Recent Submissions

  • Journal Article

    Comparing Open-Source Toolboxes for Processing and Analysis of Spike and Local Field Potentials Data 

    Unakafova, Valentina A.; Gail, Alexander
    Frontiers in Neuroinformatics 2019; 13: Art. 57
    Analysis of spike and local field potential (LFP) data is an essential part of neuroscientific research. Today there exist many open-source toolboxes for spike and LFP data analysis implementing various functionality. Here we aim to provide a practical guidance for neuroscientists in the choice of an open-source toolbox best satisfying their needs. We overview major open-source toolboxes for spike and LFP data analysis as well as toolboxes with tools for connectivity analysis, dimensionality reduction and generalized linear modeling. We focus on comparing toolboxes functionality, statistical and visualization tools, documentation and support quality. To give a better insight, we compare and illustrate functionality of the toolboxes on open-access dataset or simulated data and make corresponding MATLAB scripts publicly available.
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  • Journal Article

    Library of actions: Implementing a generic robot execution framework by using manipulation action semantics 

    Aein, Mohamad Javad; Aksoy, Eren Erdal; Wörgötter, Florentin
    The International Journal of Robotics Research 2019; 38(8) p.910-934
    When a robot has to imitate an observed action sequence, it must first understand the inherent characteristic features of the individual actions. Such features need to reflect the semantics of the action with a high degree of invariance between different demonstrations of the same action. At the same time the machine needs to be able to execute the action sequence in any appropriate situation. In this study, we introduce a new library of actions, which is a generic framework for executing manipulation actions on robotic systems by combining features that capture action semantics with a framework for execution. We focus on manipulation actions and first create a generic representation consisting of symbolic and subsymbolic components. To link these two domains we introduce a finite state machine allowing for sequential execution with error handling. The framework is developed from observing humans which provides us with a high degree of grounding. To quantitatively evaluate the scalability of the proposed approach, we conducted a large set of experiments involving different actions performed either individually or sequentially with various types of objects in different scene contexts.
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  • Journal Article

    Local field potentials are induced by visually evoked spiking activity in macaque cortical area MT 

    Esghaei, Moein; Daliri, Mohammad Reza; Treue, Stefan
    Scientific Reports 2017; 7(1)
    Local field potentials (LFP) have been the focus of many recent studies in systems neuroscience. However, the exact neural basis of these signals remains unclear. To address this question, we determined the relationship between LFP signals and another, much better understood, signature of neural activity: action potentials. Specifically, we focused on the relationship between the amplitude of stimulus-induced LFPs and the magnitude of spiking activity in visual cortex of non-human primates. Our trial-by-trial correlation analyses between these two components of extracellular signals in macaque visual cortex show that the spike rate is coupled to the LFP amplitude with a surprisingly long latency, typically 50 ms. Our analysis shows that the neural spike rate is a significant predictor of the LFP amplitude. This limits the functional interpretation of LFP signals beyond that based on spiking activities.
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  • Journal Article

    Spontaneous termination of chaotic spiral wave dynamics in human cardiac ion channel models 

    Aron, Marcel; Herzog, Sebastian; Parlitz, Ulrich; Luther, Stefan; Lilienkamp, Thomas
    PLOS ONE 2019; 14(8): Art. e0221401
    Chaotic spiral or scroll wave dynamics can be found in diverse systems. In cardiac dynamics, spiral or scroll waves of electrical excitation determine the dynamics during life-threatening arrhythmias like ventricular fibrillation. In numerical studies it was found that chaotic episodes of spiral and scroll waves can be transient, thus they terminate spontaneously. We show in this study that this behavior can also be observed using models which describe the ion channel dynamics of human cardiomyocytes (Bueno-Orovio-Cherry-Fenton model and the Ten Tusscher-Noble-Noble-Panfilov model). For both models we find that the average lifetime of the chaotic transients grows exponentially with the system size. With this behavior, we classify the systems into the group of type-II supertransients. We observe a significant difference of the breakup behavior between the models, which results in a distinct dynamics during the final phase just before the termination. The observation of a (temporally) stable single-spiral state affects the prevailing description of the dynamics of type-II supertransients as being "quasi-stationary" and also the feasibility of predicting the spontaneous termination of the spiral wave dynamics. In the long term, the relation between the breakup behavior of spiral waves and properties of chaotic transients like predictability or average transient lifetime may contribute to an improved understanding and classification of cardiac arrhythmias.
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  • Journal Article

