Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder. To date, proven neuroprotective strategies remain elusive. Part of the problem has been that most of the trials have attempted intervening at a time when the degenerative process is already far advanced and hence when it would be difficult even for the most effective therapy to demonstrate any benefit. Treatment of HD is likely to be most beneficial in the early, possibly pre-manifestation stage. The challenge is to determine the best time for intervention and evaluate putative neuroprotection in the absence of clinical symptoms. Therefore noninvasive, objective, sensitive biomarkers to identify the early dysfunction in the HD brain are strongly needed. Resting state-fMRI (rs-fMRI) is a promising tool in detecting early neuronal dysfunction in HD brain, because it allows us to study multiple brain networks without confounding effects of cognitive ability to perform a given behavioral task, which makes the rs-fMRI more promising as a translational bridge in HD. Altered resting-state functional brain connectivity was detected by rs-fMRI in prodromal and early manifest HD subjects (1-3). However, little is known regarding the association between altered functional connectivity and clinical presentations. Mouse models of HD become valuable in such studies. The study in HD mice will provide an important bridge between HD patients and mouse models of HD, enabling us to make stronger conclusions about how regionally specific neuronal dysfunction relates to phenotype and neuropathology. In this study, we investigated the functional connectivity and structural changes in a mouse model of HD, and revealed relationships between functional MRI measures and structural atrophy, as well as behavioral performance in the mouse model. N171-82Q HD mouse model has been widely used in HD research; these HD mice display progressive and selective brain atrophy and motor dysfunction which recapitulate the key neuropathology and phenotype of HD (4). Thirteen HD and seven littermate wild-type (WT) control mice were included in this study. During imaging, the animal was anaesthetized with 0.5% isoflurane and i.p. infusion of dexmedetomidine similar to the setting used in (5). Structural and functional MRI scans were performed on a horizontal 11.7 Tesla scanner with a 72 mm volume transmitter and a 15 mm planar surface coil and the following imaging parameters: i) T2-weighted MRI (RARE): TE/TR = 40/4000 ms, echo train length=8, NA=2, in-plane resolution = 0.1 mm x 0.1 mm, 33 slices with 0.5 mm thickness; ii) rs-fMRI (GE-EPI): single shot, TE/TR = 13.8/1200 ms, in-plane resolution = 0.25 mm x 0.25 mm, 21 slices with 0.5 mm thickness, and 300 repetitions. Structural volumes were obtained from the T2-weighted MRI as described in (4). Analyses of rs-fMRI data were conducted using SPM8 and GIFT software. The striatum functional network was defined by independent component analysis with GIFT. Correlation analyses were performed between striatal functional connectivity and volumes and between striatal functional connectivity and motor behavior scores (balance beam test).HD mice demonstrated significantly lower functional connectivity in bilateral striatum and higher connectivity between the striatum and anterior cingulate cortex compared to the WT mice (Fig. 1). Structural MRI confirmed significant striatal atrophy in the HD mice compared to the WT group, and behavioral tests showed significant motor deficits in the HD mice indicated by prolonged transverse time on balance beam (p < 0.05). The functional connectivity within left striatum and between left striatum and right striatum were negatively correlated with the transverse time on the balance beam in these mice (p =0.005, r2 = 0.369; p = 0.021, r2 = 0.261), and the left striatum-anterior cingulate cortex functional connectivity was negatively correlated with the left striatal volumes (Fig. 2) (p = 0.002, r2 = 0.423). The striatal connectivity was also negatively correlated with the left striatal volumes (Fig. 3) (p =0.009, r2 = 0.321; p = 0.022, r2 = 0.260).While rs-fMRI has been used to study HD patients (1-3), little is known regarding the relation of the altered functional brain connectivity to clinical presentations as many factors can affect rs-fMRI signals. Our results demonstrated altered striatal functional connectivity in the HD mice and significant correlations between striatal functional connectivity and striatal atrophy/behavior deficits. Further validation of the potential use of rs-fMRI measure as an early biomarker for HD will have significant impact on future clinical trials to evaluate the treatment efficacy using sensitive biomarker and instruct critical treatment time.