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    • Ulrich H. Schroeder
    • 2010
    • European Journal of Surgical Oncology
    • 1
    • 72-77
    • HERG1 gene expression as a specific tumor marker in colorectal tissues
    • <p>Introduction: Colorectal carcinomas exhibit a frequent recurrence after curative surgery, which may partially be due to histopathologically inconspicuous minimal residual disease. Reliable markers for tumor cells in colorectal tissue are still missing. Therefore, in this study we compared the predictive value of the putative tumor markers carcinoembryonic antigen (CEA), cytokeratin-19 (CK19) and cytokeratin-20 (CK20) to that of a novel marker, the human ether-a-go-go-related gene (HERG1) K<sup>+</sup> channel, a suggested regulator of tumor cell proliferation. Materials and methods: Using RT-PCR we studied HERG, CEA, CK19 and CK20 expression in colorectal carcinomas and non-carcinoma controls. HERG1 immunhistochemistry was performed in a total of 66 specimens, in colorectal carcinoma (n = 23), in matched histopathologically negative samples (n = 23) taken near the excision site from the same tumor patients and in healthy control biopsies (n = 20). In order to verify the relevance of HERG1 for tumor proliferation we studied the effect of HERG1 inhibition in the Colo-205 colon cancer carcinoma cell line using the MTT-assay. Results: HERG1 was expressed in all tumor samples regardless of their stage and in adenomas larger than 0.4 cm, but absent in small adenomas, sigmadiverticulitis specimen and healthy histopathologically negative samples, except for one which developed a tumor recurrence. In contrast, CEA, CK19 and CK20 were absent in some tumors. The selective HERG1 inhibitor E-4031 dose-dependently impaired tumor growth in the proliferation assays. Discussion: Our data indicate that HERG1, but not CEA, CK19 or CK20, is a highly sensitive and reliable tumor biomarker that may constitute a novel molecular target for tumor treatment.</p>
    • http://www.scopus.com/inward/record.url?scp=73249122449&partnerID=8YFLogxK
    • Ulrich H. Schroeder
    • 2010
    • Wiener Medizinische Wochenschrift
    • 5-6
    • 139-146
    • De-novo Generierung von vaskularisiertem Gewebe mittels unterschiedlicher Gefässstielkonfigurationen in perforierten und geschlossenen Wachstumskammern
    • <p>Growing three-dimensional tissue within a chamber requires vigorous angiogenesis initiated by, for example, an arteriovenous fistula or a ligated vascular pedicle. Growth may also be enhanced by contact with the external environment. In this study tissue growth in a rat model, vascularized via an arteriovenous loop (AV Loop) or ligated pedicle, was compared in chambers that were either closed or perforated. Chambers were harvested at 4 weeks and tissue volume and histology compared. In perforated chambers, more tissue were generated using the ligated pedicle (0.75 ml∼0.04) than the AV Loop (0.59 ml∼0.01). Perforated chambers generated larger volumes of tissue than closed chambers because they encouraged tissue ingrowth through the perforations. Both vessel configurations supported tissue growth but, interestingly, the ligated pedicle resulted in significantly more tissue in the perforated chambers.</p>
    • http://www.scopus.com/inward/record.url?scp=77952503989&partnerID=8YFLogxK
    • P. Henrich-Noack, Monika Riek-Burchardt, KG Reymann
    • 2010
    • Journal of Neuroscience Research
    • 4
    • 850-857
    • Cellular expression pattern of the protease-activated receptor 4 in the hippocampus in Naïve rats and after global ischaemia
    • <p>A pronounced hippocampal expression of the Protease-activated Receptor 4 (PAR4) has recently been shown. In the current study the authors define the PAR4-associated sub-cellular structures and the influence of global ischaemia on the expression of PAR4. For that purpose the authors performed double labelling with fluorescence immunohistochemistry on tissue from naïve and post-ischaemic rats. In naïve animals - apart from the expression in granular and pyramidal neurons - there was an intensive lamellar expression of PAR4 in the CA4 region. Further analysis revealed that PAR4 was localised exclusively on mossy fibre axons in CA4 as detected by double-labelling with calbindin D-28k, but there was no overlap with markers of the neuronal cell body, interneurons, and post-synaptic, pre-synaptic and dendritic structures. Three and 14 days post ischaemia, CA1 neurons were