    Strategic deployment of feature-based attentional gain in primate visual cortex 

    Kozyrev, Vladislav; Daliri, Mohammad Reza; Schwedhelm, Philipp; Treue, Stefan
    PLOS Biology 2019; 17(8): Art. e3000387
    Attending to visual stimuli enhances the gain of those neurons in primate visual cortex that preferentially respond to the matching locations and features (on-target gain). Although this is well suited to enhance the neuronal representation of attended stimuli, it is nonoptimal under difficult discrimination conditions, as in the presence of similar distractors. In such cases, directing attention to neighboring neuronal populations (off-target gain) has been shown to be the most efficient strategy, but although such a strategic deployment of attention has been shown behaviorally, its underlying neural mechanisms are unknown. Here, we investigated how attention affects the population responses of neurons in the middle temporal (MT) visual area of rhesus monkeys to bidirectional movement inside the neurons' receptive field (RF). The monkeys were trained to focus their attention onto the fixation spot or to detect a direction or speed change in one of the motion directions (the "target"), ignoring the distractor motion. Population activity profiles were determined by systematically varying the patterns' directions while maintaining a constant angle between them. As expected, the response profiles show a peak for each of the 2 motion directions. Switching spatial attention from the fixation spot into the RF enhanced the peak representing the attended stimulus and suppressed the distractor representation. Importantly, the population data show a direction-dependent attentional modulation that does not peak at the target feature but rather along the slopes of the activity profile representing the target direction. Our results show that attentional gains are strategically deployed to optimize the discriminability of target stimuli, in line with an optimal gain mechanism proposed by Navalpakkam and Itti.
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  • Journal Article

    Antibody-driven capture of synaptic vesicle proteins on the plasma membrane enables the analysis of their interactions with other synaptic proteins 

    Richter, Katharina N.; Patzelt, Christina; Phan, Nhu T. N.; Rizzoli, Silvio O.
    Scientific Reports 2019; 9(1): Art. 9231
    Many organelles from the secretory pathway fuse to the plasma membrane, to exocytose different cargoes. Their proteins are then retrieved from the plasma membrane by endocytosis, and the organelles are re-formed. It is generally unclear whether the organelle proteins colocalize when they are on the plasma membrane, or whether they disperse. To address this, we generated here a new approach, which we tested on synaptic vesicles, organelles that are known to exo- and endocytose frequently. We tagged the synaptotagmin molecules of newly exocytosed vesicles using clusters of primary and secondary antibodies targeted against the luminal domains of these molecules. The antibody clusters are too large for endocytosis, and thus sequestered the synaptotagmin molecules on the plasma membrane. Immunostainings for other synaptic molecules then revealed whether they colocalized with the sequestered synaptotagmin molecules. We suggest that such assays may be in the future extended to other cell types and other organelles.
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  • Journal Article

    Ultrafast optogenetic stimulation of the auditory pathway by targeting‐optimized Chronos 

    Keppeler, Daniel; Merino, Ricardo Martins; Lopez de la Morena, David; Bali, Burak; Huet, Antoine Tarquin; Gehrt, Anna; Wrobel, Christian; Subramanian, Swati; Dombrowski, Tobias; Wolf, Fred; et al.
    Rankovic, VladanNeef, AndreasMoser, Tobias
    The EMBO Journal 2018; 37(24): Art. e99649
    Optogenetic tools, providing non‐invasive control over selected cells, have the potential to revolutionize sensory prostheses for humans. Optogenetic stimulation of spiral ganglion neurons (SGNs) in the ear provides a future alternative to electrical stimulation used in cochlear implants. However, most channelrhodopsins do not support the high temporal fidelity pertinent to auditory coding because they require milliseconds to close after light‐off. Here, we biophysically characterized the fast channelrhodopsin Chronos and revealed a deactivation time constant of less than a millisecond at body temperature. In order to enhance neural expression, we improved its trafficking to the plasma membrane (Chronos‐ES/TS). Following efficient transduction of SGNs using early postnatal injection of the adeno‐associated virus AAV‐PHP.B into the mouse cochlea, fiber‐based optical stimulation elicited optical auditory brainstem responses (oABR) with minimal latencies of 1 ms, thresholds of 5 μJ and 100 μs per pulse, and sizable amplitudes even at 1,000 Hz of stimulation. Recordings from single SGNs demonstrated good temporal precision of light‐evoked spiking. In conclusion, efficient virus‐mediated expression of targeting‐optimized Chronos‐ES/TS achieves ultrafast optogenetic control of neurons.
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  • Journal Article

