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    • 2019
    • PLoS ONE
    • 1
    • Human scalp evoked potentials related to the fusion between a sound source and its simulated reflection
    • <p>The auditory system needs to fuse the direct wave (lead) from a sound source and its time-delayed reflections (lag) to achieve a single sound image perception. This lead-lag fusion plays crucial roles in auditory processing in reverberant environments. Here, we investigated neural correlates of the lead-lag fusion by tracking human cortical potentials evoked by a break in the correlation (BIC) between the lead and lag when the time delay between the two was 0, 2, or 4 ms. The BIC evoked a scalp potential consisting of an N1 and a P2 component. Both components were modulated by the delay. The effects of the delay on the amplitude of the two components were similar, an increase of the delay resulting in a decrease of the amplitude. In contrast, the delay differently modulated the latency of the two components, an increase of the delay resulting in an increase of the P2 latency but not an increase of the N1 latency. Similar to the P2 latency, the reaction time for subjective detection of the BIC also increased with the delay. These findings suggest that both the N1 and the P2 evoked by the BIC are neural correlates of the lead-lag fusion and that, relative to the N1, the P2 may be more closely related to listeners' perception of the fusion. Our study thus provides a neurophysiological and objective approach for investigating the fusion between the direct sound wave from a sound source and its reflections.</p>
    • http://www.scopus.com/inward/record.url?scp=85059796477&partnerID=8YFLogxK
    • 2019
    • Current Opinion in Neurobiology
    • 146-154
    • Connectomics and function of a memory network
    • <p>The Drosophila larva is a relatively simple, 10 000-neuron study case for learning and memory with enticing analytical power, combining genetic tractability, the availability of robust behavioral assays, the opportunity for single-cell transgenic manipulation, and an emerging synaptic connectome of its complete central nervous system. Indeed, although the insect mushroom body is a much-studied memory network, the connectome revealed that more than half of the classes of connection within the mushroom body had escaped attention. The connectome also revealed circuitry that integrates, both within and across brain hemispheres, higher-order sensory input, intersecting valence signals, and output neurons that instruct behavior. Further, it was found that activating individual dopaminergic mushroom body input neurons can have a rewarding or a punishing effect on olfactory stimuli associated with it, depending on the relative timing of this activation, and that larvae form molecularly dissociable short-term, long-term, and amnesia-resistant memories. Together, the larval mushroom body is a suitable study case to achieve a nuanced account of molecular function in a behaviorally meaningful memory network.</p>
    • http://www.scopus.com/inward/record.url?scp=85055260920&partnerID=8YFLogxK
    • 2019
    • Biology Letters
    • 7
    • An optogenetic analogue of second-order reinforcement in Drosophila
    • <p>In insects, odours are coded by the combinatorial activation of ascending pathways, including their third-order representation in mushroom body Kenyon cells. Kenyon cells also receive intersecting input from ascending and mostly dopaminergic reinforcement pathways. Indeed, in Drosophila, presenting an odour together with activation of the dopaminergic mushroom body input neuron PPL1-01 leads to a weakening of the synapse between Kenyon cells and the approach-promoting mushroom body output neuron MBON-11. As a result of such weakened approach tendencies, flies avoid the shock-predicting odour in a subsequent choice test. Thus, increased activity in PPL1-01 stands for punishment, whereas reduced activity in MBON-11 stands for predicted punishment. Given that punishment-predictors can themselves serve as punishments of second order, we tested whether presenting an odour together with the optogenetic silencing of MBON-11 would lead to learned odour avoidance, and found this to be the case. In turn, the optogenetic activation of MBON-11 together with odour presentation led to learned odour approach. Thus, manipulating activity in MBON-11 can be an analogue of predicted, second-order reinforcement.</p>
    • http://www.scopus.com/inward/record.url?scp=85069261878&partnerID=8YFLogxK
    • 2019
    • Journal of Ethnopharmacology
    • 320-328
    • Rhodiola rosea root extract has antipsychotic-like effects in rodent models of sensorimotor gating
    • <p>Ethnopharmacological relevance: The plant arctic root (Rhodiola rosea, L.) is growing in northern regions of Europe, Asia and North America. Extracts of R. rosea are used in traditional medicine for various conditions related to nervous system function. According to scientific studies from the last decades, the plant might have potential for use in the treatment of memory impairments, stress and depression, but reports concerning other neuropsychiatric disorders are scarce. Aim of the study: In this context, our study aimed to examine potential antipsychotic-like effects of R. rosea root extract. Materials and methods: We tested the effects of R. rosea root extract on prepulse inhibition in rats and mice. Prepulse inhibition is an established operational measure of sensorimotor gating, which is impaired in schizophrenia and other psychotic disorders. Results: R. rosea root extract increased prepulse inhibition in rats and mice. Interestingly, the R. rosea extract had stronger effects in those individual animals that had low baseline levels of prepulse inhibition. Therefore, we performed further experiments in which we pharmacologically induced a prepulse inhibition deficit by two different psychostimulants, either the dopamine D2 receptor agonist apomorphine or the NMDA receptor antagonist dizocilpine (MK-801). Pre-treatment with the R. rosea extract significantly restored both, apomorphine- and dizocilpine-induced prepulse inhibition deficits. Conclusions: The present study demonstrates that R. rosea extract robustly reverses prepulse inhibition deficits in rodents. This suggests antipsychotic-like effects of R. rosea extract. Future studies should focus on the pharmacological mechanisms underlying these effects.</p>
