title: Evidence of functional brain reorganization on the basis of blood flow changes in the CAG140 knock-in mouse model of Huntington's disease.
abstract: Neuroimaging, especially functional brain mapping, may provide insights into the distributed involvement of multiple brain regions and loops in disorders classically associated with pathology of a localized region. One example is Huntington's disease (HD), typically classified as a basal ganglia disorder. Here, we report genotypic differences in cerebral perfusion mapping in an HD mouse model characterized by a gene knock-in (KI) of a human exon 1 CAG140 expansion repeat (CAG140 KI mice). Animals were examined at 6 months and compared with wild-type littermates. Regional cerebral blood flow (rCBF) was mapped in the awake, nonrestrained, male mouse at rest using [C]-iodoantipyrine autoradiography and analyzed in three-dimensionally reconstructed brains by statistical parametric mapping. Our results showed significant changes in rCBF between CAG140 KI and WT mice, such that CAG140 KI animals showed hypoperfusion of the basal ganglia motor circuit and hyperperfusion of cerebellar-thalamic and somatosensory regions. Significant hypoperfusion was also noted in CAG140 KI mice in the prelimbic and cingulate cortex (medial prefrontal area) and the hippocampus - areas associated with cognitive processing and mood. Changes in rCBF were apparent in the absence of motor deficits (rotarod test) or atrophy in the striatum (caudate-putamen) or hemispheric volume. Our results suggest a functional reorganization of whole-brain networks at a presymptomatic stage in the life of the CAG140 KI mouse. Functional brain mapping in animals may, in the future, serve as a translational biomarker for identifying sites of early synaptic change in the HD brain and for directing targeted preclinical molecular studies and clinical therapies.
authors.affiliation: Departments of aPsychiatry and Behavioral Sciences bNeurology cCell and Neurobiology, Biomedical Engineering, University of Southern California, Los Angeles, California, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Stefanko
authors.forename: Yumei
authors.initials: Y
authors.lastname: Guo
authors.forename: William A
authors.initials: WA
authors.lastname: Toy
authors.forename: Giselle M
authors.initials: GM
authors.lastname: Petzinger
authors.forename: Michael W
authors.initials: MW
authors.lastname: Jakowec
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Holschneider
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D001345:Autoradiography; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002560:Cerebrovascular Circulation / Q000235:genetics*; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D021621:Imaging, Three-Dimensional; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D045442:Rotarod Performance Test; D018911:Trinucleotide Repeats / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D002250:Carbon Radioisotopes; C000615233:Carbon-11; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D000071058:Huntingtin Protein; D014446:Tyrosine 3-Monooxygenase; D000983:Antipyrine; C008135:iodoantipyrine