Depression in Huntington's disease: Modulation of environment and gender

Of the plethora of symptoms that arise in HD, depression is the most diagnosed psychiatric symptom, with 30-50% of patients developing depression. This makes depression far more prevalent in the HD population than in the general populace and indeed, significantly more conspicuous compared to other neurodegenerative diseases such as Parkinson’s or Alzheimer’s disease. Due to depression’s ubiquity, impact and also the fact that it can appear decades before crippling motor symptoms, treatment and management of depression would significantly prolong the symptom-free period of patients’ lives. The overrepresentation of depression is most likely an endemic reflection of pathophysiology caused by the HD mutation. However, the aetiology of depression in the context of HD has not been well understood. The hypothalamic-pituitary-adrenal (HPA) axis is the major endocrine system responsible for stress adaptation and its dysfunction has been implicated in clinical depression. Few studies have examined the HPA-axis in HD to date. Our group has previously found, using the R6/1 mouse model of HD, a female-specific depression-like behavioural phenotype. In this thesis, examining the HPA-axis in these animals, it was found that female, but not male, R6/1 mice displayed a hyperactive HPA-axis in response to stressors. Further pharmacological challenges, gene expression analyses and in vitro studies discerned the source of the abnormality to a hypersensitive adrenal gland; a novel finding of a peripheral source for what has been largely seen as a centrally mediated pathology. Environmental factors have been found to produce significant modulation to the progression of HD. Previously, our lab has shown that environmental enrichment is able to delay the onset of various symptoms in the R6/1 mice, including depression-like behavioural phenotype in the female mice. In this thesis, environmental enrichment was also found to be able to rescue the abnormalities of the HPA-axis both in vivo an