    • http://www.scopus.com/inward/record.url?scp=85061712060&partnerID=8YFLogxK
    • 2019
    • PLoS ONE
    • 1
    • A neural hallmark of auditory implicit learning is altered in older adults
    • <p>Temporal regularities in the environment are often learned implicitly. In an auditory target-detection paradigm using EEG, Jongsma and colleagues (2006) showed that the neural response to these implicit regularities results in a reduction of the P3-N2 complex. Here, we utilized the same paradigm, this time in both young and old participants, to determine if this EEG signature of implicit learning was altered with age. Behaviorally, both groups of participants showed similar benefits for the presence of temporal regularity, with faster and more accurate responses given when the auditory targets were presented in a temporally regular vs. random pattern. In the brain, the younger adults showed the expected decrease in amplitude of this complex for regular compared to irregular trials. Older adults, in contrast, showed no difference in the amplitude of the P3-N2 complex between the irregular and regular condition. These data suggest that, although auditory implicit learning may be behaviorally spared in aging, older adults are not using the same neural substrates as younger adults to achieve this.</p>
    • http://www.scopus.com/inward/record.url?scp=85060789636&partnerID=8YFLogxK
    • 2019
    • eLife
    • Associations between sounds and actions in early auditory cortex of nonhuman primates
    • <p>An individual may need to take different actions to the same stimulus in different situations to achieve a given goal. The selection of the appropriate action hinges on the previously learned associations between stimuli, actions, and outcomes in the situations. Here, using a go/no-go paradigm and a symmetrical reward, we show that early auditory cortex of nonhuman primates represents such associations, in both the spiking activity and the local field potentials. Sound-evoked neuronal responses changed with sensorimotor associations shortly after sound onset, and the neuronal responses were largest when the sound signaled that a no-go response was required in a trial to obtain a reward. Our findings suggest that association processes take place in the auditory system and do not necessarily rely on association cortex. Thus, auditory cortex may contribute to a rapid selection of the appropriate motor responses to sounds during goal-directed behavior.</p>
    • 2019
    • Journal of Experimental Biology
    • Pt 7
    • Softness sensing and learning in Drosophila larvae
    • <p>Mechanosensation provides animals with important sensory information in addition to olfaction and gustation during feeding behavior. Here, we used Drosophila melanogaster larvae to investigate the role of softness sensing in behavior and learning. In the natural environment, larvae need to dig into soft foods for feeding. Finding foods that are soft enough to dig into is likely to be essential for their survival. We report that larvae can discriminate between different agar concentrations and prefer softer agar. Interestingly, we show that larvae on a harder surface search for a softer surface using memory associated with an odor, and that they evaluate foods by balancing softness and sweetness. These findings suggest that larvae integrate mechanosensory information with chemosensory input while foraging. Moreover, we found that the larval preference for softness is affected by genetic background. </p>
    • http://www.scopus.com/inward/record.url?scp=85064194422&partnerID=8YFLogxK
    • André Brechmann, Norman Peitek
    • 2019
    • 126-129
    • CodersMUSE: Multi-Modal Data Exploration of Program-Comprehension Experiments
    • André Brechmann, Frank Ohl
    • 2019
    • 2583-2588
    • Intention-Based Anticipatory Interactive Systems
    • <p>Intention-based, anticipatory, interactive systems (IAIS) represent a new class of user-centered assistance systems. IAIS uses actions and system intentions derived from signal data, and the affective state of the user. By anticipating the further action of the user, solutions are interactively negotiated. The active roles of humans and systems change strategically, which requires behavioral models, which in turn can be specified by life sciences' results. Deployed human-machine-systems and lab tests have the goal of understanding of the situated interaction. This supports integration of assistance systems for Industry 4.0 and in the context of demographic change. We provide a definition of IAIS, discuss the underlying requirements, goals and challenges and provide a brief review of the state-of-the-art in the involved research areas.</p>
    • http://www.scopus.com/inward/record.url?scp=85062215732&partnerID=8YFLogxK
    • André Brechmann, Norman Peitek
    • 2019
    • Communications of the ACM
    • Studying Programming in the Neuroage: Just a Crazy Idea?
