Neuroanatomical Visualization of the Impaired Striatal Connectivity in Huntington's Disease Mouse Model

Abstract

Huntington’s disease (HD) is a movement disorder characterized by the early selective degeneration of striatum. For motor control, the striatum receives excitatory inputs from multiple brain regions and projects the information to other basal ganglia nuclei. Despite the pathological importance of the striatal degeneration in HD, there are little anatomical data that show impaired striatal connectivity in HD. For the anatomical mapping of the striatum, we injected here a neurotracer DiD to the dorsal striatum of HD mouse model (YAC128). Compared with littermate controls, the number of the traced inputs to the striatum was reduced dramatically in YAC128 mice at 12 months of age suggesting massive destruction of the striatal connections. Basal ganglia inputs were significantly damaged in HD mice by showing 61 % decrease in substantia nigra pars compacta, 85 % decrease in thalamic centromedian nucleus, and 55 % decrease in thalamic parafascicular nucleus. Cortical inputs were also greatly decreased by 43 % in motor cortex, 48 % in somatosensory cortex, and 72 % in visual cortex. Besides the known striatal connections, the neurotracer DiD also traced inputs from amygdala and the amygdala inputs were decreased by 68 % in YAC128 mice. Considering the role of amygdala in emotion processing, the impairment in amygdalostriatal connectivity strongly suggests that emotional disturbances could occur in HD mice. Indeed, openfield tests further indicated that YAC128 mice exhibited changes in emotional behaviors related to symptoms of depression and anxiety. Although onset of HD is clinically determined on the basis of motor abnormality, emotional deficits are also common features of the disease. Therefore, our anatomical connectivity mapping of the striatum provides a new insight to interpret brain dysfunction in HD.