The most prominent neuropathology in Huntington’s disease (HD) includes loss of medium spiny projection neurons expressing cAMP regulated phosphoprotein (DARPP-32) in the striatum. Recent studies have indicated that hypothalamic neuropathology with loss of orexin neurons is part of HD. As hypothalamic changes may in fact occur before striatal pathology in HD and ventral striatum receives projections from the hypothalamus, we hypothesised that hypothalamic expression of mutant huntingtin (HTT) may be involved in the development of striatal pathology in HD. Aims: Our aim was therefore to investigate the striatal effects of selective mutant HTT expression in the hypothalamus.

Methods Wild-type mice were injected bilaterally with adeno-associated viral vectors expressing a mutant (79Q) or a normal (18Q) HTT fragment in the hypothalamus. Stereological quantification of brains processed for DARPP-32, NeuN and cresyl violet was performed in the striatum at 40–52 weeks post-injection.

Results Selective hypothalamic expression of a long mutant HTT fragment (853 aa) leads to orexin loss and a specific reduction in the number of DARPP-32 and NeuN positive neurons with no increase in the number of glial cell profiles in the ventral striatum. Hypothalamic overexpression of shorter fragments (171 aa) with both 79 Q and 18 Q leads to a similar loss of both orexin and striatal neurons.

Conclusions These results suggest that hypothalamic overexpression of HTT fragments can lead to loss of medium spiny neurons in the striatum and opens up the possibility that there may be a contribution of dysfunctional hypothalamic neurocircuitries to HD striatal pathology.