A neuroanatomical analysis of striosome-matrix compartmentalization and motor deficits in YAC mouse models of Huntington's disease

Abstract

The striatum contains mu opioid receptor-rich (MOR) cells called striosomes embedded in an extrastriosomal matrix. In Huntington's disease (HD), the striosomes and matrix may be differentially targeted and contribute to motor symptoms. To determine if differential pathology occurs and contributes to symptoms in an HD mouse model, we analyzed striosome-matrix changes and complex motor behaviors over time in the YAC72 and YAC128 transgenic mouse models, and in healthy wild-type (WT) mice using the MOR specific toxin dermorphin-saporin (DS). YACs and WTs were tested on motor tasks and striatal compartments were analyzed volumetrically and stereologically. Compared to WTs, mild motor deficits were uncovered in YAC72 mice, while greater motor deficits were confirmed in YAC128s. Both YAC models showed similar striosome volume loss, while YAC128 mice also showed a small matrix volume decrease. YAC128 mice experienced cell loss in both compartments, but a greater percentage of cell loss in the striosomes. In WT mice with DS lesions to the dorsolateral striatum, motor deficits were dependent on lesion extent. Cell loss was restricted to the striosomes in DS mice and correlated with the extent of striosome volume loss. Though one cohort of DS lesioned mice showed a greater percentage of striosome volume loss than both YAC models, their motor deficits were not as severe. From these data we conclude that striosomes are differentially targeted in a mouse model for HD, and that they play a distinctive role in some motor behaviors. However, dorsolateral striosome integrity is not critical to modulate all motor behavior in normal mice. In conclusion, this combination of lesion and HD mutant studies shows that a population of MOR expressing cells in the striatum belongs to a distributed network of neurons, which in conjunction with the matrix neurons contributes to motor behavior.