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Hardwick R.M.,Center for Behavioural Brain science | Apperly I.A.,Center for Behavioural Brain science | Hansen P.C.,Center for Behavioural Brain science
Human Brain Mapping | Year: 2016

When required to represent a perspective that conflicts with one's own, functional magnetic resonance imaging (fMRI) suggests that the right ventrolateral prefrontal cortex (rvlPFC) supports the inhibition of that conflicting self-perspective. The present task dissociated inhibition of self-perspective from other executive control processes by contrasting belief reasoning-a cognitive state where the presence of conflicting perspectives was manipulated-with a conative desire state wherein no systematic conflict existed. Linear modeling was used to examine the effect of continuous theta burst stimulation (cTBS) to rvlPFC on participants' reaction times in belief and desire reasoning. It was anticipated that cTBS applied to rvlPFC would affect belief but not desire reasoning, by modulating activity in the Ventral Attention System (VAS). We further anticipated that this effect would be mediated by functional connectivity within this network, which was identified using resting state fMRI and an unbiased model-free approach. Simple reaction-time analysis failed to detect an effect of cTBS. However, by additionally modeling individual measures from within the stimulated network, the hypothesized effect of cTBS to belief (but, importantly, not desire) reasoning was demonstrated. Structural morphology within the stimulated region, rvlPFC, and right temporoparietal junction were demonstrated to underlie this effect. These data provide evidence that inconsistencies found with cTBS can be mediated by the composition of the functional network that is being stimulated. We suggest that the common claim that this network constitutes the VAS explains the effect of cTBS to this network on false belief reasoning. © 2016 Wiley Periodicals, Inc.


Beesley P.W.,Royal Holloway, University of London | Herrera-Molina R.,Leibniz Institute for Neurobiology | Herrera-Molina R.,University of Chile | Smalla K.-H.,Leibniz Institute for Neurobiology | And 3 more authors.
Journal of Neurochemistry | Year: 2014

The Neuroplastins Np65 and Np55 are neuronal and synapse-enriched immunoglobulin superfamily molecules that play important roles in a number of key neuronal and synaptic functions including, for Np65, cell adhesion. In this review we focus on the physiological roles of the Neuroplastins in promoting neurite outgrowth, regulating the structure and function of both inhibitory and excitatory synapses in brain, and in neuronal and synaptic plasticity. We discuss the underlying molecular and cellular mechanisms by which the Neuroplastins exert their physiological effects and how these are dependent upon the structural features of Np65 and Np55, which enable them to bind to a diverse range of protein partners. In turn this enables the Neuroplastins to interact with a number of key neuronal signalling cascades. These include: binding to and activation of the fibroblast growth factor receptor; Np65 trans-homophilic binding leading to activation of p38 MAPK and internalization of glutamate (GluR1) receptor subunits; acting as accessory proteins for monocarboxylate transporters, thus affecting neuronal energy supply, and binding to GABAA α1, 2 and 5 subunits, thus regulating the composition and localization of GABAA receptors. An emerging theme is the role of the Neuroplastins in regulating the trafficking and subcellular localization of specific binding partners. We also discuss the involvement of Neuroplastins in a number of pathophysiological conditions, including ischaemia, schizophrenia and breast cancer and the role of a single nucleotide polymorphism in the human Neuroplastin (NPTN) gene locus in impairment of cortical development and cognitive functions. © 2014 International Society for Neurochemistry.


