title: Circadian dysfunction in response to in vivo treatment with the mitochondrial toxin 3-nitropropionic acid.
abstract: Sleep disorders are common in neurodegenerative diseases including Huntington's disease (HD) and develop early in the disease process. Mitochondrial alterations are believed to play a critical role in the pathophysiology of neurodegenerative diseases. In the present study, we evaluated the circadian system of mice after inhibiting mitochondrial complex II of the respiratory chain with the toxin 3-nitropropionic acid (3-NP). We found that a subset of mice treated with low doses of 3-NP exhibited severe circadian deficit in behavior. The temporal patterning of sleep behavior is also disrupted in some mice with evidence of difficulty in the initiation of sleep behavior. Using the open field test during the normal sleep phase, we found that the 3-NP-treated mice were hyperactive. The molecular clockwork responsible for the generation of circadian rhythms as measured by PER2::LUCIFERASE was disrupted in a subset of mice. Within the SCN, the 3-NP treatment resulted in a reduction in daytime firing rate in the subset of mice which had a behavioral deficit. Anatomically, we confirmed that all of the treated mice showed evidence for cell loss within the striatum but we did not see evidence for gross SCN pathology. Together, the data demonstrates that chronic treatment with low doses of the mitochondrial toxin 3-NP produced circadian deficits in a subset of treated mice. This work does raise the possibility that the neural damage produced by mitochondrial dysfunction can contribute to the sleep/circadian dysfunction seen so commonly in neurodegenerative diseases.
authors: *Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, U.S.A.
authors: Takashi
authors: T
authors: Kudo
authors: *Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, U.S.A.
authors: Dawn H
authors: DH
authors: Loh
authors: Yu
authors: Y
authors: Tahara
authors: *Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, U.S.A.
authors: Danny
authors: D
authors: Truong
authors: ‡Neurofisiología del desarrollo y la neurodegeneración, Unidad de Biomedicina, Universidad Nacional Autónoma de México.
authors: Elizabeth
authors: E
authors: Hernández-Echeagaray
authors: *Laboratory of Circadian and Sleep Medicine, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, U.S.A.
authors: Christopher S
authors: CS
authors: Colwell
mesh_terms: D000818:Animals; D057906:Circadian Clocks / Q000187:drug effects / Q000502:physiology*; D003292:Convulsants / Q000633:toxicity; D055879:Gene Knock-In Techniques; D006816:Huntington Disease / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009574:Nitro Compounds / Q000633:toxicity; D018408:Patch-Clamp Techniques; D056950:Period Circadian Proteins / Q000378:metabolism; D011422:Propionates / Q000633:toxicity; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D003292:Convulsants; D009574:Nitro Compounds; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D011422:Propionates; C015392:3-nitropropionic acid