membrane potentialYO-PRO-1-Assay for the rate of mitochondrial apoptosisResultsHypothalamic neuron cultures had a lower overall metabolic activity than primary neurons of WT controls. These cells also showed an increased survival rate compared to control cells. The same effects were observed in the striatum, whereas cells from the cortex showed no significant reduction of the metabolic activity, but a decreased survival rate. Since the experiments are still onging at the date of the abstract submission no further results can be shown.ConclusionOur preliminary data and upcoming results will establish BACHD primary neurons as a valuable tool for the investigation of metabolic dysfunction in HD.

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