Brandewiede J.,University of Hamburg | Stork O.,Otto Von Guericke University of Magdeburg | Stork O.,Center for Behavioural Brain science | Schachner M.,University of Hamburg | And 2 more authors.
Genes, Brain and Behavior | Year: 2014

The neural cell adhesion molecule (NCAM) has been implicated in the development and plasticity of neural circuits and the control of hippocampus- and amygdala-dependent learning and behaviour. Previous studies in constitutive NCAM nullmutants identified emotional behaviour deficits related to disturbances of hippocampal and amygdala functions. Here, we studied these behaviours in mice conditionally deficient in NCAM in the postmigratory forebrain neurons. We report deficits in both innate and learned avoidance behaviours, as observed in elevated plus maze and passive avoidance tasks. In contrast, general locomotor activity, trait anxiety or neophobia were unaffected by the mutation. Altered avoidance behaviour of the conditional NCAM mutantswas associated with a deficit in serotonergic signalling, as indicated by their reduced responsiveness to (±)-8-hydroxy-2-(dipropylamino)-tetralin-induced hypothermia. Another serotonin-dependent behaviour, namely intermale aggression that is massively increased in constitutively NCAM-deficient mice, was not affected in the forebrain-specific mutants. Our data suggest that genetically or environmentally induced changes of NCAM expression in the late postnatal and mature forebrain determine avoidance behaviour and serotonin (5-HT)1A receptor signalling. © 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.


Albrecht A.,Otto Von Guericke University of Magdeburg | Bergado-Acosta J.R.,Otto Von Guericke University of Magdeburg | Pape H.-C.,University of Munster | Stork O.,Otto Von Guericke University of Magdeburg | Stork O.,Center for Behavioural Brain Science
International Journal of Neuropsychopharmacology | Year: 2010

Evidence suggests that the neural cell adhesion molecule (NCAM) is an important molecular constituent of adaptive and maladaptive circuit (re-)organization in the central nervous system. Here, we further investigate its putative involvement in amygdala and hippocampus functions during context fear memory formation. Using laser capture microdissection and quantitative RT-PCR, we show high NCAM mRNA expression levels in the lateral and basolateral subnuclei of the amygdala, as well as their training intensity-and context-dependent regulation during fear memory consolidation. Moreover, we demonstrate that deficits of NCAM-/- mice in context fear memory can be overcome through contextual pre-exposure, i.e. by reducing the modulatory influence of the amygdala on this hippocampus-dependent memory. On the contrary, NCAM-/- mice failed to increase contextual fear memory after salient overtraining, although they adequately increased their response to auditory-cued fear stimuli. Finally, we demonstrate a reduction of amygdalo-hippocampal theta synchronization in NCAM-/- mice during fear memory retrieval. Together, these results suggest an involvement of NCAM-mediated cell recognition processes in information processing of the amygdalo-hippocampal system and in the amygdala-mediated modulation of context fear memory according to stimulus salience. © 2010 CINP.


Hoffmann M.B.,Otto Von Guericke University of Magdeburg | Hoffmann M.B.,Center for Behavioural Brain science | Thieme H.,Otto Von Guericke University of Magdeburg | Liedecke K.,Otto Von Guericke University of Magdeburg | And 3 more authors.
Investigative Ophthalmology and Visual Science | Year: 2015

PURPOSE. Numerous animal studies demonstrated the importance of components of the ephrin/Eph system for correct visual system development. Analogous investigations in humans are entirely missing. Here, we examined the visual system in humans with ephrin-B1 deficiency, which is x-linked and associated with the cranio-fronto-nasal syndrome (CFNS) in heterozygous females. METHODS. For one male hemizygous for ephrin-B1 deficiency and three affected heterozygous females with molecular-genetically confirmed mutations, the integrity of the partial decussation of the optic nerves was assessed with visual evoked potentials (VEPs) and compared with albinotic, achiasmic, and control participants with healthy vision. Further, retinal morphology and function and the gross-retinotopic representation of the primary visual cortex were examined with spectral-domain optical coherence tomography (SD-OCT), ERG, and multifocal (mf) VEPs for the male participant and part of the carriers. RESULTS. Strabismus and lack of stereovision was evident in the male and two of the females. Other characteristics of the visual system organization and function were normal: (1) retina: SD-OCT and funduscopy indicated normal foveal and optic nerve head morphology. Electroretinograms indicated normal retinal function, (2) optic chiasm: conventional (c)VEP showed no evidence for misrouting and mfVEPs were only suggestive of, if any, very minor local misrouting, and (3) visual cortex: mfVEP characteristics indicated normal retinotopic gross-representations of the contralateral visual hemifield in each hemisphere. CONCLUSIONS. While ephrin-B1 deficiency leads to abnormal visual pathways in mice, it leaves the human visual system, apart from deficits in binocular vision, largely normal. We presume that other components of the ephrin-system can substitute the lack of ephrin-B1 in humans. © 2015 The Association for Research in Vision and Ophthalmology, Inc.