degenerated and, consequently, there was no PAR4 signal in the CA1 band. In most other hippocampal structures no change in the PAR4 expression was detectable, with the exception of the CA3 region. Here, the fibre-associated PAR4 signal was diminished and disintegrated post ischaemia. Additionally, a redistribution from the membrane-bound neuronal localisation of PAR4 in control animals to a diffuse localisation all over the cell soma was revealed in the CA3 area 14 days post ischaemia. In conclusion, the current study proves for the first time that PAR4 is localised in mossy fibre axons. The altered expression in CA3 neurons after ischaemia indicates that PAR4 may be involved in postischaemic adaptive mechanisms.</p>
    • http://www.scopus.com/inward/record.url?scp=76549104243&partnerID=8YFLogxK
    • Monika Riek-Burchardt, Angela Kolodziej, P. Henrich-Noack, KG Reymann
    • 2010
    • Neuropharmacology
    • 1
    • 199-207
    • Differential regulation of CXCL12 and PACAP mRNA expression after focal and global ischemia
    • <p>Pituitary adenylate cyclase activating peptide (PACAP) and the chemokine stromal cell-derived factor (SDF-1) have been implicated in neuroprotection, neurogenesis, and regeneration. Focal ischemia is associated with rapid upregulation of PACAP in perifocal neurons and delayed induction of SDF-1 in hypoxic/ischemic tissues, the latter process being involved in the recruitment of stem cells and inflammatory cells. Here, we studied mRNA patterns of PACAP, SDF-1 and the cognate receptors PAC1 and CXCR4 by in situ hybridization in the rat hippocampus after transient global ischemia, a rat model for programmed death of CA1 pyramidal neurons. Cell death in CA1 was not associated with local induction of PACAP and SDF-1 expression or recruitment of CXCR4-expressing infiltrates. However, there was a transient, almost complete loss of SDF-1 expression in microvessels in all hippocampal regions. Granule cells transiently showed a decrease of SDF-1 and an increase of PACAP expression. While PAC1 mRNA was moderately decreased throughout the hippocampus, CXCR4 expression was selectively increased in the subgranular layer. We propose that altered PACAP and SDF-1 gene expression in granule cells plays a role in regulated neurogenesis after global ischemia. The finding that programmed neuronal death after global ischemia was not associated with SDF-1 upregulation or recruitment of CXCR4-expressing cells is in sharp contrast to SDF-1/CXCR4-mediated infiltration of infarct tissue after focal ischemia. Hence, the different modes of neuronal death after focal and global ischemia are associated with distinct SDF-1 and PACAP gene regulation patterns and distinct reorganization mechanisms.</p>
    • http://www.scopus.com/inward/record.url?scp=71549170474&partnerID=8YFLogxK
    • Thomas Behnisch, Julietta U. Frey
    • 2010
    • Neuroscience
    • 4
    • 1520-1526
    • Protein degradation by the proteasome is required for synaptic tagging and the heterosynaptic stabilization of hippocampal late-phase long-term potentiation
    • <p>Activity-dependent regulation of synaptic efficacy is believed to underlie learning and memory formation. Here we show that protein degradation by the proteasome is required for the induction of the protein synthesis-dependent late-phase of long-term potentiation (late-LTP) but not for its maintenance. Proteasome activity was also key to the polarity of heterosynaptic interactions between synapses expressing synaptic plasticity and newly activated synapses. In fact, proteasome activity was required for the consolidation of an otherwise transient potentiation (early-LTP) into late-LTP by strong tetanization of a separate afferent pathway both in the "weak-before-strong" and in the "strong-before-weak" two-pathway paradigms [Frey and Morris (1997) Nature 385:533-536; Frey and Morris (1998) Neuropharmacology 37:545-552], suggesting that proteasome activity plays a role in the synaptic tagging and capture of plasticity-related proteins at stimulated synapses. Additionally, proteasome inhibition abrogated immunity against heterosynaptic depotentiation of an established late-LTP when applied during weak tetanic stimulation in the "strong-before-weak" two-pathway paradigm. Such a heterosynaptic destabilizing effect of proteasome inhibition was abolished by concomitant inhibition of N-methyl-d-aspartate (NMDA) receptors, suggesting that it is an active process. Together, these results indicate that the proteasome plays important roles in the establishment of late-LTP and in the preservation of potentiated synapses when a subsequent synaptic plasticity is induced within the same neuronal population.</p>
