Experimental neurology
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Experimental neurology · Sep 2013
Alternative splicing of AMPA receptor subunits in the 6-OHDA-lesioned rat model of Parkinson's disease and L-DOPA-induced dyskinesia.
Abnormal corticostriatal plasticity is a key mechanism of L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). Antagonists at glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, such as IEM 1460, reduce induction and expression of dyskinesia in rat and non-human primate models of PD. AMPA receptor function is regulated by post-transcriptional splicing of subunit mRNA to produce flip and flop isoforms, which may therefore influence corticostriatal plasticity. ⋯ There were no changes in expression of flop isoforms. Alternative splicing of AMPAR subunits contributes to abnormal striatal plasticity in the induction and expression of LID. Increases in GluR2-flip expression depend on activation of Ca(2+)-permeable AMPA receptors, which are a potential target of anti-dyskinetic therapies.
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Experimental neurology · Sep 2013
Diaphragm activation via high frequency spinal cord stimulation in a rodent model of spinal cord injury.
As demonstrated in a canine model, high frequency spinal cord stimulation (HF-SCS) is a novel and more physiologic method of electrical activation of the inspiratory muscles compared to current techniques. The dog model, however, has significant limitations due to cost and societal concerns. Since the rodent respiratory system is also a relevant model for the study of neuronal circuitry function, the aims of the present study were to a) assess the effects of HF-SCS and b) determine the methodology of application of this technique in rats. ⋯ Moreover, HF-SCS was successful in pacing these animals over a 60-min period without evidence of system fatigue. Our results suggest that, similar to the dog model, HF-SCS in the rat results in the activation of spinal cord tracts which synapse with the phrenic motoneuron pool, allowing the processing of the stimulus and consequent physiologic activation of the inspiratory muscles. The rat may be a useful model for further studies evaluating phrenic motoneuron physiology.
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Experimental neurology · Sep 2013
Endoplasmic reticulum stress contributes to prediabetic peripheral neuropathy.
Growing evidence suggests that prediabetes and metabolic syndrome are associated with increased risk for the development of microvascular complications including retinopathy, nephropathy, and, most commonly, peripheral painful neuropathy and/or autonomic neuropathy. The etiology of these disabling neuropathies is unclear, and several clinical and experimental studies implicated obesity, impaired fasting glycemia/impaired glucose tolerance, elevated triglyceride and non-esterified fatty acids, as well as oxidative-nitrative stress. Endoplasmic reticulum stress resulting from abnormal folding of newly synthesized proteins and leading to the impairment of metabolism, transcriptional regulation, and gene expression, is emerging as a key mechanism of metabolic diseases including obesity and diabetes. ⋯ A chemical chaperone, trimethylamine oxide, blunted endoplasmic reticulum stress and alleviated sensory nerve conduction velocity deficit, thermal and mechanical hypoalgesia, and tactile allodynia. A selective inhibitor of eukaryotic initiation factor-2α dephosphorylation, salubrinal, improved glucose intolerance and alleviated peripheral nerve dysfunction in high-fat diet fed mice. Our findings suggest an important role of endoplasmic reticulum stress in the neurobiology of prediabetic peripheral neuropathy, and identify a new therapeutic target.
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Experimental neurology · Sep 2013
Lesion of the pedunculopontine tegmental nucleus in rat augments cortical activation and disturbs sleep/wake state transitions structure.
The pedunculopontine tegmental nucleus (PPT) represents a major aggregation of cholinergic neurons in the mammalian brainstem, which is important in the generation and maintenance of REM sleep. We investigated the effects of unilateral and bilateral PPT lesions on sleep and all the conventional sleep-state related EEG frequency bands amplitudes, in an attempt to find the EEG markers for the onset and progression of PPT cholinergic neuronal degeneration. The experiments were performed on 35 adult male Wistar rats, chronically implanted for sleep recording. ⋯ The unilateral PPT lesion augmented both Wake theta and REM beta while it also attenuated the relative amplitude of the Wake delta frequency, with a delay of one week. Following a bilateral PPT lesion there was augmentation of the relative amplitude of the Wake, NREM, and REM beta and REM gamma frequency which occurred simultaneously to NREM and Wake delta attenuation. We have shown that the PPT cholinergic neuronal loss sustainably increased the number of the Wake/REM and REM/Wake transitions and augmented sleep-states related cortical activation that was simultaneously expressed by the high frequency amplitude augmentation, as well as Wake and NREM delta frequency attenuation.
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Experimental neurology · Sep 2013
Anatomical correlates of recovery in single pellet reaching in spinal cord injured rats.
Modeling spinal cord injury (SCI) in animals is challenging because an appropriate combination of lesion location, lesion severity and behavioral testing is essential to analyze recovery of motor function. For particular tests such as single pellet reaching, the contribution of individual descending tracts to recovery has been investigated using specific tract ablation or graded lesions. However, it has not been established whether single pellet reaching is sufficiently sensitive for assessing the efficacy of treatments for cervical SCI (e.g., one of the currently most successful treatment approaches: rehabilitative training). ⋯ The DLQ lesion likely strikes a balance between tissue sparing and functional impairment and is, therefore, best suited to maximize the potential to observe treatment effects of plasticity-promoting treatments using single pellet reaching. Because of the specific lesion size that is necessary to observe treatment effects, the single pellet skilled reaching task can be considered a stringent behavioral test and therefore may be useful for predicting translational success of potential treatments. However, due to the variability in the success rate, the labor-intensive nature, and the limited usefulness to test functional outcome of a wide range of lesion severities, we are hesitant to continue to use single pellet reaching to assess the effectiveness of currently available treatments for cervical SCI.