Dysfunctional processing of reward and punishment may play an important role in depression. However, functional magnetic resonance imaging (fMRI) studies have shown heterogeneous results for reward processing in fronto-striatal regions. We examined neural responsivity associated with the processing of reward and loss during anticipation and receipt of incentives and related prediction error (PE) signalling in depressed individuals. Thirty medication-free depressed persons and 28 healthy controls performed an fMRI reward paradigm. Regions of interest analyses focused on neural responses during anticipation and receipt of gains and losses and related PE-signals. Additionally, we assessed the relationship between neural responsivity during gain/loss processing and hedonic capacity. When compared with healthy controls, depressed individuals showed reduced fronto-striatal activity during anticipation of gains and losses. The groups did not significantly differ in response to reward and loss outcomes. In depressed individuals, activity increases in the orbitofrontal cortex and nucleus accumbens during reward anticipation were associated with hedonic capacity. Depressed individuals showed an absence of reward-related PEs but encoded loss-related PEs in the ventral striatum. Depression seems to be linked to blunted responsivity in fronto-striatal regions associated with limited motivational responses for rewards and losses. Alterations in PE encoding might mirror blunted reward- and enhanced loss-related associative learning in depression.

Signal processing in bacterial chemotaxis relies on large sensory complexes consisting of thousands of protein molecules. These clusters create a scaffold that increases the efficiency of pathway reactions and amplifies and integrates chemotactic signals. The cluster core in Escherichia coli comprises a ternary complex composed of receptors, kinase CheA, and adaptor protein CheW. All other chemotaxis proteins localize to clusters by binding either directly to receptors or to CheA. Here, we used fluorescence recovery after photobleaching (FRAP) to investigate the turnover of chemotaxis proteins at the cluster and their mobility in the cytoplasm. We found that cluster exchange kinetics were proteinspecific and took place on several characteristic time scales that correspond to excitation, adaptation, and cell division, respectively. We further applied analytical and numerical data fitting to analyze intracellular protein diffusion and to estimate the rate constants of cluster equilibration in vivo. Our results indicate that the rates of protein turnover at the cluster have evolved to ensure optimal performance of the chemotaxis pathway.T he relatively simple chemotaxis signaling pathway in Escherichia coli, with analogues of its components-receptors, kinase, phosphatase, and adaptation system-common to many other networks, is an ideal model system for studying general principles of signal transduction (1-3). In E. coli, allosteric interactions among receptors in chemosensory arrays or clusters (Fig. 1), where receptors of different ligand specificities are intermixed (4, 5), integrate and amplify chemotactic stimuli. The networked receptors regulate the autophosphorylation activity of an associated kinase, CheA, which in turn controls the phosphorylation state of a small response regulator protein, CheY, to modulate the cell's flagellar motors. The signaling pathway also includes CheZ, a phosphatase of CheY-P. Excitatory signaling is rapid: changes in CheY phosphorylation level upon repellent or attractant stimulation take place in several hundreds of milliseconds (6-9).In addition, the pathway includes an adaptation system, comprising methyltransferase CheR and methylesterase CheB, that adjusts the activity and sensitivity of the sensory complex by methylating and demethylating receptors. The adaptation system uses feedback from receptor and kinase activity to return CheY phosphorylation to a preset level even in the presence of high levels of chemoeffectors. The time course of the adaptation process depends on stimulus strength (10, 11), varying from several seconds for weak stimuli to several minutes for strong stimuli.Most of the reaction rates and binding constants for chemotaxis proteins have been measured in vitro, and the average intracellular protein concentrations under standard growth conditions were determined (12,13). This abundance of biochemical data has inspired multiple attempts at detailed kinetic analysis of the chemotaxis pathway (9, 13-17), making it the most thoroughly modeled signaling pathw...

The giant, nanoporous Keplerate (NH4)42[Mo132O372(CH3COO)30(H2O)72] was incorporated into a permeable ultrathin film using a stepwise self-assembly strategy. Alternating adsorption of the Keplerate anions and PAH results in single layers with an apparent surface coverage of ≈50%. Such permeable composite coatings may lead into a practical approach to utilize nanoporous polyoxometalate clusters in sensors or heterogeneous catalysts.

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Self-regulation of brain activation using real-time functional magnetic resonance imaging has been used to train subjects to modulate activation in various brain areas and has been associated with behavioral changes such as altered pain perception. The aim of this study was to assess the comparability of upregulation versus downregulation of activation in the rostral anterior cingulate cortex (rACC) and left posterior insula (pInsL) and its effect on pain intensity and unpleasantness. In a first study, we trained 10 healthy subjects to separately upregulate and downregulate the blood oxygenation level-dependent response in the rACC or pInsL (six trials on 4 days) in response to painful electrical stimulation. The participants learned to significantly downregulate activation in pInsL and rACC and upregulate pInsL but not rACC. Success in the modulation of one region and direction of the modulation was not significantly correlated with success in another condition, indicating that the ability to control pain-related brain activation is site-specific. Less covariation between the areas in response to the nociceptive stimulus was positively correlated with learning success. Upregulation or downregulation of either region was unrelated to pain intensity or unpleasantness; however, our subjects did not learn rACC upregulation, which might be important for pain control. A significant increase in pain unpleasantness was found during upregulation of pInsL when covariation with the rACC was low. These initial results suggest that the state of the network involved in the processing of pain needs to be considered in the modulation of pain-evoked activation and its behavioral effects.

The neural circuits underlying fear learning have been intensively investigated in pavlovian fear conditioning paradigms across species. These studies established a predominant role for the amygdala in fear acquisition, while the ventromedial prefrontal cortex (vmPFC) has been shown to be important in the extinction of conditioned fear. However, studies on morphological correlates of fear learning could not consistently confirm an association with these structures. The objective of the present study was to investigate if interindividual differences in morphology of the amygdala and the vmPFC are related to differences in fear acquisition and extinction learning in humans. We performed structural magnetic resonance imaging in 68 healthy participants who underwent a differential cued fear conditioning paradigm. Volumes of subcortical structures as well as cortical thickness were computed by the semi-automated segmentation software Freesurfer. Stronger acquisition of fear as indexed by skin conductance responses was associated with larger right amygdala volume, while the degree of extinction learning was positively correlated with cortical thickness of the right vmPFC. Both findings could be conceptually replicated in an independent sample of 53 subjects. The data complement our understanding of the role of human brain morphology in the mechanisms of the acquisition and extinction of conditioned fear.

No abstract

The goal of this study was to investigate the function of the ventral striatum and brain regions involved in anxiety and learning during aversive contextual conditioning. Functional magnetic resonance imaging was used to assess the hemodynamic brain response of 118 healthy volunteers during a differential fear conditioning paradigm. Concurrently obtained skin conductance responses and self-reports indicated successful context conditioning. Increased hemodynamic responses in the ventral striatum during presentation of the conditioned visual stimulus that predicted the aversive event (CS+) compared to a second stimulus never paired with the aversive event (CS-) were observed in the late acquisition phase. Additionally, we found significant brain responses in the amygdala, hippocampus, insula and medial prefrontal cortex. Our data suggest the involvement of the ventral striatum during contextual fear conditioning, and underline its role in the processing of salient stimuli in general, not only during reward processing.