    • http://www.scopus.com/inward/record.url?scp=77955413166&partnerID=8YFLogxK
    • Eike Budinger, Hans-Jochen Heinze, Carsten N Boehler, Eike Budinger, Hans Jochen Heinze
    • 2010
    • Journal of Neuroscience
    • 41
    • 13609-13623
    • Sound-induced enhancement of low-intensity vision
    • <p>Combining information across modalities can affect sensory performance. We studied how co-occurring sounds modulate behavioral visual detection sensitivity (d′), and neural responses, for visual stimuli of higher or lower intensity. Co-occurrence of a sound enhanced human detection sensitivity for lower- but not higher-intensity visual targets. Functional magnetic resonance imaging (fMRI) linked this to boosts in activity-levels for sensory-specific visual and auditory cortex, plus multisensory superior temporal sulcus (STS), specifically for a lower-intensity visual event when paired with a sound. Thalamic structures in visual and auditory pathways, the lateral and medial geniculate bodies, respectively (LGB, MGB), showed a similar pattern. Subject-by-subject psychophysical benefits correlated with corresponding fMRI signals in visual, auditory, and multisensory regions. We also analyzed differential "coupling" patterns of LGB and MGB with other regions in the different experimental conditions. Effective-connectivity analyses showed enhanced coupling of sensory-specific thalamic bodies with the affected cortical sites during enhanced detection of lower-intensity visual events paired with sounds. Coupling strength between visual and auditory thalamus with cortical regions, including STS, covaried parametrically with the psychophysical benefit for this specific multisensory context. Our results indicate that multisensory enhancement of detection sensitivity for low-contrast visual stimuli by co-occurring sounds reflects a brain network involving not only established multisensory STS and sensoryspecific cortex but also visual and auditory thalamus.</p>
    • http://www.scopus.com/inward/record.url?scp=77958040762&partnerID=8YFLogxK
    • Anna Fejtova, Eckart D. Gundelfinger, Anna Fejtova, Alexandra Heyden, Eckart D. Gundelfinger
    • 2010
    • Neuropsychopharmacology
    • 7
    • 1531-1540
    • TrkB/BDNF-dependent striatal plasticity and behavior in a genetic model of epilepsy
    • <p>In mice lacking the central domain of the presynaptic scaffold Bassoon the occurrence of repeated cortical seizures induces cell-type-specific plasticity changes resulting in a general enhancement of the feedforward inhibition within the striatal microcircuit. Early antiepileptic treatment with valproic acid (VPA) reduces epileptic attacks, inhibits the emergence of pathological form of plasticity in fast-spiking (FS) interneurons and restores physiological striatal synaptic plasticity in medium spiny (MS) neurons. Brain-derived neurotrophic factor (BDNF) is a key factor for the induction and maintenance of synaptic plasticity and it is also implicated in the mechanisms underlying epilepsy-induced adaptive changes. In this study, we explore the possibility that the TrkB/BDNF system is involved in the striatal modifications associated with the Bassoon gene (Bsn) mutation. In epileptic mice abnormal striatum-dependent learning was paralleled by higher TrkB levels and an altered distribution of BDNF. Accordingly, subchronic intrastriatal administration of k252a, an inhibitor of TrkB receptor tyrosine kinase activity, reversed behavioral alterations in Bsn mutant mice. In addition, in vitro manipulations of the TrkB/BDNF complex by k252a, prevented the emergence of pathological plasticity in FS interneurons. Chronic treatment with VPA, by reducing seizures, was able to rebalance TrkB to control levels favoring a physiological redistribution of BDNF between MS neurons and FS interneurons with a concomitant recovery of striatal plasticity. Our results provide the first indication that BDNF is involved in determining the striatal alterations occurring in the early-onset epileptic syndrome associated with the absence of presynaptic protein Bassoon.</p>
    • http://www.scopus.com/inward/record.url?scp=77952430686&partnerID=8YFLogxK
    • Martin Heine
    • 2010
    • Biochemical and Biophysical Research Communications
    • 3
    • 489-494