    A Theoretical Framework to Derive Simple, Firing-Rate-Dependent Mathematical Models of Synaptic Plasticity 

    Lappalainen, Janne; Herpich, Juliane; Tetzlaff, Christian
    Frontiers in Computational Neuroscience 2019; 13: Art. 26
    Synaptic plasticity serves as an essential mechanism underlying cognitive processes as learning and memory. For a better understanding detailed theoretical models combine experimental underpinnings of synaptic plasticity and match experimental results. However, these models are mathematically complex impeding the comprehensive investigation of their link to cognitive processes generally executed on the neuronal network level. Here, we derive a mathematical framework enabling the simplification of such detailed models of synaptic plasticity facilitating further mathematical analyses. By this framework we obtain a compact, firing-rate-dependent mathematical formulation, which includes the essential dynamics of the detailed model and, thus, of experimentally verified properties of synaptic plasticity. Amongst others, by testing our framework by abstracting the dynamics of two well-established calcium-dependent synaptic plasticity models, we derived that the synaptic changes depend on the square of the presynaptic firing rate, which is in contrast to previous assumptions. Thus, the here-presented framework enables the derivation of biologically plausible but simple mathematical models of synaptic plasticity allowing to analyze the underlying dependencies of synaptic dynamics from neuronal properties such as the firing rate and to investigate their implications in complex neuronal networks.
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  • Journal Article

    Dementia with Lewy bodies: an update and outlook 

    Outeiro, Tiago Fleming; Koss, David J.; Erskine, Daniel; Walker, Lauren; Kurzawa-Akanbi, Marzena; Burn, David; Donaghy, Paul; Morris, Christopher; Taylor, John-Paul; Thomas, Alan; et al.
    Attems, JohannesMcKeith, Ian
    Molecular Neurodegeneration 2019; 14(1): Art. 5
    Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB is characterised by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson's disease (PD). Extrapyramidal motor features characteristic of PD, are common in DLB patients, but are not essential for the clinical diagnosis of DLB. Since many PD patients develop dementia as disease progresses, there has been controversy about the separation of DLB from PD dementia (PDD) and consensus reports have put forward guidelines to assist clinicians in the identification and management of both syndromes. Here, we present basic concepts and definitions, based on our current understanding, that should guide the community to address open questions that will, hopefully, lead us towards improved diagnosis and novel therapeutic strategies for DLB and other synucleinopathies.
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  • Journal Article

    Peri-hand space expands beyond reach in the context of walk-and-reach movements 

    Berger, Michael; Neumann, Peter; Gail, Alexander
    Scientific Reports 2019; 9(1): Art. 3013
    The brain incorporates sensory information across modalities to be able to interact with our environment. The peripersonal space (PPS), defined by a high level of crossmodal interaction, is centered on the relevant body part, e.g. the hand, but can spatially expand to encompass tools or reach targets during goal-directed behavior. Previous studies considered expansion of the PPS towards goals within immediate or tool-mediated reach, but not the translocation of the body as during walking. Here, we used the crossmodal congruency effect (CCE) to quantify the extension of the PPS and test if PPS can also expand further to include far located walk-and-reach targets accessible only by translocation of the body. We tested for orientation specificity of the hand-centered reference frame, asking if the CCE inverts with inversion of the hand orientation during reach. We show a high CCE with onset of the movement not only towards reach targets but also walk-and-reach targets. When participants must change hand orientation, the CCE decreases, if not vanishes, and does not simply invert. We conclude that the PPS can expand to the action space beyond immediate or tool-mediated reaching distance but is not purely hand-centered with respect to orientation.
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  • Journal Article