Tiede R.,Leibniz Institute for Neurobiology | Krautwald K.,Functional Neuroimaging Group | Fincke A.,Leibniz Institute for Neurobiology | Angenstein F.,Leibniz Institute for Neurobiology | And 3 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2012

The role of N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms in the formation of a blood oxygen level-dependent (BOLD) response was studied using electrical stimulation of the right perforant pathway. Stimulation of this fiber bundle triggered BOLD responses in the right hippocampal formation and in the left entorhinal cortex. The perforant pathway projects to and activates the dentate gyrus monosynaptically, activation in the contralateral entorhinal cortex is multisynaptic and requires forwarding and processing of signals. Application of the NMDA receptor antagonist MK801 during stimulation had no effect on BOLD responses in the right dentate gyrus, but reduced the BOLD responses in the left entorhinal cortex. In contrast, application of MK801 before the first stimulation train reduced the BOLD response in both regions. Electrophysiological recordings revealed that the initial stimulation trains changed the local processing of the incoming signals in the dentate gyrus. This altered electrophysiological response was not further changed by a subsequent application of MK801, which is in agreement with an unchanged BOLD response. When MK801 was present during the first stimulation train, a dissimilar electrophysiological response pattern was observed and corresponds to an altered BOLD response, indicating that NMDA-dependent mechanisms indirectly affect the BOLD response, mainly via modifying local signal processing and subsequent propagation. © 2012 ISCBFM All rights reserved.


Krautwald K.,Functional Neuroimaging Group | Angenstein F.,Leibniz Institute for Neurobiology Magdeburg | Angenstein F.,Otto Von Guericke University of Magdeburg | Angenstein F.,Center for Behavioural Brain science
Journal of Cerebral Blood Flow and Metabolism | Year: 2012

To study how various anesthetics affect the relationship between stimulus frequency and generated functional magnetic resonance imaging (fMRI) signals in the rat dentate gyrus, the perforant pathway was electrically stimulated with repetitive low frequency (i.e., 0.625, 1.25, 2.5, 5, and 10 Hz) stimulation trains under isoflurane/N 2 O, isoflurane, medetomidine, and α-chloralose. During stimulation, the blood oxygen level-dependent signal intensity (BOLD response) and local field potentials in the dentate gyrus were simultaneously recorded to prove whether the present anesthetic controls the generation of a BOLD response via targeting general hemodynamic parameters, by affecting mechanisms of neurovascular coupling, or by disrupting local signal processing. Using this combined electrophysiological/fMRI approach, we found that the threshold frequency (i.e., the minimal frequency required to trigger significant BOLD responses), the optimal frequency (i.e., the frequency that elicit the strongest BOLD response), and the spatial distribution of generated BOLD responses are specific for each anesthetic used. Concurrent with anesthetic-dependent characteristics of the BOLD response, we found the pattern of stimulus-induced neuronal activity in the dentate gyrus is also specific for each anesthetic. Consequently, the anesthetic-specific influence on local signaling processes is the underlying cause for the observation that an identical stimulus elicits different BOLD responses under various anesthetics. © 2012 ISCBFM All rights reserved.