    • Tracking of fast moving neuronal vesicles with ageladine A
    • <p>Ageladine A is a marine natural product that can be used to fluorescently stain living tissues and cells. Its fluorescence is highly pH dependent with the highest intensities under acidic conditions. We have used ageladine A to stain acidic vesicles in cells and found the compound especially useful for tracking transport vesicles in cultured nerve cells. Inward as well as outward ionic currents appear not to be influenced by ageladine A at concentrations of 10 μM or less. Higher concentrations than 30 μM reduce whole cell voltage dependent outward currents whereas inward currents remain unchanged up to 100 μM ageladine A (PC12 cells). Incubation with ageladine A (10 μM) in cultured hippocampal neurons does not alter miniature excitatory postsynaptic currents (mEPCS) amplitudes, frequency, rise or decay times. Fast moving vesicles are stained the brightest, suggesting they are the most acidic and likely to be Golgi derived and endocytotic vesicles for the fast anterograde and retrograde transport of proteins and other compounds needing an acidic environment.</p>
    • http://www.scopus.com/inward/record.url?scp=78549271417&partnerID=8YFLogxK
    • Martin Heine, Renato Frischknecht, Eckart D. Gundelfinger, Eckart D. Gundelfinger, Renato Frischknecht
    • 2010
    • European Journal of Neuroscience
    • 12
    • 2156-2165
    • Converting juvenile into adult plasticity
    • <p>In higher vertebrates, the extracellular matrix (ECM) wrapping cells of the adult brain differs significantly from that of the developing and juvenile brain. The mature ECM is established at the end of critical periods for wiring and it restricts the regenerative potential and constrains the plasticity of the adult brain. In particular, perineuronal nets, elaborate ECM structures that surround distinct neurons and wrap synapses, are hallmarks of the adult brain and seem to massively affect brain plasticity. Why have these, at first glance futile, limitations evolved? What is the return for these drawbacks? What are the mechanisms of restriction and how is adult plasticity implemented? Recent progress both at the systemic level and at the molecular physiological level has shed some new light on these questions. In this review we will survey the evidence for potential functions of the adult ECM in making established brain features, including imprinted memories, resistant to extinction, and we will discuss potential mechanisms by which the ECM limits juvenile and implements adult plasticity. In particular we will focus on some aspects of adult ECM function. First we will discuss its influence on diffusion of cations in the extracellular space and on volume transmission, second we will consider its potential role in regulating the lateral diffusion of cell surface receptors and finally we will discuss mechanisms to locally modulate ECM functions.</p>
    • http://www.scopus.com/inward/record.url?scp=77953790535&partnerID=8YFLogxK
    • Ying Huang, Ying Huang
    • 2010
    • Ear and Hearing
    • 4
    • 579-583
    • The effect of voice cuing on releasing speech from informational masking disappears in older adults
    • <p>Objectives: To investigate whether older adults can use voice information to unmask speech. Design: Under a voice-priming condition, before a target-speech sentence was presented with a noise or speech masker, one or two voice-priming sentences were recited with the same voice reciting the target sentence. Eighteen younger adults and 12 older adults with clinically normal hearing were instructed to loudly repeat the target sentence. Results: Presenting the voice-priming sentence(s) improved target-speech identification only when the masker was speech in younger adults but not older adults. Conclusions: For older adults, the inability to use voice information to reduce informational masking contributes to their speech-recognition difficulties in "cocktail-party" environments.</p>
    • http://www.scopus.com/inward/record.url?scp=77955847939&partnerID=8YFLogxK
    • Ying Huang, Ying Huang
    • 2010
    • Journal of Cognitive Neuroscience
    • 4
    • 1003-1014
    • Perceptual fusion tendency of speech sounds
