Neuroscience
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l-3,4-Dihydroxyphenylalanine (l-DOPA) is the therapeutic gold standard in Parkinson's disease. However, most patients develop debilitating abnormal involuntary movements termed l-DOPA-induced dyskinesia (LID) as therapy-complicating side effects. The underlying mechanisms of LID pathogenesis are still not fully understood. ⋯ Interestingly, similar changes were observed in intact non-deafferentiated striata, demonstrating an l-DOPA-responsive transcriptional TH regulation independently from nigrostriatal lesion severity. Consolidation with our previous study on TH protein level (Keber et al., 2015) impressively highlights that LID is associated with both a deficient downregulation of TH transcription and an excessive translation of TH protein in intrastriatal neurons. As TH protein levels in comparison to mRNA levels showed a stronger correlation with development and severity of LID, antidyskinetic treatment strategies should focus on translational and posttranslational modulations of TH as a promising target.
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Motor neuron (MN) diseases are characterized by progressive cell degeneration, and excitotoxicity has been postulated as a causal factor. Using two experimental procedures for inducing excitotoxic spinal MN degeneration in vivo, by acute and chronic overactivation of α-amino-3-hydroxy-5-methyl-4-isoxazoleacetic acid (AMPA) receptors, we characterized the time course of the neuropathological changes. Electron transmission microscopy showed that acute AMPA perfusion by microdialysis caused MN swelling 1.5h after surgery and lysis with membrane rupture as early as 3h; no cleaved caspase 3 was detected by immunochemistry. ⋯ We conclude that acute AMPA-induced excitotoxicity induces MN loss by necrosis, while the progress of degeneration induced by chronic infusion is slow, starting with an early apoptotic process followed by necrosis. In both the acute and chronic procedures a correlation could be established between the loss of MN by necrosis, but not by caspase 3-linked apoptosis, and severe motor deficits and hindlimb paralysis. Our findings are relevant for understanding the mechanisms of neuron death in degenerative diseases and thus for the design of pharmacological therapeutic strategies.
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While variability of the motor responses to transcranial magnetic stimulation (TMS) is widely acknowledged, little is known about its central origin. One plausible explanation for such variability may relate to different neuronal states defining the reactivity of the cortex to TMS. In this study intrinsic spatio-temporal neuronal dynamics were estimated with Long-Range Temporal Correlations (LRTC) in order to predict the inter-individual differences in the strength of intra-cortical facilitation (ICF) and short-interval intracortical inhibition (SICI) produced by paired-pulse TMS (ppTMS) of the left primary motor cortex. ⋯ This in turn attests to the existence of subject-specific neuronal phenotypes defining the reactivity of the brain to ppTMS. In addition, we also showed that ICF was associated with the changes in neuronal dynamics in the EEG session after the application of the stimulation. This result provides a complementary evidence for the recent findings demonstrating that the cortical stimulation with sparse non-regular stimuli might have considerable long-lasting effects on the cortical activity.
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Mild cognitive impairment (MCI) represents a transitional state between normal aging and Alzheimer's disease (AD). Non-invasive diagnostic methods are desirable to identify MCI for early therapeutic interventions. In this study, we proposed a support vector machine (SVM)-based method to discriminate between MCI patients and normal controls (NCs) using multi-level characteristics of magnetic resonance imaging (MRI). ⋯ Applying the proposed method to the experimental data from 29 MCI patients and 33 healthy subjects, we achieved a classification accuracy of up to 96.77%, with a sensitivity of 93.10% and a specificity of 100%, and the area under the curve (AUC) yielded up to 0.97. Furthermore, the most discriminative features for classification were found to predominantly involve default-mode regions, such as hippocampus (HIP), parahippocampal gyrus (PHG), posterior cingulate gyrus (PCG) and middle frontal gyrus (MFG), and subcortical regions such as lentiform nucleus (LN) and amygdala (AMYG). Therefore, our method is promising in distinguishing MCI patients from NCs and may be useful for the diagnosis of MCI.
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Adult brain plasticity can be investigated using reversible methods that remove afferent innervation but allow return of sensory input. Repeated intranasal irrigation with Triton X-100 in adult zebrafish diminishes innervation to the olfactory bulb, resulting in a number of alterations in bulb structure and function, and cessation of the treatment allows for reinnervation and recovery. Using bromodeoxyuridine, Hu, and caspase-3 immunoreactivity we examined cell proliferation, differentiation, migration, and survival under conditions of acute and chronic deafferentation and reafferentation. ⋯ While the amount of cell migration into the olfactory bulbs was not affected by fish age, more of the newly formed cells became neurons in older fish. Younger fish displayed more cell death under conditions of chronic deafferentation. In sum, our results show that reversible deafferentation affects several aspects of cell fate, including cell differentiation, migration, and survival, and age of the fish influences the response to deafferentation.