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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.

SUBMITTER: Kudo T

PROVIDER: S-EPMC3891360 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Circadian dysfunction in response to in vivo treatment with the mitochondrial toxin 3-nitropropionic acid.

Kudo Takashi T Loh Dawn H DH Tahara Yu Y Truong Danny D Hernández-Echeagaray Elizabeth E Colwell Christopher S CS

ASN neuro 20140113 1

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 ...[more]

PMID: 24328694

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Project description:BackgroundOsteopontin (OPN, SPP1) is upregulated in response to acute brain injury, and based on its immunoreactivity, two distinct forms have been identified: intracellular OPN within brain macrophages and small granular OPN, identified as OPN-coated degenerated neurites. This study investigates the spatiotemporal relationship between punctate OPN deposition and astroglial and microglial reactions elicited by 3-nitropropionic acid (3-NP).MethodsMale Sprague-Dawley rats were intraperitoneally injected with mitochondrial toxin 3-NP and euthanized at 3, 7, 14, and 28 days. Quantitative and qualitative light and electron microscopic techniques were used to assess the relationship between OPN and glial cells. Statistical significance was determined by Student's t test or a one-way analysis of variance followed by Tukey's multiple comparisons test.ResultsPunctate OPN-immunoreactive profiles were synthesized and secreted by amoeboid-like brain macrophages in the lesion core, but not by reactive astrocytes and activated microglia with a stellate shape in the peri-lesional area. Punctate OPN accumulation was detected only in the lesion core away from reactive astrocytes in the peri-lesional area at day 3, but had direct contact with, and even overlapped with astroglial processes at day 7. The distance between the OPN-positive area and the astrocytic scar significantly decreased from days 3 to 7. By days 14 and 28 post-lesion, when the glial scar was fully formed, punctate OPN distribution mostly overlapped with the astrocytic scar. Three-dimensional reconstructions and quantitative image analysis revealed numerous granular OPN puncta inside the cytoplasm of reactive astrocytes and brain macrophages. Reactive astrocytes showed prominent expression of the lysosomal marker lysosomal-associated membrane protein 1, and ultrastructural analysis confirmed OPN-coated degenerating neurites inside astrocytes, suggesting the phagocytosis of OPN puncta by reactive astrocytes after injury.ConclusionsPunctate OPN-immunoreactive profiles corresponded to OPN-coated degenerated neurites, which were closely associated with, or completely engulfed by, the reactive astrocytes forming the astroglial scar in 3-NP lesioned striatum, suggesting that OPN may cause astrocytes to migrate towards these degenerated neurites in the lesion core to establish physical contact with, and possibly, to phagocytose them. Our results provide novel insights essential to understanding the recovery and repair of the central nervous system tissue.

Project description:ObjectiveSecondary dystonia commonly presents as hemidystonia and is often refractory to current treatments. We aimed to establish an inducible rat model of hemidystonia utilizing 3-nitropropionic acid (3-NP) and to determine the pathophysiology of this model.MethodsTwo different doses of 3-NP were stereotactically administered into the ipsilateral caudate putamen (CPu) of Wistar rats. Behavioral changes and alterations in the neurotransmitter levels in the basal ganglia were analyzed. We also performed an electromyogram, 7.0-T magnetic resonance imaging and transmission electron microscopy examination to determine the pathophysiology of the model.ResultsIn the CPu region, 3-NP produced mitochondrial cristae rupture, axonal degeneration, increased excitatory synaptic vesicles and necrosis. The extracellular concentrations of excitatory amino acids increased, whereas the inhibitory amino acids decreased in the CPu. Furthermore, an imbalance of neurotransmitters was found in other regions of the basal ganglia with the exception of the external globus pallidus. This study demonstrated that 3-NP administration results in CPu damage, and combined with a neurotransmitter imbalance in the basal ganglia, it produces specific neurobehavioral changes in rats. Right limb (contralateral side of CPu lesion) and trunk dystonic postures, shortened step length and ipsiversive dystonic posturing were observed in these rats. Furthermore, EMG recordings confirmed that co-contraction of the agonist and antagonist muscles could be seen for several seconds in right limbs.ConclusionsStereotactic injection of 3-NP into the ipsilateral CPu of rats established an inducible model for hemidystonia. This effect might result from an imbalance of neurotransmitter levels, which induce dysfunctional activity of the basal ganglia mainly via the cortico-striato-GPi direct pathway. Symptoms in this model were present for 1 week. Activation of the cortico-striato-GPe indirect pathway and rebalance of neurotransmitters may lead to recovery. This rat model may be a suitable tool used to understand and further investigate the pathophysiology of dystonia.

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Circadian dysfunction in response to in vivo treatment with the mitochondrial toxin 3-nitropropionic acid.

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Circadian dysfunction in response to in vivo treatment with the mitochondrial toxin 3-nitropropionic acid.

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