    • <p>To discriminate and to recognize sound sources in a noisy, reverberant environment, listeners need to perceptually integrate the direct wave with the reflections of each sound source. It has been confirmed that perceptual fusion between direct and reflected waves of a speech sound helps listeners recognize this speech sound in a simulated reverberant environment with disrupting sound sources. When the delay between a direct sound wave and its reflected wave is sufficiently short, the two waves are perceptually fused into a single sound image as coming from the source location. Interestingly, compared with nonspeech sounds such as clicks and noise bursts, speech sounds have a much larger perceptual fusion tendency. This study investigated why the fusion tendency for speech sounds is so large. Here we show that when the temporal amplitude fluctuation of speech was artificially time reversed, a large perceptual fusion tendency of speech sounds disappeared, regardless of whether the speech acoustic carrier was in normal or reversed temporal order. Moreover, perceptual fusion of normal-order speech, but not that of time-reversed speech, was accompanied by increased coactivation of the attention-control-related, spatial-processing-related, and speech-processing-related cortical areas. Thus, speech-like acoustic carriers modulated by speech amplitude fluctuation selectively activate a cortical network for top-down modulations of speech processing, leading to an enhancement of perceptual fusion of speech sounds. This mechanism represents a perceptual-grouping strategy for unmasking speech under adverse conditions.</p>
    • http://www.scopus.com/inward/record.url?scp=78650797205&partnerID=8YFLogxK
    • Frank Ohl, Achim Engelhorn, Jürgen Goldschmidt, Max Happel, Jürgen Goldschmidt, Tim Wanger, Achim Engelhorn, Max F.K. Happel, Anton Ilango, Frank W. Ohl, Henning Scheich
    • 2010
    • NeuroImage
    • 1
    • 303-315
    • High-resolution mapping of neuronal activity using the lipophilic thallium chelate complex TlDDC
    • <p>In neurons the rate of K<sup>+</sup>-uptake increases with increasing activity. K<sup>+</sup>-analogues like the heavy metal ion thallium (Tl<sup>+</sup>) can be used, therefore, as tracers for imaging neuronal activity. However, when water-soluble Tl<sup>+</sup>-salts are injected systemically only minute amounts of the tracer enter the brain and the Tl<sup>+</sup>-uptake patterns are influenced by regional differences in blood-brain barrier (BBB) K<sup>+</sup>-permeability. We here show that the BBB-related limitations in using Tl<sup>+</sup> for imaging neuronal activity are no longer present when the lipophilic Tl<sup>+</sup> chelate complex thallium diethyldithiocarbamate (TlDDC) is applied. We systemically injected rodents with TlDDC and mapped the Tl<sup>+</sup>-distribution in the brain using an autometallographic (AMG) technique, a histochemical method for detecting heavy metals. We find that Tl<sup>+</sup>-doses for optimum AMG staining could be substantially reduced, and regional differences attributable to differences in BBB K<sup>+</sup>-permeability were no longer detectable, indicating that TlDDC crosses the BBB. At the cellular level, however, the Tl<sup>+</sup>-distribution was essentially the same as after injection of water-soluble Tl<sup>+</sup>-salts, indicating Tl<sup>+</sup>-release from TlDDC prior to neuronal or glial uptake. Upon sensory stimulation or intracortical microstimulation neuronal Tl<sup>+</sup>-uptake increased after TlDDC injection, upon muscimol treatment neuronal Tl<sup>+</sup>-uptake decreased. We present a protocol for mapping neuronal activity with cellular resolution, which is based on intravenous TlDDC injections during ongoing activity in unrestrained behaving animals and short stimulation times of 5 min.</p>
    • http://www.scopus.com/inward/record.url?scp=70349969955&partnerID=8YFLogxK
    • Frank Ohl, Frank W. Ohl
    • 2010
    • Magnetic Resonance Imaging
    • 8
    • 1087-1094
    • Coupling of neural activity and fMRI-BOLD in the motion area MT
