Non-motor symptoms and signs such as metabolic and psychiatric disturbances have been reported to occur early in Huntington's disease (HD), a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene.

However, there is a lack of understanding of the underlying neurobiological mechanisms responsible for the early non-motor features.

The hypothalamus has emerged as an important site of pathology in HD and since this brain region is well known to regulate metabolism and emotions we hypothesized that expression of mutant huntingtin in this area would be involved in causing metabolic and psychiatric aspects of HD.

Therefore, the general aim of the work in this thesis was to investigate such potential relationships using different experimental models of HD. This could be of particular importance since no disease-modifying treatments exist today and the elucidation of the early pathogenesis in HD could facilitate the identification of new targets for therapeutic intervention.

In this thesis, we showed that the BACHD mouse, a model engineered to allow conditional inactivation of mutant huntingtin expression, displays early psychiatric-like behaviors in addition to metabolic disturbances. The development of metabolic alterations could be prevented and depressive-like behavior reduced in young BACHD mice by selective inactivation of mutant huntingtin expression in the hypothalamus.

In a second mouse model, viral vector-mediated expression of mutant huntingtin in the hypothalamus was sufficient to recapitulate the metabolic phenotype observed in the BACHD mice.

Importantly, both studies revealed adverse effects on the hypothalamic orexin system. By contrast, inactivation of mutant huntingtin in leptin receptor-expressing neurons in the BACHD mice had no effect on the observed phenotypes, indicating that leptin is unlikely to be involved.

Taken together, these results suggest a link between mutant huntingtin acting in the hypothalamus and the development of psychiatric and metabolic disturbances in HD.