    • Alessandro-Dario Confettura
    • 2019
    • Frontiers in Aging Neuroscience
    • Traditional Japanese Herbal Medicine Yokukansan Targets Distinct but Overlapping Mechanisms in Aged Mice and in the 5xFAD Mouse Model of Alzheimer's Disease
    • <p>Yokukansan (YKS) is a traditional Japanese herbal medicine that has been used in humans for the treatment of several neurological conditions, such as age-related anxiety and behavioral and psychological symptoms (BPSD) related to multiple forms of dementia, including Alzheimer's disease (AD). However, the cellular and molecular mechanisms targeted by YKS in the brain are not completely understood. Here, we compared the efficacy of YKS in ameliorating the age- and early-onset familial AD-related behavioral and cellular defects in two groups of animals: 18- to 22-month-old C57BL6/J wild-type mice and 6- to 9-month-old 5xFAD mice, as a transgenic mouse model of this form of AD. Animals were fed food pellets that contained YKS or vehicle. After 1-2 months of YKS treatment, we evaluated the cognitive improvements in both the aged and 5xFAD transgenic mice, and their brain tissues were further investigated to assess the molecular and cellular changes that occurred following YKS intake. Our results show that both the aged and 5xFAD mice exhibited impaired behavioral performance in novel object recognition and contextual fear conditioning (CFC) tasks, which was significantly improved by YKS. Further analyses of the brain tissue from these animals indicated that in aged mice, this improvement was associated with a reduction in astrogliosis, microglia activation and downregulation of the extracellular matrix (ECM), whereas in 5xFAD mice, none of these mechanisms were evident. These results show the differential action of YKS in healthy aged and 5xFAD mice. However, both aged and 5xFAD YKS-treated mice showed increased neuroprotective signaling through protein kinase B/Akt as the common mode of action. Our data suggest that YKS may impart its beneficial effects through Akt signaling in both 5xFAD mice and aged mice, with multiple additional mechanisms potentially contributing to its beneficial effects in aged animals.</p>
    • Camilla Fusi
    • 2019
    • Frontiers in Molecular Neuroscience
    • Caldendrin and Calneurons-EF-Hand CaM-Like Calcium Sensors With Unique Features and Specialized Neuronal Functions
    • <p>The calmodulin (CaM)-like Ca2+-sensor proteins caldendrin, calneuron-1 and -2 are members of the neuronal calcium-binding protein (nCaBP)-family, a family that evolved relatively late during vertebrate evolution. All three proteins are abundant in brain but show a strikingly different subcellular localization. Whereas caldendrin is enriched in the postsynaptic density (PSD), calneuron-1 and -2 accumulate at the trans-Golgi-network (TGN). Caldendrin exhibit a unique bipartite structure with a basic and proline-rich N-terminus while calneurons are the only EF-Hand CaM-like transmembrane proteins. These uncommon structural features come along with highly specialized functions of calneurons in Golgi-to-plasma-membrane trafficking and for caldendrin in actin-remodeling in dendritic spine synapses. In this review article, we will provide a synthesis of available data on the structure and biophysical properties of all three proteins. We will then discuss their cellular function with special emphasis on synaptic neurotransmission. Finally, we will summarize the evidence for a role of these proteins in neuropsychiatric disorders.</p>
    • http://www.scopus.com/inward/record.url?scp=85064213862&partnerID=8YFLogxK
    • Reinhard König, Aida Hajizadeh, Artur Matysiak
    • 2019
    • Biological Cybernetics
    • 3
    • 321-345
    • Explaining event-related fields by a mechanistic model encapsulating the anatomical structure of auditory cortex