    • <p>The fMRI-BOLD contrast is widely used to study the neural basis of sensory perception and cognition. This signal, however, reflects neural activity only indirectly, and the detailed mechanisms of neurovascular coupling and the neurophysiological correlates of the BOLD signal remain debated. Here we investigate the coupling of BOLD and electrophysiological signals in the motion area MT of the macaque monkey by simultaneously recording both signals. Our results demonstrate that a prominent neuronal response property of area MT, so-called motion opponency, can be used to induce dissociations of BOLD and neuronal firing. During the presentation of a stimulus optimally driving the local neurons, both field potentials [local field potentials (LFPs)] and spiking activity [multi-unit activity (MUA)] correlated with the BOLD signal. When introducing the motion opponency stimulus, however, correlations of MUA with BOLD were much reduced, and LFPs were a much better predictor of the BOLD signal than MUA. In addition, for a subset of recording sites we found positive BOLD and LFP responses in the presence of decreases in MUA, regardless of the stimulus used. Together, these results demonstrate that correlations between BOLD and MUA are dependent on the particular site and stimulus paradigm, and foster the notion that the fMRI-BOLD signal reflects local dendrosomatic processing and synaptic activity rather than principal neuron spiking responses.</p>
    • http://www.scopus.com/inward/record.url?scp=77956879557&partnerID=8YFLogxK
    • Frank Ohl, Jason Shumake, Anton Ilango, Henning Scheich, Wolfram Wetzel, Frank W. Ohl
    • 2010
    • Journal of Neuroscience
    • 17
    • 5876-5883
    • Differential neuromodulation of acquisition and retrieval of avoidance learning by the lateral habenula and ventral tegmental area
    • <p>Several studies suggest an opponent functional relationship between the lateral habenula (LHb) and the ventral tegmental area (VTA). Previous work has linked LHb activation to the inhibition of dopaminergic neurons during loss of reward, as well as to deficits in escape and avoidance learning. We hypothesized that a dopamine signal might underlie the negative reinforcement of avoidance responses and that LHb activation could block this signal and thereby cause avoidance deficits. To test this idea, we implanted stimulating electrodes in either the VTA or LHb of gerbils engaged in two-way active avoidance learning, a task that shows learning-associated dopamine changes and that is acquired faster following LH blesions.We delivered brief electrical brain stimulation whenever the animal performed a correct response, i.e., when the successful avoidance of foot shock was hypothesized to trigger an intrinsic reward signal. During the acquisition phase, VTA stimulation improved avoidance performance, while LHb stimulation impaired it. VTA stimulation appeared to improve both acquisition and asymptotic performance of the avoidance response, as VTA-stimulated animals reached above-normal performance but reverted to normal responding when stimulation was discontinued. The effects of LHb stimulation during avoidance acquisition were long lasting and persisted even after stimulation was discontinued. However, when given after successful acquisition of avoidance behavior, LHb stimulation had no effect, indicating that LHb stimulation specifically impaired avoidance acquisition without affecting memory retrieval or motivation or ability to perform the avoidance response. These results demonstrate opponent roles of LHb and VTA during acquisition but not during retrieval of avoidance learning.</p>
    • http://www.scopus.com/inward/record.url?scp=77951664276&partnerID=8YFLogxK
    • Frank Ohl, Anton Ilango, Wolfram Wetzel, Henning Scheich, Frank W. Ohl
    • 2010
    • Neuroscience
    • 3
    • 752-762
    • The combination of appetitive and aversive reinforcers and the nature of their interaction during auditory learning
    • <p>Learned changes in behavior can be elicited by either appetitive or aversive reinforcers. It is, however, not clear whether the two types of motivation, (approaching appetitive stimuli and avoiding aversive stimuli) drive learning in the same or different ways, nor is their interaction understood in situations where the two types are combined in a single experiment. To investigate this question we have developed a novel learning paradigm for Mongolian gerbils, which not only allows rewards and punishments to be presented in isolation or in combination with each other, but also can use these opposite reinforcers to drive the same learned behavior. Specifically, we studied learning of tone-conditioned hurdle crossing in a shuttle box driven by either an appetitive reinforcer (brain stimulation reward) or an aversive reinforcer (electrical footshock), or by a combination of both. Combination of the two reinforcers potentiated speed of acquisition, led to maximum possible performance, and delayed extinction as compared to either reinforcer alone. Additional experiments, using partial reinforcement protocols and experiments in which one of the reinforcers was omitted after the animals had been previously trained with the combination of both reinforcers, indicated that appetitive and aversive reinforcers operated together but acted in different ways: in this particular experimental context, punishment appeared to be more effective for initial acquisition and reward more effective to maintain a high level of conditioned responses (CRs). The results imply that learning mechanisms in problem solving were maximally effective when the initial punishment of mistakes was combined with the subsequent rewarding of correct performance.</p>
