Stromal interaction molecules (STIM) 1 and 2 are sensors of the calcium concentration in the endoplasmic reticulum. Depletion of endoplasmic reticulum calcium stores activates STIM proteins which, in ...turn, bind and open calcium channels in the plasma membrane formed by the proteins ORAI1, ORAI2, and ORAI3. The resulting store-operated calcium entry (SOCE), mostly controlled by the principal components STIM1 and ORAI1, has been particularly characterized in immune cells. In the nervous system, all STIM and ORAI homologs are expressed. This review summarizes current knowledge on distribution and function of STIM and ORAI proteins in central neurons and glial cells, i.e. astrocytes and microglia. STIM2 is required for SOCE in hippocampal synapses and cortical neurons, whereas STIM1 controls calcium store replenishment in cerebellar Purkinje neurons. In microglia, STIM1, STIM2, and ORAI1 regulate migration and phagocytosis. The isoforms ORAI2 and ORAI3 are candidates for SOCE channels in neurons and astrocytes, respectively. Due to the role of SOCE in neuronal and glial calcium homeostasis, dysfunction of STIM and ORAI proteins may have consequences for the development of neurodegenerative disorders, such as Alzheimer's disease.
Na(+)/Ca(2+) exchangers (NCXs) and members of the canonical transient receptor potential (TRPC) channels play an important role in Ca(2+) homeostasis in heart and brain. With respect to their ...overlapping expression and their role as physiological Ca(2+) influx pathways a functional discrimination of both mechanisms seems to be necessary. Here, the effect of the reverse-mode NCX inhibitor KB-R7943 was investigated on different TRPC channels heterologously expressed in HEK293 cells. In patch-clamp recordings KB-R7943 potently blocked currents through TRPC3 (IC(50)=0.46 microM), TRPC6 (IC(50)=0.71 microM), and TRPC5 (IC(50)=1.38 microM). 1-Oleoyl-2-acetyl-sn-glycerol-induced Ca(2+) entry was nearly completely suppressed by 10 microM KB-R7943 in TRPC6-transfected cells. Thus, KB-R7943 is able to block receptor-operated TRP channels at concentrations which are equal or below those required to inhibit reverse-mode NCX activity. These data further suggest that the protective effects of KB-R7943 in ischemic tissue may, at least partly, be due to inhibition of TRPC channels.
Previous brain imaging studies investigating the brain processing of scratching used an exogenous intervention mimicking scratching, performed not by the subjects themselves, but delivered by an ...investigator. In real life, scratching is a conscious, voluntary, controlled motor response to itching, which is directed to the perceived site of distress. In this study we aimed to visualize in real-time by brain imaging the core mechanisms of the itch-scratch cycle when scratching was performed by subjects themselves. Secondly, we aimed to assess the correlations between brain patterns of activation and psychophysical ratings of itch relief or pleasurability of scratching. We also compared the patterns of brain activity evoked by self-scratching vs. passive scratching. We used a robust tridimensional Arterial Spin Labeling fMRI technique that is less sensitive to motion artifacts: 3D gradient echo and spin echo (GRASE)--Propeller. Active scratching was accompanied by a higher pleasurability and induced a more pronounced deactivation of the anterior cingulate cortex and insula, in comparison with passive scratching. A significant involvement of the reward system including the ventral tegmentum of the midbrain, coupled with a mechanism deactivating the periaqueductal gray matter (PAG), suggests that itch modulation operates in reverse to the mechanism known to suppress pain. Our findings not only confirm a role for the central networks processing reward in the pleasurable aspects of scratching, but also suggest they play a role in mediating itch relief.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The subjective experience of one's environment is constructed by interactions among sensory, cognitive, and affective processes. For centuries, meditation has been thought to influence such processes ...by enabling a nonevaluative representation of sensory events. To better understand how meditation influences the sensory experience, we used arterial spin labeling functional magnetic resonance imaging to assess the neural mechanisms by which mindfulness meditation influences pain in healthy human participants. After 4 d of mindfulness meditation training, meditating in the presence of noxious stimulation significantly reduced pain unpleasantness by 57% and pain intensity ratings by 40% when compared to rest. A two-factor repeated-measures ANOVA was used to identify interactions between meditation and pain-related brain activation. Meditation reduced pain-related activation of the contralateral primary somatosensory cortex. Multiple regression analysis was used to identify brain regions associated with individual differences in the magnitude of meditation-related pain reductions. Meditation-induced reductions in pain intensity ratings were associated with increased activity in the anterior cingulate cortex and anterior insula, areas involved in the cognitive regulation of nociceptive processing. Reductions in pain unpleasantness ratings were associated with orbitofrontal cortex activation, an area implicated in reframing the contextual evaluation of sensory events. Moreover, reductions in pain unpleasantness also were associated with thalamic deactivation, which may reflect a limbic gating mechanism involved in modifying interactions between afferent input and executive-order brain areas. Together, these data indicate that meditation engages multiple brain mechanisms that alter the construction of the subjectively available pain experience from afferent information.