    Technical challenges of quantitative chest MRI data analysis in a large cohort pediatric study 

    Nguyen, Anh H.; Perez-Rovira, Adria; Wielopolski, Piotr A.; Hernandez Tamames, Juan A.; Duijts, Liesbeth; de Bruijne, Marleen; Aliverti, Andrea; Pennati, Francesca; Ivanovska, Tetyana; Tiddens, Harm A. W. M.; et al.
    Ciet, Pierluigi
    European Radiology
    OBJECTIVES: This study was conducted in order to evaluate the effect of geometric distortion (GD) on MRI lung volume quantification and evaluate available manual, semi-automated, and fully automated methods for lung segmentation. METHODS: A phantom was scanned with MRI and CT. GD was quantified as the difference in phantom's volume between MRI and CT, with CT as gold standard. Dice scores were used to measure overlap in shapes. Furthermore, 11 subjects from a prospective population-based cohort study each underwent four chest MRI acquisitions. The resulting 44 MRI scans with 2D and 3D Gradwarp were used to test five segmentation methods. Intraclass correlation coefficient, Bland-Altman plots, Wilcoxon, Mann-Whitney U, and paired t tests were used for statistics. RESULTS: Using phantoms, volume differences between CT and MRI varied according to MRI positions and 2D and 3D Gradwarp correction. With the phantom located at the isocenter, MRI overestimated the volume relative to CT by 5.56 ± 1.16 to 6.99 ± 0.22% with body and torso coils, respectively. Higher Dice scores and smaller intraobject differences were found for 3D Gradwarp MR images. In subjects, semi-automated and fully automated segmentation tools showed high agreement with manual segmentations (ICC = 0.971-0.993 for end-inspiratory scans; ICC = 0.992-0.995 for end-expiratory scans). Manual segmentation time per scan was approximately 3-4 h and 2-3 min for fully automated methods. CONCLUSIONS: Volume overestimation of MRI due to GD can be quantified. Semi-automated and fully automated segmentation methods allow accurate, reproducible, and fast lung volume quantification. Chest MRI can be a valid radiation-free imaging modality for lung segmentation and volume quantification in large cohort studies. KEY POINTS: • Geometric distortion varies according to MRI setting and patient positioning. • Automated segmentation methods allow fast and accurate lung volume quantification. • MRI is a valid radiation-free alternative to CT for quantitative data analysis.
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  • Journal Article

    Activity Correlations between Direction-Selective Retinal Ganglion Cells Synergistically Enhance Motion Decoding from Complex Visual Scenes 

    Kühn, Norma Krystyna; Gollisch, Tim
    Neuron 2019; 101(5): Art. 976.e7
    Neurons in sensory systems are often tuned to particular stimulus features. During complex naturalistic stimulation, however, multiple features may simultaneously affect neuronal responses, which complicates the readout of individual features. To investigate feature representation under complex stimulation, we studied how direction-selective ganglion cells in salamander retina respond to texture motion where direction, velocity, and spatial pattern inside the receptive field continuously change. We found that the cells preserve their direction preference under this stimulation, yet their direction encoding becomes ambiguous due to simultaneous activation by luminance changes. The ambiguities can be resolved by considering populations of direction-selective cells with different preferred directions. This gives rise to synergistic motion decoding, yielding more information from the population than the summed information from single-cell responses. Strong positive response correlations between cells with different preferred directions amplify this synergy. Our results show how correlated population activity can enhance feature extraction in complex visual scenes.
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  • Journal Article

    Precisely measured protein lifetimes in the mouse brain reveal differences across tissues and subcellular fractions. 