    • <p>Event-related fields of the magnetoencephalogram are triggered by sensory stimuli and appear as a series of waves extending hundreds of milliseconds after stimulus onset. They reflect the processing of the stimulus in cortex and have a highly subject-specific morphology. However, we still have an incomplete picture of how event-related fields are generated, what the various waves signify, and why they are so subject-specific. Here, we focus on this problem through the lens of a computational model which describes auditory cortex in terms of interconnected cortical columns as part of hierarchically placed fields of the core, belt, and parabelt areas. We develop an analytical approach arriving at solutions to the system dynamics in terms of normal modes: damped harmonic oscillators emerging out of the coupled excitation and inhibition in the system. Each normal mode is a global feature which depends on the anatomical structure of the entire auditory cortex. Further, normal modes are fundamental dynamical building blocks, in that the activity of each cortical column represents a combination of all normal modes. This approach allows us to replicate a typical auditory event-related response as a weighted sum of the single-column activities. Our work offers an alternative to the view that the event-related field arises out of spatially discrete, local generators. Rather, there is only a single generator process distributed over the entire network of the auditory cortex. We present predictions for testing to what degree subject-specificity is due to cross-subject variations in dynamical parameters rather than in the cortical surface morphology.</p>
    • http://www.scopus.com/inward/record.url?scp=85062629758&partnerID=8YFLogxK
    • Liv Mahnke
    • 2019
    • Frontiers in Neuroscience
    • MAY
    • Electrical Stimulation of the Lateral Entorhinal Cortex Causes a Frequency-Specific BOLD Response Pattern in the Rat Brain
    • <p>Although deep brain stimulation of the entorhinal cortex has recently shown promise in the treatment of early forms of cognitive decline, the underlying neurophysiological processes remain elusive. Therefore, the lateral entorhinal cortex (LEC) was stimulated with trains of continuous 5 Hz and 20 Hz pulses or with bursts of 100 Hz pulses to visualize activated neuronal networks, i.e., neuronal responses in the dentate gyrus and BOLD responses in the entire brain were simultaneously recorded. Electrical stimulation of the LEC caused a wide spread pattern of BOLD responses. Dependent on the stimulation frequency, BOLD responses were only triggered in the amygdala, infralimbic, prelimbic, and dorsal peduncular cortex (5 Hz), or in the nucleus accumbens, piriform cortex, dorsal medial prefrontal cortex, hippocampus (20 Hz), and contralateral entorhinal cortex (100 Hz). In general, LEC stimulation caused stronger BOLD responses in frontal cortex regions than in the hippocampus. Identical stimulation of the perforant pathway, a fiber bundle projecting from the entorhinal cortex to the dentate gyrus, hippocampus proper, and subiculum, mainly elicited significant BOLD responses in the hippocampus but rarely in frontal cortex regions. Consequently, BOLD responses in frontal cortex regions are mediated by direct projections from the LEC rather than via signal propagation through the hippocampus. Thus, the beneficial effects of deep brain stimulation of the entorhinal cortex on cognitive skills might depend more on an altered prefrontal cortex than hippocampal function.</p>
    • http://www.scopus.com/inward/record.url?scp=85068535834&partnerID=8YFLogxK
    • Norman Peitek
    • 2019
    • 154-164
    • Indentation: Simply a Matter of Style or Support for Program Comprehension?