    • http://www.scopus.com/inward/record.url?scp=77249108276&partnerID=8YFLogxK
    • Frank Ohl, Max Happel, Max F.K. Happel, Marcus Jeschke, Frank W. Ohl
    • 2010
    • Journal of Neuroscience
    • 33
    • 11114-11127
    • Spectral integration in primary auditory cortex attributable to temporally precise convergence of thalamocortical and intracortical input
    • <p>Primary sensory cortex integrates sensory information from afferent feedforward thalamocortical projection systems and convergent intracortical microcircuits. Both input systems have been demonstrated to provide different aspects of sensory information. Here we have used high-density recordings of laminar current source density (CSD) distributions in primary auditory cortex of Mongolian gerbils in combination with pharmacological silencing of cortical activity and analysis of the residual CSD, to dissociate the feedforward thalamocortical contribution and the intracortical contribution to spectral integration. We found a temporally highly precise integration of both types of inputs when the stimulation frequency was in close spectral neighborhood of the best frequency of the measurement site, in which the overlap between both inputs is maximal. Local intracortical connections provide both directly feedforward excitatory and modulatory input from adjacent cortical sites, which determine how concurrent afferent inputs are integrated. Through separate excitatory horizontal projections, terminating in cortical layers II/III, information about stimulus energy in greater spectral distance is provided even over long cortical distances. These projections effectively broaden spectral tuning width. Based on these data, we suggest a mechanism of spectral integration in primary auditory cortex that is based on temporally precise interactions of afferent thalamocortical inputs and different short-and long-range intracortical networks. The proposed conceptual framework allows integration of different and partly controversial anatomical and physiological models of spectral integration in the literature.</p>
    • http://www.scopus.com/inward/record.url?scp=77955888799&partnerID=8YFLogxK
    • Frank Ohl, Frank W. Ohl
    • 2010
    • Experimental Brain Research
    • 3
    • 629-635
    • Resonance phenomena in the human auditory cortex
    • <p>The brain can be considered a dynamical system which is able to oscillate at multiple frequencies. To study the brain's preferred oscillation frequencies, the resonance frequencies in the frequency response of the system can be assessed by stimulating the brain at various stimulation frequencies. Furthermore, the event-related potential (ERP) can be considered as the brain's impulse response. For linear dynamical systems, the frequency response should be equivalent to the frequency transform of the impulse response. The present study test whether this fundamental relation is also true for the frequency transform of the ERP and the frequency response of the brain. Results show that the spectral characteristics of both impulse and frequency response in the gamma frequency range are significantly correlated. Thus, we speculate that the resonance frequencies determine the frequency spectrum of the impulse response. This, in turn, implies that both measures are determined by the same, individually specific, neuronal generator mechanisms.</p>
    • http://www.scopus.com/inward/record.url?scp=77956198686&partnerID=8YFLogxK
    • Matthias Prigge
    • 2010
    • Channels
    • 3
    • 241-247
    • Fast, repetitive light-activation of Ca<sub>V</sub>3.2 using channelrhodopsin 2