    Fornasiero, Eugenio F.; Mandad, Sunit; Wildhagen, Hanna; Alevra, Mihai; Rammner, Burkhard; Keihani, Sarva; Opazo, Felipe; Urban, Inga; Ischebeck, Till; Sakib, M. Sadman; et al.
    Fard, Maryam K.Kirli, KorayCenteno, Tonatiuh PenaVidal, Ramon O.Rahman, Raza-UrBenito, EvaFischer, AndréDennerlein, SvenRehling, PeterFeussner, IvoBonn, StefanSimons, MikaelUrlaub, HenningRizzoli, Silvio O.
    Nature Communications 2018; 9(1): Art. 4230
    The turnover of brain proteins is critical for organism survival, and its perturbations are linked to pathology. Nevertheless, protein lifetimes have been difficult to obtain in vivo. They are readily measured in vitro by feeding cells with isotopically labeled amino acids, followed by mass spectrometry analyses. In vivo proteins are generated from at least two sources: labeled amino acids from the diet, and non-labeled amino acids from the degradation of pre-existing proteins. This renders measurements difficult. Here we solved this problem rigorously with a workflow that combines mouse in vivo isotopic labeling, mass spectrometry, and mathematical modeling. We also established several independent approaches to test and validate the results. This enabled us to measure the accurate lifetimes of ~3500 brain proteins. The high precision of our data provided a large set of biologically significant observations, including pathway-, organelle-, organ-, or cell-specific effects, along with a comprehensive catalog of extremely long-lived proteins (ELLPs).
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  • Journal Article

    Assessment of stress responses in rhesus macaques (Macaca mulatta) to daily routine procedures in system neuroscience based on salivary cortisol concentrations 

    Pfefferle, Dana; Plümer, Sina; Burchardt, Leonore; Treue, Stefan; Gail, Alexander
    PLOS ONE 2018; 13(1): Art. e0190190
    Non-human primates participating in neurophysiological research are exposed to potentially stressful experimental procedures, such as dietary control protocols, surgical implants and their maintenance, or social separation during training and experimental session. Here, we investigated the effect of controlled access to fluid, surgical implants, implant-related cleaning of skin margins, and behavioral training sessions on salivary cortisol levels of adult male rhesus macaques participating in neurophysiological research. The animals were trained to chew flavored cotton swabs to non-invasively collect saliva samples. Our data show no differences in cortisol levels between animals with and without implants, but both, controlled access to fluid and cleaning of implants individually increased salivary cortisol concentrations, while both together did not further increase the concentration. Specifically, before cleaning, individuals with controlled access to fluid had 55% higher cortisol concentrations than individuals with free access to fluid. Under free access to fluid, cortisol concentrations were 27% higher after cleaning while no effect of cleaning was found for individuals under controlled fluid access. Training sessions under controlled access to fluid also did not affect salivary cortisol concentrations. The observed changes in cortisol concentrations represent mild stress responses, as they are only a fraction of the range of the regular circadian changes in cortisol levels in rhesus monkeys. They also indicate that combinations of procedures do not necessarily lead to cumulative stress responses. Our results indicate that salivary cortisol levels of rhesus monkeys respond to neurophysiological experimental procedures and, hence, may be used to assess further refinements of such experimental methods.
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  • Journal Article

    Correlated microtiming deviations in jazz and rock music 

    Sogorski, Mathias; Geisel, Theo; Priesemann, Viola
    PLOS ONE 2018; 13(1): Art. e0186361
    Musical rhythms performed by humans typically show temporal fluctuations. While they have been characterized in simple rhythmic tasks, it is an open question what is the nature of temporal fluctuations, when several musicians perform music jointly in all its natural complexity. To study such fluctuations in over 100 original jazz and rock/pop recordings played with and without metronome we developed a semi-automated workflow allowing the extraction of cymbal beat onsets with millisecond precision. Analyzing the inter-beat interval (IBI) time series revealed evidence for two long-range correlated processes characterized by power laws in the IBI power spectral densities. One process dominates on short timescales (t < 8 beats) and reflects microtiming variability in the generation of single beats. The other dominates on longer timescales and reflects slow tempo variations. Whereas the latter did not show differences between musical genres (jazz vs. rock/pop), the process on short timescales showed higher variability for jazz recordings, indicating that jazz makes stronger use of microtiming fluctuations within a measure than rock/pop. Our results elucidate principles of rhythmic performance and can inspire algorithms for artificial music generation. By studying microtiming fluctuations in original music recordings, we bridge the gap between minimalistic tapping paradigms and expressive rhythmic performances.
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  • Journal Article

    Model-free inference of direct network interactions from nonlinear collective dynamics. 