Teuber J.,Otto Von Guericke University of Magdeburg | Mueller B.,Otto Von Guericke University of Magdeburg | Fukabori R.,Otto Von Guericke University of Magdeburg | Lang D.,Otto Von Guericke University of Magdeburg | And 3 more authors.
PLoS ONE | Year: 2013

Evidence suggests that regulated ubiquitination of proteins plays a critical role in the development and plasticity of the central nervous system. We have previously identified the ubiquitin ligase Praja1 as a gene product induced during fear memory consolidation. However, the neuronal function of this enzyme still needs to be clarified. Here, we investigate its involvement in the nerve growth factor (NGF)-induced differentiation of rat pheochromocytoma (PC12) cells. Praja1 co-localizes with cytoskeleton components and the neurotrophin receptor interacting MAGE homologue (NRAGE). We observed an enhanced expression of Praja1 after 3 days of NGF treatment and a suppression of neurite formation upon Praja1 overexpression in stably transfected PC12 cell lines, which was associated with a proteasome-dependent reduction of NRAGE levels. Our data suggest that Praja1, through ubiquitination and degradation of NRAGE, inhibits neuronal differentiation. The two murine isoforms, Praja1.1 and Praja1.2, appear to be functionally homologous in this respect. © 2013 Teuber et al.


Sharvit A.,Haifa University | Segal M.,Weizmann Institute of Science | Kehat O.,Haifa University | Stork O.,Otto Von Guericke University of Magdeburg | And 2 more authors.
Stress | Year: 2015

Depending on its severity, timing and context, stress has been shown to have a differential regional effect on hippocampal synaptic plasticity. While the focus of attention in most recent studies is on excitatory synapses and generation, modifications of inhibitory synapses and local interneurons cannot be ignored. We have now examined the effects of corticosterone (CORT) on extrinsic afferent and local circuit plasticity of the perforant path on the dentate gyrus (DG) and the ventral hippocampal commissure on CA1. Local circuit activity was measured by responses to paired-pulse stimulation. Control rats expressed afferent long-term potentiation (LTP) and local circuit plasticity in both the DG and CA1. Administration of a high dosage of CORT-reduced paired-pulse inhibition and increased facilitation in DG but not in CA1, whereas administration of a moderate CORT dosage had no effect. Moderate CORT doses caused enhancement of LTP in the DG but not in CA1, while high CORT doses converted LTP to long-term depression in the CA1 but had no effect in the DG. CORT blocked theta burst stimulation-induced local circuit plasticity otherwise found in control DG. These findings suggest that elevation of the level of CORT results in a regionally differentiated physiological response. In addition, the results indicate that CORT affects aspects of local circuit activity and plasticity in the DG but less so in the CA1. It is possible that these differentiated alterations underlie some of the behavioral consequences and memory processes under stressful conditions. © 2015 © 2015 Informa UK Ltd.


Albrecht A.,Otto Von Guericke University of Magdeburg | Thiere M.,Otto Von Guericke University of Magdeburg | Bergado-Acosta J.R.,Otto Von Guericke University of Magdeburg | Poranzke J.,Otto Von Guericke University of Magdeburg | And 4 more authors.
PLoS ONE | Year: 2013

Pharmacological evidence suggests that the neuropeptide somatostatin (SST) exerts anxiolytic action via the amygdala, but findings concerning the putative role of endogenous SST in the regulation of emotional responses are contradictory. We hypothesized that an endogenous regulation of SST expression over the course of the day may determine its function and tested both SST gene expression and the behavior of SST knock out (SST-/-) mice in different aversive tests in relation to circadian rhythm. In an open field and a light/dark avoidance test, SST-/- mice showed significant hyperactivity and anxiety-like behavior during the second, but not during the first half of the active phase, failing to show the circadian modulation of behavior that was evident in their wild type littermates. Behavioral differences occurred independently of changes of intrinsically motivated activity in the home cage. A circadian regulation of SST mRNA and protein expression that was evident in the basolateral complex of the amygdala of wild type mice may provide a neuronal substrate for the observed behavior. However, fear memory towards auditory cue or the conditioning context displayed neither a time- nor genotype-dependent modulation. Together this indicates that SST, in a circadian manner and putatively via its regulation of expression in the amygdala, modulates behavior responding to mildly aversive conditions in mice. © 2013 Albrecht et al.

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