Buurherbert6139

Parkinson's disease (PD) is a common neurodegenerative disease, the pathological features of which include the presence of Lewy bodies and the neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta. However, until recently, research on the pathogenesis and treatment of PD have progressed slowly. Glutamate and dopamine are both important central neurotransmitters in mammals. A lack of enzymatic decomposition of extracellular glutamate results in glutamate accumulating at synapses, which is mainly absorbed by excitatory amino acid transporters (EAATs). Glutamate exerts its physiological effects by binding to and activating ligand-gated ion channels [ionotropic glutamate receptors (iGluRs)] and a class of G-protein-coupled receptors [metabotropic glutamate receptors (mGluRs)]. Timely clearance of glutamate from the synaptic cleft is necessary because high levels of extracellular glutamate overactivate glutamate receptors, resulting in excitotoxic effects in the central nervous system. Adoxicity in order to posit a holistic view and molecular mechanism of glutamate toxicity in PD.The successful development of novel therapies is closely linked with understanding the underlying pathomechanisms of a disease. To do so, model systems that reflect human diseases and allow for the evaluation of new therapeutic approaches are needed. Yet, preclinical animal studies often have limited success in predicting human physiology, pathology, and therapeutic responses. Moreover, animal testing is facing increasing ethical and bureaucratic hurdles, while human cell cultures are limited in their ability to represent in vivo situations due to the lack of the tissue microenvironment, which may alter cellular responses. To overcome these struggles, organ cultures, especially those of complex organs such as the retina, can be used to study physiological reactions to substances or stressors. (R,S)-3,5-DHPG compound library chemical Human and animal organ cultures are now well established and recognized. This mini-review discusses how retinal organ cultures can be used to preserve tissue architecture more realistically and therefore better represent disease-related changes. It also shows how molecular biological, biochemical, and histological techniques can be combined to investigate how anatomical localization may alter cellular responses. Examples for the use of retinal organ cultures, including models to study age-related macular degeneration (AMD), retinitis pigmentosa (RP), central artery occlusion (CRAO), and glaucoma are presented, and their advantages and disadvantages are discussed. We conclude that organ cultures significantly improve our understanding of complex retinal diseases and may advance treatment testing without the need for animal testing.There is empirical evidence that expected yet not current affect predicts decisions. However, common research designs in affective decision-making show consistent methodological problems (e.g., conceptualization of different emotion concepts; measuring only emotional valence, but not arousal). We developed a gambling task that systematically varied learning experience, average feedback balance and feedback consistency. In Experiment 1 we studied whether predecisional current affect or expected affect predict recurrent gambling responses. Furthermore, we exploratively examined how affective information is represented on a neuronal level in Experiment 2. Expected and current valence and arousal ratings as well as Blood Oxygen Level Dependent (BOLD) responses were analyzed using a within-subject design. We used a generalized mixed effect model to predict gambling responses with the different affect variables. Results suggest a guiding function of expected valence for decisions. In the anticipation period, we found activity in brain areas previously associated with valence-general processing (e.g., anterior cingulate cortex, nucleus accumbens, thalamus) mostly independent of contextual factors. These findings are discussed in the context of the idea of a valence-general affective work-space, a goal-directed account of emotions, and the hypothesis that current affect might be used to form expectations of future outcomes. In conclusion, expected valence seems to be the best predictor of recurrent decisions in gambling tasks.Schizophrenia (SCZ) is an inherited disease, with the familial risk being among the most important factors when evaluating an individual's risk for SCZ. However, robust imaging biomarkers for the disease that can be used for diagnosis and determination of the prognosis are lacking. Here, we explore the potential of functional connectivity (FC) for use as a biomarker for the early detection of high-risk first-degree relatives (FDRs). Thirty-eight first-episode SCZ patients, 38 healthy controls (HCs), and 33 FDRs were scanned using resting-state functional magnetic resonance imaging. The subjects' brains were parcellated into 200 regions using the Craddock atlas, and the FC between each pair of regions was used as a classification feature. Multivariate pattern analysis using leave-one-out cross-validation achieved a correct classification rate of 88.15% [sensitivity 84.06%, specificity 92.18%, and area under the receiver operating characteristic curve (AUC) 0.93] for differentiating SCZ patients from HCs. FC located within the default mode, frontal-parietal, auditory, and sensorimotor networks contributed mostly to the accurate classification. The FC patterns of each FDR were input into each classification model as test data to obtain a corresponding prediction label (a total of 76 individual classification scores), and the averaged individual classification score was then used as a robust measure to characterize whether each FDR showed an SCZ-type or HC-type FC pattern. A significant negative correlation was found between the average classification scores of the FDRs and their semantic fluency scores. link2 These findings suggest that FC combined with a machine learning algorithm could help to predict whether FDRs are likely to show an SCZ-specific or HC-specific FC pattern.The neurovisceral integration model (NVM) proposes that an organism's ability to flexibly adapt to its environment is related to biological flexibility within the central autonomic network (CAN). One important aspect of this flexibility is behavioral inhibition (Thayer and Friedman, 2002). During a behavioral inhibition task, the CAN, which comprises a series of feedback loops, must be able to integrate information and react to these inputs flexibly to facilitate optimal performance. The functioning of the CAN is shown to be associated with respiratory sinus arrhythmia (RSA), as the vagus nerve is part of this feedback system. Although the NVM has been examined through neural imaging and RSA, only a few studies have examined these measures simultaneously during the neuroimaging procedure. Furthermore, these studies were done at rest or used tasks that were not targeted at processes associated with the NVM, such as behavioral inhibition and cognitive flexibility. For this reason, the present study assessed RSA and neural activation in the pre-frontal cortex simultaneously while participants completed a behavior inhibition task. RSA and functional near-infrared spectroscopy were collected in 38 adults, and resting levels of pre-frontal activation were negatively related to RSA, but pre-frontal activation during the behavior inhibition task was not. The negative relationship between RSA and oxygenated hemoglobin is consistent with previous functional magnetic resonance imaging work examining the NVM at baseline and should be further studied. link3 Additional research investigating how this relationship may change based on task demands or environmental contexts would help clarify the applicability of the model.Optic Atrophy 1 (OPA1) is a mitochondrially targeted GTPase that plays a pivotal role in mitochondrial health, with mutations causing severe mitochondrial dysfunction and typically associated with Dominant Optic Atrophy (DOA), a progressive blinding disease involving retinal ganglion cell loss and optic nerve damage. In the current study, we investigate the use of codon-optimized versions of OPA1 isoform 1 and 7 as potential therapeutic interventions in a range of in vitro and in vivo models of mitochondrial dysfunction. We demonstrate that both isoforms perform equally well in ameliorating mitochondrial dysfunction in OPA1 knockout mouse embryonic fibroblast cells but that OPA1 expression levels require tight regulation for optimal benefit. Of note, we demonstrate for the first time that both OPA1 isoform 1 and 7 can be used independently to protect spatial visual function in a murine model of retinal ganglion cell degeneration caused by mitochondrial dysfunction, as well as providing benefit to mitochondrial bioenergetics in DOA patient derived fibroblast cells. These results highlight the potential value of OPA1-based gene therapy interventions.