    Casadiego, Jose; Nitzan, Mor; Hallerberg, Sarah; Timme, Marc
    Nature Communications 2017; 8(1): Art. 2192
    The topology of interactions in network dynamical systems fundamentally underlies their function. Accelerating technological progress creates massively available data about collective nonlinear dynamics in physical, biological, and technological systems. Detecting direct interaction patterns from those dynamics still constitutes a major open problem. In particular, current nonlinear dynamics approaches mostly require to know a priori a model of the (often high dimensional) system dynamics. Here we develop a model-independent framework for inferring direct interactions solely from recording the nonlinear collective dynamics generated. Introducing an explicit dependency matrix in combination with a block-orthogonal regression algorithm, the approach works reliably across many dynamical regimes, including transient dynamics toward steady states, periodic and non-periodic dynamics, and chaos. Together with its capabilities to reveal network (two point) as well as hypernetwork (e.g., three point) interactions, this framework may thus open up nonlinear dynamics options of inferring direct interaction patterns across systems where no model is known.
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  • Journal Article

    Neural and Response Correlations to Complex Natural Sounds in the Auditory Midbrain. 

    Lyzwa, Dominika; Wörgötter, Florentin
    Frontiers in neural circuits 2016; 10: Art. 89
    How natural communication sounds are spatially represented across the inferior colliculus, the main center of convergence for auditory information in the midbrain, is not known. The neural representation of the acoustic stimuli results from the interplay of locally differing input and the organization of spectral and temporal neural preferences that change gradually across the nucleus. This raises the question of how similar the neural representation of the communication sounds is across these gradients of neural preferences, and whether it also changes gradually. Analyzed neural recordings were multi-unit cluster spike trains from guinea pigs presented with a spectrotemporally rich set of eleven species-specific communication sounds. Using cross-correlation, we analyzed the response similarity of spiking activity across a broad frequency range for neurons of similar and different frequency tuning. Furthermore, we separated the contribution of the stimulus to the correlations to investigate whether similarity is only attributable to the stimulus, or, whether interactions exist between the multi-unit clusters that lead to neural correlations and whether these follow the same representation as the response correlations. We found that similarity of responses is dependent on the neurons' spatial distance for similarly and differently frequency-tuned neurons, and that similarity decreases gradually with spatial distance. Significant neural correlations exist, and contribute to the total response similarity. Our findings suggest that for multi-unit clusters in the mammalian inferior colliculus, the gradual response similarity with spatial distance to natural complex sounds is shaped by neural interactions and the gradual organization of neural preferences.
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  • Journal Article

    A Neurocomputational Model of Goal-Directed Navigation in Insect-Inspired Artificial Agents. 

    Goldschmidt, Dennis; Manoonpong, Poramate; Dasgupta, Sakyasingha
    Frontiers in neurorobotics 2017; 11: Art. 20
    Despite their small size, insect brains are able to produce robust and efficient navigation in complex environments. Specifically in social insects, such as ants and bees, these navigational capabilities are guided by orientation directing vectors generated by a process called path integration. During this process, they integrate compass and odometric cues to estimate their current location as a vector, called the home vector for guiding them back home on a straight path. They further acquire and retrieve path integration-based vector memories globally to the nest or based on visual landmarks. Although existing computational models reproduced similar behaviors, a neurocomputational model of vector navigation including the acquisition of vector representations has not been described before. Here we present a model of neural mechanisms in a modular closed-loop control-enabling vector navigation in artificial agents. The model consists of a path integration mechanism, reward-modulated global learning, random search, and action selection. The path integration mechanism integrates compass and odometric cues to compute a vectorial representation of the agent's current location as neural activity patterns in circular arrays. A reward-modulated learning rule enables the acquisition of vector memories by associating the local food reward with the path integration state. A motor output is computed based on the combination of vector memories and random exploration. In simulation, we show that the neural mechanisms enable robust homing and localization, even in the presence of external sensory noise. The proposed learning rules lead to goal-directed navigation and route formation performed under realistic conditions. Consequently, we provide a novel approach for vector learning and navigation in a simulated, situated agent linking behavioral observations to their possible underlying neural substrates.
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  • Journal Article

    Differential Effects of HCN Channel Block on On and Off Pathways in the Retina as a Potential Cause for Medication-Induced Phosphene Perception. 

