title: Focal expression of mutant huntingtin in the songbird basal ganglia disrupts cortico-basal ganglia networks and vocal sequences.
abstract: The basal ganglia (BG) promote complex sequential movements by helping to select elementary motor gestures appropriate to a given behavioral context. Indeed, Huntington's disease (HD), which causes striatal atrophy in the BG, is characterized by hyperkinesia and chorea. How striatal cell loss alters activity in the BG and downstream motor cortical regions to cause these disorganized movements remains unknown. Here, we show that expressing the genetic mutation that causes HD in a song-related region of the songbird BG destabilizes syllable sequences and increases overall vocal activity, but leave the structure of individual syllables intact. These behavioral changes are paralleled by the selective loss of striatal neurons and reduction of inhibitory synapses on pallidal neurons that serve as the BG output. Chronic recordings in singing birds revealed disrupted temporal patterns of activity in pallidal neurons and downstream cortical neurons. Moreover, reversible inactivation of the cortical neurons rescued the disorganized vocal sequences in transfected birds. These findings shed light on a key role of temporal patterns of cortico-BG activity in the regulation of complex motor sequences and show how a genetic mutation alters cortico-BG networks to cause disorganized movements.
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710;
authors.forename: Masashi
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710;
authors.forename: Jonnathan
authors.initials: J
authors.lastname: Singh Alvarado
authors.affiliation: Department of Psychology, Princeton University, Princeton, NJ 08544.
authors.forename: Malavika
authors.initials: M
authors.lastname: Murugan
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710; mooney@neuro.duke.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Mooney
mesh_terms: D000818:Animals; D017209:Apoptosis; D001479:Basal Ganglia / Q000378:metabolism / Q000503:physiopathology*; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology*; D046369:Finches / Q000502:physiology*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005813:Genes, Synthetic; D005822:Genetic Vectors / Q000235:genetics; D000071058:Huntingtin Protein; D016086:Lentivirus / Q000235:genetics; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009434:Neural Pathways / Q000503:physiopathology*; D009474:Neurons / Q000473:pathology; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013569:Synapses / Q000502:physiology; D016704:Synapsins / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic; D014828:Vocalization, Animal / Q000502:physiology*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D016704:Synapsins
keywords: Huntington’s disease; basal ganglia; motor sequence; songbird; vocalization