Previous PET and fMRI brain imaging studies targeting neural networks processing itch sensation have used histamine as the sole itch inducer. In contrast with histamine, cowhage-induced itch is ...mediated via proteinase activated receptors PAR2 and is transmitted through a separate spinothalamic pathway, therefore imaging the brain activation evoked by cowhage could provide further insight into central processing of itch. We report for the first time a functional MRI Arterial Spin Labeling (ASL) study of neuronal processing of itch induced by cowhage, analyzed in contrast with histamine-induced itch. We also explored the brain responses induced by histamine and cowhage combined in a tight sequence. The results of our analyses obtained in a group of 15 healthy volunteers suggested that cowhage and histamine co-activated a core group of brain structures, while also revealing notable differences. Core areas activated by both stimuli were found in the thalamus, primary and secondary somatosensory cortices, posterior parietal cortex, superior and middle temporal cortices, PCC, ACC, precuneus and cuneus. Cowhage induced a notably distinct and more extensive involvement of the insular cortex, claustrum, basal ganglia, putamen, thalamic nuclei and pulvinar. The differences observed between these two itch modalities were investigated to determine the impact of quantitative versus qualitative factors, and correlations between itch intensity and the patterns in brain activation were explored. Our analysis revealed that the most significant differences between cowhage and histamine itch were not affected by stimulus intensity, although a subset of regions displayed activations which were intensity-dependent. The combined application of cowhage and histamine highlighted the role of insula and claustrum in the processing of both itch modalities in the same time. The present results suggest the existence of overlapping but also distinct neuronal networks processing these two different types of itch.
Analysis and interpretation of functional MRI (fMRI) data have traditionally been based on identifying areas of significance on a thresholded statistical map of the entire imaged brain volume. This ...form of analysis can be likened to a “fishing expedition.” As we become more knowledgeable about the structure–function relationships of different brain regions, tools for a priori hypothesis testing are needed. These tools must be able to generate region of interest masks for a priori hypothesis testing consistently and with minimal effort. Current tools that generate region of interest masks required for a priori hypothesis testing can be time-consuming and are often laboratory specific. In this paper we demonstrate a method of hypothesis-driven data analysis using an automated atlas-based masking technique. We provide a powerful method of probing fMRI data using automatically generated masks based on lobar anatomy, cortical and subcortical anatomy, and Brodmann areas. Hemisphere, lobar, anatomic label, tissue type, and Brodmann area atlases were generated in MNI space based on the Talairach Daemon. Additionally, we interfaced these multivolume atlases to a widely used fMRI software package, SPM99, and demonstrate the use of the atlas tool with representative fMRI data. This tool represents a necessary evolution in fMRI data analysis for testing of more spatially complex hypotheses.