    Bemme, Sebastian; Weick, Michael; Gollisch, Tim
    Investigative ophthalmology & visual science 2017-09-01; 58(11) p.4754-4767
    Purpose: Phosphene perception is a characteristic side effect of heart rate-reducing medication that acts on hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels. It is hypothesized that these phosphenes are caused by blocking HCN channels in photoreceptors and neurons of the retina, yet the underlying changes in visual signal processing in the retina caused by the HCN channel block are still unknown. Methods: We examined the effects of pharmacologic HCN channel block on the encoding of visual signals in retinal ganglion cells by recording ganglion cell spiking activity from isolated mouse retinas mounted on multielectrode arrays. Spontaneous activity and responses to various visual stimuli were measured before, during, and after administration of 3 μM ivabradine. Results: Retinal ganglion cells generally showed slower response kinetics and reduced sensitivity to high temporal frequencies under ivabradine. Moreover, ivabradine differentially affected the sensitivity of On and Off ganglion cells. On cells showed reduced response gain, whereas Off cells experienced an increase in response threshold. In line with these differential effects, Off cells, in contrast to On cells, also showed reduced baseline activity during visual stimulation and reduced spontaneous activity. Furthermore, Off cells, but not On cells, showed increased burst-like spiking activity in the presence of ivabradine. Conclusions: Our data suggest that pharmacologic HCN channel block in the retina leads to a shift in the relative activity of the On and Off pathways of the retina. We hypothesize that this imbalance may underlie the medication-induced perception of phosphenes.
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  • Journal Article

    Environmental enrichment accelerates ocular dominance plasticity in mouse visual cortex whereas transfer to standard cages resulted in a rapid loss of increased plasticity. 

    Kalogeraki, Evgenia; Pielecka-Fortuna, Justyna; Löwel, Siegrid
    PloS one 2017; 12(10): Art. e0186999
    In standard cage (SC) raised mice, experience-dependent ocular dominance (OD) plasticity in the primary visual cortex (V1) rapidly declines with age: in postnatal day 25-35 (critical period) mice, 4 days of monocular deprivation (MD) are sufficient to induce OD-shifts towards the open eye; thereafter, 7 days of MD are needed. Beyond postnatal day 110, even 14 days of MD failed to induce OD-plasticity in mouse V1. In contrast, mice raised in a so-called "enriched environment" (EE), exhibit lifelong OD-plasticity. EE-mice have more voluntary physical exercise (running wheels), and experience more social interactions (bigger housing groups) and more cognitive stimulation (regularly changed labyrinths or toys). Whether experience-dependent shifts of V1-activation happen faster in EE-mice and how long the plasticity promoting effect would persist after transferring EE-mice back to SCs has not yet been investigated. To this end, we used intrinsic signal optical imaging to visualize V1-activation i) before and after MD in EE-mice of different age groups (from 1-9 months), and ii) after transferring mice back to SCs after postnatal day 130. Already after 2 days of MD, and thus much faster than in SC-mice, EE-mice of all tested age groups displayed a significant OD-shift towards the open eye. Transfer of EE-mice to SCs immediately abolished OD-plasticity: already after 1 week of SC-housing and MD, OD-shifts could no longer be visualized. In an attempt to rescue abolished OD-plasticity of these mice, we either administered the anti-depressant fluoxetine (in drinking water) or supplied a running wheel in the SCs. OD-plasticity was only rescued for the running wheel- mice. Altogether our results show that raising mice in less deprived environments like large EE-cages strongly accelerates experience-dependent changes in V1-activation compared to the impoverished SC-raising. Furthermore, preventing voluntary physical exercise of EE-mice in adulthood immediately precludes OD-shifts in V1.
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