Background Psychiatric disturbances including anxiety and depression are common in Huntington disease (HD). These psychiatric impairments cause significant distress and often precede motor dysfunction. We have previously shown that psychiatric-like disturbances as well as metabolic dysfunction are already present at 2 months of age in the BACHD mouse model (expressing full-length human mutant huntingtin (mhtt)). Interestingly, inactivation of mtt in the hypothalamus prevented the development of depressive-like behaviour as well as metabolic dysfunction in young BACHD mice. However, neither the underlying mechanisms of these non-motor aspects nor how they may change over time are fully known.
Aim The aim of our study was to characterise the developmental profile of the psychiatric impairments and metabolic dysfunction in the BACHD mice.
Methods/techniques We conducted a systematic analysis using a battery of behavioural tests (elevated plus maze, novelty-induced suppressed feeding test, Porsolt forced swim test, open field test) on adult BACHD mice at 4, 12 and 18 months of age across both genotype and gender. Isolation-induced ultrasonic vocalisations were also recorded in pups at P0, P5 and P10 as a measure of potential early anxiety-like behaviours.
Results/outcome We show that the BACHD mice exhibit early signs of anxiety and depressive-like behaviours which become progressively abated with age. The metabolic dysfunction develops early on and continues to prevail at 18 months of age.
Conclusions Together, these observations indicate that the psychiatric and metabolic phenotype do not appear to be present from birth but develops in young adulthood, suggesting a critical therapeutic window for disease-modifying treatments for HD.Supported by a grant from Royal Physiographic Society, The Swedish Association of Persons with Neurological Disabilities (NHR) and the Swedish Research Council.
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