Characterization of metabolic dysfunction in the BACHD rat model of Huntington disease and therapeutic targeting with olesoxime

The current work addresses the characterization of metabolic abnormalities in the BACHD rat and the therapeutic effects of olesoxime treatment. The BACHD rat is a recently established transgenic model of Huntington disease (HD), which expresses full-length human mutant huntingtin (mHTT) with 97 CAG repeats. It is shown here that metabolic dysfunction is a prominent, early feature of the HD-related pathological phenotype in these rats. BACHD rats suffer from growth impairment and obesity due to deficits in energy metabolism. These deficits are traceable during growth and senescence based on altered physiological parameters. It can be concluded that metabolic abnormalities underlie temporal changes, which when considered a general feature of HD, could explain discrepancies in the outcomes of earlier studies on metabolic dysfunction in HD patients and animal models. In order to therapeutically address metabolic dysfunction in the BACHD rat, a long-term treatment study with the mitochondria-targeting, neuroprotective compound olesoxime was conducted. Although olesoxime did not influence the growth deficit and development of obesity in the BACHD rat, it revealed a positive influence on mitochondrial function and specific behavioral and neuropathological phenotypes. It is suggested that these benefits resulted from improved mitochondrial function and a stabilizing effect on intracellular calcium homeostasis, leading to decreased calcium-dependent activation of the protease calpain-1 and reduced calpain-mediated proteolysis of mutant huntingtin. Further studies with earlier start of olesoxime treatment could help to understand why the compound only exerted selective beneficial effects in the BACHD rat, and to provide further insight into the mechanism of action

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

The BACHD rat is a recently developed transgenic animal model of Huntington disease, a progressive neurodegenerative disorder characterized by extensive loss of striatal neurons. Cognitive impairments are common among patients, and characterization of similar deficits in animal models of the disease is therefore of interest. The present study assessed the BACHD rats' performance in the delayed alternation and the delayed non-matching to position test, two Skinner box-based tests of short-term memory function. The transgenic rats showed impaired performance in both tests, indicating general problems with handling basic aspects of the tests, while short-term memory appeared to be intact. Similar phenotypes have been found in rats with fronto-striatal lesions, suggesting that Huntington disease-related neuropathology might be present in the BACHD rats. Further analyses indicated that the performance deficit in the delayed alternation test might be due to impaired inhibitory control, which has also been implicated in Huntington disease patients. The study ultimately suggests that the BACHD rats might suffer from neuropathology and cognitive impairments reminiscent of those of Huntington disease patients

Video-scored behavior in relation to performance on delayed non-matching to position.

<p>The graphs show various aspects of the behaviors scored from video recordings in relation to the rats' performance in the delayed non-matching to position test. Graphs indicate group mean plus standard error. (B) concerns the 25-second delay step. In (F), the data that is labeled "theoretical" displays the theoretical success rates, as if the rats had responded according to their initial lever interest and not performed a correction behavior. Further details regarding the scored behaviors are described in the Material and Methods section. Results from two-way repeated measures ANOVA are shown inside the graphs. For (C)–(E), separate two-way ANOVAs were performed for each kind of behavior, and the respective results are indicated in small tables. Results from <i>post-hoc</i> analysis are indicated in case significant genotype differences were found. * (<i>P</i> < 0.05) ** (<i>P</i> < 0.01) *** (<i>P</i> < 0.001). In (D), ‘ee’ indicates a genotype difference (<i>P</i> < 0.01) for trials with established focus, and ‘m’ indicates a genotype difference (<i>P</i> < 0.05) for trials with maintained focus.</p

Video-scored behavior in relation to performance on delayed alternation.

<p>The graphs show various aspects of the behaviors scored from video recordings in relation to the rats' performance in the delayed alternation test. Graphs indicate group mean plus standard error. (B) concerns the 20-second delay step. In (F), the data that is labeled "theoretical" displays the theoretical success rates, as if the rats had responded according to their initial lever interest and not performed a correction behavior. Further details regarding the scored behaviors are described in the Material and Methods section. Results from two-way repeated measures ANOVA are shown inside the graphs. For (C)–(E), separate two-way ANOVAs were performed for each kind of behavior, and the respective results are indicated in small tables. Results from <i>post-hoc</i> analysis are indicated in case significant genotype differences were found. * (<i>P</i> < 0.05) ** (<i>P</i> < 0.01) *** (<i>P</i> < 0.001). In (D), ‘e’ notes a genotype difference (<i>P</i> < 0.05) for trials with established focus.</p

Age development of free non-matching to position performance.

<p>The graphs show the main readouts of the free non-matching to position protocol over the four test ages. (A) shows the number of training sessions required for reaching criterion. (B)–(H) show the mean performance of rats during sessions where their success rate was at criterion level. Session to criterion data was corrected for the change in criterion between the first test age and retesting. Curves show group mean plus standard error. Results from two-way repeated measures ANOVA are shown inside the graphs. Results from <i>post-hoc</i> analysis are indicated in case significant genotype differences were found. * (<i>P</i> < 0.05) ** (<i>P</i> < 0.01) *** (<i>P</i> < 0.001).</p

Time spent in different parts of the Skinner boxes during delay steps.

<p>The graphs show the time spent in different parts of the Skinner boxes during delays in the delayed alternation and delayed non-matching to position tests, as measured by video scoring. Specific details regarding the data and scoring method is available in the Material and Methods section. Graphs indicate group mean plus standard error. Results from two-way repeated measures ANOVA are shown inside the graphs. Results from <i>post-hoc</i> analysis are indicated in case significant genotype differences were found. * (<i>P</i> < 0.05) ** (<i>P</i> < 0.01) *** (<i>P</i> < 0.001).</p

Success rate per delay in the delayed alternation test.

<p>The graphs show the success rate on trials preceded by delays of different durations in the delayed alternation test. (A) shows the stable baseline performance of rats maintained on the standard food restriction protocol at four months of age. (B) and (C) show the age progression of performance for WT and BACHD rats. Curves display group mean plus standard error. Results from two-way repeated measures ANOVA are shown inside the graphs. For (A), results from <i>post-hoc</i> analysis are indicated in case significant genotype differences were found. * (<i>P</i> < 0.05) ** (<i>P</i> < 0.01) *** (<i>P</i> < 0.001).</p

Head entry behavior during delays on the delayed non-matching to position protocol.

<p>The graphs show several aspects of head entries made into the pellet trough during delay steps of the delayed non-matching to position test. Curves were created based on the overall performance on all test ages, as no consistent change with age was found for the parameters. (C) concerns the 25-second delay step. Graphs indicate group mean plus standard error. Results from two-way repeated measures ANOVA are shown inside the graphs. Results from <i>post-hoc</i> analysis are indicated in case significant genotype differences were found. * (<i>P</i> < 0.05) ** (<i>P</i> < 0.01) *** (<i>P</i> < 0.001).</p