    • <p>Channelrhodopsin-2 (ChR2) is a light-gated ion channel that is successfully used in neurosciences to depolarize cells with blue light. in this regard control of membrane voltage with light opens new perspectives for the characterization of ion channels and the search for inhibitors or modulators. here, we report a control of membrane potential with ChR2 and the potassium channel mTrek for the purpose of screening for ion channel specific drugs. To verify principle we have chosen the voltage gated calcium channel Ca <sub>V</sub>3.2 as potential drug target. For this purpose we transfected the ChR2 gene into a HEK293T-cell line that permanently expresses Ca<sub>V</sub>3.2 and the K-channel mTrek. The resting potential was adjusted with low concentration of extracellular potassium ions whereas transient depolarization was achieved by activation of ChR2 with short pulses of blue light. Calcium ion influx through Ca<sub>V</sub>3.2 was monitored by observing fura-2 fluorescence. This approach allowed a repetitive activation of Ca<sub>V</sub>3.2. The Ca <sup>2+</sup> influx was specifically blocked by the inhibitor mibefradil. Since this assay is genetically-encoded, it may be employed for a variety of voltage-gated calcium channels and should be applicable to multi-well reader formats for high-throughput screening.</p>
    • http://www.scopus.com/inward/record.url?scp=77953891111&partnerID=8YFLogxK
    • Matthias Prigge
    • 2010
    • Biophysical Journal
    • 5
    • 753-761
    • Two open states with progressive proton selectivities in the branched channelrhodopsin-2 photocycle
    • <p>Channelrhodopsins are light-gated ion channels that mediate vision in phototactic green algae like Chlamydomonas. In neurosciences, channelrhodopsins are widely used to light-trigger action potentials in transfected cells. All known channelrhodopsins preferentially conduct H(+). Previous studies have indicated the existence of an early and a late conducting state within the channelrhodopsin photocycle. Here, we show that for channelrhodopsin-2 expressed in Xenopus oocytes and HEK cells, the two open states have different ion selectivities that cause changes in the channelrhodopsin-2 reversal voltage during a light pulse. An enzyme kinetic algorithm was applied to convert the reversal voltages in various ionic conditions to conductance ratios for H(+) and divalent cations (Ca(2+) and/or Mg(2+)), as compared to monovalent cations (Na(+) and/or K(+)). Compared to monovalent cation conductance, the H(+) conductance, alpha, is approximately 3 x 10(6) and the divalent cation conductance, beta, is approximately 0.01 in the early conducting state. In the stationary mixture of the early and late states, alpha is larger and beta smaller, both by a factor of approximately 2. The results suggest that the ionic basis of light perception in Chlamydomonas is relatively nonspecific in the beginning of a light pulse but becomes more selective for protons during longer light exposures.</p>
    • http://www.scopus.com/inward/record.url?scp=77749306541&partnerID=8YFLogxK
    • Björn Schott, Constanze Seidenbecher, Renato Frischknecht, Kathrin Ohl, Eckart D. Gundelfinger, B. Schott, Renato Frischknecht, Nora Fischer, Eckart D. Gundelfinger
    • 2010
    • Frontiers in Psychiatry
    • OCT
    • Membrane-bound catechol-O-methyl transferase in cortical neurons and glial cells is intracellularly oriented
    • <p>Catechol-O-methyl transferase (COMT) is involved in the inactivation of dopamine in brain regions in which the dopamine transporter (DAT1) is sparsely expressed. The membrane-bound isoform of COMT (MB-COMT) is the predominantly expressed form in the mammalian central nervous system (CNS). It has been a matter of debate whether in neural cells of the CNS the enzymatic domain of MB-COMT is oriented toward the cytoplasmic or the extracellular compartment. Here we used live immunocytochemistry on cultured neocortical neurons and glial cells to investigate the expression and membrane orientation of native COMT and of transfected MB-COMT fused to green fluorescent protein (GFP). After live staining, COMT immunoreactivity was reliably detected in both neurons and glial cells after permeabilization, but not on unpermeabilized cells. Similarly, autofluorescence of COMT-GFP fusion protein and antibody fluorescence showed overlap only in permeabilized neurons. Our data provide converging evidence for an intracellular membrane orientation of MB-COMT in neurons and glial cells, suggesting the presence of a DAT1-independent postsynaptic uptake mechanism for dopamine, prior to its degradation via COMT.</p>
    • http://www.scopus.com/inward/record.url?scp=84866746665&partnerID=8YFLogxK
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