Activation of microglia is the first and main immune response to brain injury. Release of the nucleotides ATP, ADP, and UDP from damaged cells regulate microglial migration and phagocytosis via ...purinergic P2Y receptors. We hypothesized that store‐operated Ca2+ entry (SOCE), the prevalent Ca2+ influx mechanism in non‐excitable cells, is a potent mediator of microglial responses to extracellular nucleotides. Expression analyses of STIM Ca2+ sensors and Orai Ca2+ channel subunits, that comprise the molecular machinery of SOCE, showed relevant levels of STIM1, STIM2, and Orai1 in cultured mouse microglia. STIM1 expression and SOCE were down‐regulated by treatment of microglia with lipopolysaccharide, suggesting that inflammation limits SOCE by lower STIM1 abundance. Ca2+ entry induced by cyclopiazonic acid, ATP, the P2Y6 receptor agonist UDP, or the P2Y12 receptor agonist 2‐methylthio‐ADP (2‐MeSADP) was clearly affected in microglia from Stim1–/–, Stim2–/–, and Orai1–/– mice. SOCE blockers or ablation of STIM1, STIM2, or Orai1 severely impaired nucleotide‐induced migration and phagocytosis in microglia. Thus, this study assigns SOCE, regulated by STIM1, STIM2, and Orai1 an essential role in purinergic signaling and activation of microglia. GLIA 2015;63:652–663
Main Points
STIM1, STIM2 and Orai1 mediate store‐operated calcium entry (SOCE) in microglia.
SOCE blockers or ablation of STIM1, STIM2 or Orai1 severely impair microglial migration and phagocytosis induced by extracellular nucleotides.
Anxiety is the cognitive state related to the inability to control emotional responses to perceived threats. Anxiety is inversely related to brain activity associated with the cognitive regulation of ...emotions. Mindfulness meditation has been found to regulate anxiety. However, the brain mechanisms involved in meditation-related anxiety relief are largely unknown. We employed pulsed arterial spin labeling MRI to compare the effects of distraction in the form of attending to the breath (ATB; before meditation training) to mindfulness meditation (after meditation training) on state anxiety across the same subjects. Fifteen healthy subjects, with no prior meditation experience, participated in 4 d of mindfulness meditation training. ATB did not reduce state anxiety, but state anxiety was significantly reduced in every session that subjects meditated. Meditation-related anxiety relief was associated with activation of the anterior cingulate cortex, ventromedial prefrontal cortex and anterior insula. Meditation-related activation in these regions exhibited a strong relationship to anxiety relief when compared to ATB. During meditation, those who exhibited greater default-related activity (i.e. posterior cingulate cortex) reported greater anxiety, possibly reflecting an inability to control self-referential thoughts. These findings provide evidence that mindfulness meditation attenuates anxiety through mechanisms involved in the regulation of self-referential thought processes.
The globular cluster M15 is unique in its display of star-to-star variations in the neutron-capture elements. Comprehensive abundance surveys have been previously conducted for handfuls of M15 red ...giant branch (RGB) and red horizontal branch (RHB) stars. No attempt has been made to perform a single, self-consistent analysis of these stars, which exhibit a wide range in atmospheric parameters. In the current effort, a new comparative abundance derivation is presented for three RGB and six RHB members of the cluster. The analysis employs an updated version of the line transfer code MOOG, which now appropriately treats coherent, isotropic scattering. The apparent discrepancy in the previously reported values for the metallicity of M15 RGB and RHB stars is addressed and a resolute disparity of Delta *D(RHB -- RGB) 0.1 dex in the iron abundance was found. The anti-correlative behavior of the light neutron-capture elements (Sr, Y, Zr) is clearly demonstrated with both Ba and Eu, standard markers of the s- and r-process, respectively. No conclusive detection of Pb was made in the RGB targets. Consequently for the M15 cluster, this suggests that the main component of the s-process has made a negligible contribution to those elements normally dominated by this process in solar system material. Additionally for the M15 sample, a large Eu abundance spread is confirmed, which is comparable to that of the halo field at the same metallicity. These abundance results are considered in the discussion of the chemical inhomogeneity and nucleosynthetic history of M15.
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