was to create an

model of human retinal detachment (RD) to study the mechanisms of photoreceptor death.

Human retinas were obtained through eye globe donations for research purposes and cultivated as explants. Cell death was investigated in retinas with (control) and without retinal pigment epithelium (RPE) cells to mimic RD. Tissues were studied at different time points and immunohistological analyses for TUNEL, Cleaved caspase3, AIF, CDK4 and the epigenetic mark H3K27me3 were performed. Human and monkey eye globes with retinal detachment served as controls.

The number of TUNEL-positive cells, compared between 1 and 7 days, increased with time in both retinas with RPE (from 1.2 ± 0.46 to 8 ± 0.89,

= 4) and without RPE (from 2.6 ± 0.73 to 16.3 ± 1.27,

< 0.014). In the group without RPE, cell death peaked at day 3 (

= 0.014) and was high until day 7. Almost no Cleaved-Caspase3 signal was observed, whereas a transient augmentation at day 3 of AIF-positive cells was observed to be about 10-foce.In the adult mouse brain, neurogenesis occurs mainly in the ventricular-subventricular zone (V-SVZ) and the subgranular zone of the hippocampal dentate gyrus. Neuroblasts generated in the V-SVZ migrate to the olfactory bulb via the rostral migratory stream (RMS) in response to guidance molecules, such as netrin-1. We previously showed that the related netrin-5 (NTN5) is expressed in Mash1-positive transit-amplifying cells and doublecortin-positive neuroblasts in the granule cell layer of the olfactory bulb, the RMS, and the subgranular zone of the adult mouse brain. However, the precise role of NTN5 in adult neurogenesis has not been investigated. In this study, we show that proliferation in the neurogenic niche is impaired in NTN5 knockout mice. The number of proliferating (EdU-labeled) cells in NTN5 KO mice was significantly lower in the V-SVZ, whereas the number of Ki67-positive proliferating cells was unchanged, suggesting a longer cell cycle and decreased cell division in NTN5 KO mice. The number of EdU-labeled cells in the RMS and olfactory bulb was unchanged. By contrast, the numbers of EdU-labeled cells in the cortex, basal ganglia/lateral septal nucleus, and corpus callosum/anterior commissure were increased, which largely represented oligodendrocyte lineage cells. Lastly, we found that chain migration in the RMS of NTN5 KO mice was disorganized. These findings suggest that NTN5 may play important roles in promoting proliferation in the V-SVZ niche, organizing proper chain migration in the RMS, and suppressing oligodendrogenesis in the brain.