Lack of mutant huntingtin in cortical efferents improves behavioral inflexibility and corticostriatal dynamics in Huntington’s disease mice.

Lack of mutant huntingtin in cortical efferents improves behavioral inflexibility and corticostriatal dynamics in Huntington’s disease mice.

Publication date: Nov 06, 2019

Abnormal communication between cerebral cortex and striatum plays a major role in the motor symptoms of Huntington’s disease (HD), a neurodegenerative disorder caused by a mutation of the huntingtin gene (mHTT). Because cortex is the main driver of striatal processing, we recorded local field potential (LFP) activity simultaneously in primary motor cortex (M1) and dorsal striatum (DS) in BACHD mice, a full-length HD gene model, and in a conditional BACHD/Emx-1 Cre (BE) model in which mHTT is suppressed in cortical efferents, while mice freely explored a plus-shaped maze beginning at 20 weeks of age. Relative to wild-type (WT) controls, BACHD mice were just as active across >40 weeks of testing but became progressively less likely to turn into a perpendicular arm as they approached the choice point of the maze, a sign of HD motor inflexibility. BE mice, in contrast, turned as freely as WT throughout testing. Although BE mice did not exactly match WT in LFP activity, the reduction in alpha (8-13 Hz), beta (13-30 Hz), and low gamma (30-50 Hz) power that occurred in M1 of turning-impaired BACHD mice was reversed. No reversal occurred in DS. In fact, BE mice showed further reductions in DS theta (4-8 Hz), beta, and low gamma relative to the BACHD model. Coherence analysis indicated a dysregulation of corticostriatal information flow in both BACHD and BE mice. Collectively, our results suggest that mHTT in cortical outputs drives the dysregulation of select cortical frequencies that accompany the loss of behavioral flexibility in HD.

Estrada-Sanchez, A.M., Blake, C.L., Barton, S.J., Howe, A.G., and Rebec, G.V. Lack of mutant huntingtin in cortical efferents improves behavioral inflexibility and corticostriatal dynamics in Huntington’s disease mice. 06755. 2019 J Neurophysiol.

Concepts Keywords
Cerebral Cortex Alpha
Conditional Motor cortex
Cortex Primary motor cortex
Cortical Striatum
Corticostriatal Cerebral cortex
Cre Huntingtin
Dorsal Striatum Cerebrum
Huntingtin Basal ganglia
Huntington Addiction
Hz Motor system
LFP Brain
Maze Striatal processing
Mice HD neurodegenerative disorder
Mutant
Mutation
Neurodegenerative Disorder
Perpendicular
Primary Motor Cortex
Striatal
Striatum
Wild Type

Semantics

Type Source Name
disease MESH neurodegenerative disorder
gene UNIPROT HTT

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