    • Adam Peterson
    • 2019
    • Journal of Neuroscience
    • 21
    • 4077-4099
    • Phase Locking of Auditory-Nerve Fibers Reveals Stereotyped Distortions and an Exponential Transfer Function with a Level-Dependent Slope
    • <p>Phase locking of auditory-nerve-fiber (ANF) responses to the fine structure of acoustic stimuli is a hallmark of the auditory system's temporal precision and is important for many aspects of hearing. Period histograms from phase-locked ANF responses to low-frequency tones exhibit spike-rate and temporal asymmetries, but otherwise retain an approximately sinusoidal shape as stimulus level increases, even beyond the level at which the mean spike rate saturates. This is intriguing because apical cochlear mechanical vibrations show little compression, and mechanoelectrical transduction in the receptor cells is thought to obey a static sigmoidal nonlinearity, which might be expected to produce peak clipping at moderate and high stimulus levels. Here we analyze phase-locked responses of ANFs from cats of both sexes. We show that the lack of peak clipping is due neither to ANF refractoriness nor to spike-rate adaptation on time scales longer than the stimulus period. We demonstrate that the relationship between instantaneous pressure and instantaneous rate is well described by an exponential function whose slope decreases with increasing stimulus level. Relatively stereotyped harmonic distortions in the input to the exponential can account for the temporal asymmetry of the period histograms, including peak splitting. We show that the model accounts for published membrane-potential waveforms when assuming a power-of-three, but not a power-of-one, relationship to exocytosis. Finally, we demonstrate the relationship between the exponential transfer functions and the sigmoidal pseudotransducer functions obtained in the literature by plotting the maxima and minima of the voltage responses against the maxima and minima of the stimuli.SIGNIFICANCE STATEMENT Phase locking of auditory-nerve-fiber responses to the temporal fine structure of acoustic stimuli is important for many aspects of hearing, but the mechanisms underlying phase locking are not fully understood. Intriguingly, period histograms retain an approximately sinusoidal shape across sound levels, even when the mean rate has saturated. We find that neither refractoriness nor spike-rate adaptation is responsible for this behavior. Instead, the peripheral auditory system operates as though it contains an exponential transfer function whose slope changes with stimulus level. The underlying mechanism is distinct from the comparatively weak cochlear mechanical compression in the cochlear apex, and likely resides in the receptor cells.</p>
    • Magdalena Sauvage
    • 2019
    • Journal of Behavior Therapy and Experimental Psychiatry
    • Visuospatial computer game play after memory reminder delivered three days after a traumatic film reduces the number of intrusive memories of the experimental trauma
    • <p>Objective: The experience of intrusive memories is a core clinical symptom of posttraumatic stress disorder (PTSD), and can be distressing in its own right. Notions of dual task interference and reconsolidation-update mechanisms suggest novel approaches to target intrusive memories. This study tested the hypothesis that a single-session cognitive intervention (memory reminder task plus Tetris gameplay)would reduce the occurrence of experimental trauma memories even when delivered 3 days post-trauma. Critically, this study tested effects against two control groups: Reminder-only, and reminder plus another computer game (a form of Quiz). Methods: 86 healthy volunteers (59% female, age M = 24.35, SD = 4.59 years)watched a trauma film and then recorded their intrusive memories in a diary for 3 days (pre-intervention). They then returned to the lab. After presentation of visual reminder cues for the film plus a 10 min wait period (memory reminder task), participants were randomized into one of three task conditions (Tetris game play, Quiz game play, vs. reminder-only). They then kept the diary for a further 3 days (post-intervention). Results: As predicted, after the experimental manipulation, the reminder + Tetris group experienced significantly fewer intrusions than the reminder-only group (d = 1.37). Further, the reminder + Tetris group also experienced significantly fewer intrusions than the reminder + Quiz (d = 0.65)group. Contrary to predictions, the reminder + Quiz group experienced significantly fewer intrusions than the reminder-only group (d = 0.69). Prior to the experimental manipulation, there was no significant difference between groups in number of intrusions. Recognition memory test scores for facts of the trauma film after 6 days were comparable between groups. Conclusions: We demonstrated that 3 days after experimental trauma (i.e. after memory consolidation)an intervention comprising a reminder task prior to a 15 min cognitive interference task (one of two computer games)led to a reduction in intrusion occurrence compared to reminder only. We interpret and discuss our findings within the framework of supposed reconsolidation-update mechanisms and competition for limited (visuospatial)working memory resources. Should these effects hold true in clinical populations, this type of simple intervention approach could help contribute to reducing intrusive memories of trauma.</p>
    • http://www.scopus.com/inward/record.url?scp=85064615397&partnerID=8YFLogxK
    • Magdalena Sauvage
    • 2019
    • Journal of Neuroscience Methods
    • 108368
    • Single-cell memory trace imaging with immediate-early genes
    • <p>For the past decades, an increasing number of studies has taken advantage of molecular imaging methods involving the detection of immediate-early genes' (IEGs) expression for investigating neural substrates underlying plasticity processes and memory function. The detection of IEGs RNA by Fluorescent In-Situ Hybridization (FISH) yields single-cell as well as high temporal resolution and has recently enabled the mapping of medial temporal lobe subareas/subnetworks activity induced by single or multiple behavioural events in the same animal. After briefly reviewing the function and the ties of the typical IEGs (Fos, Zif268, Arc, Homer1a) used for mapping plasticity, we focus on discussing technical considerations vital for the successful detection of IEGs with FISH with emphasis on the design of RNA probes, the optimization of experimental conditions and the necessity for controls. Finally, we discuss recent developments in brain clearing methods that in combination with FISH detection of IEGs' expression allow for 3D imaging with single cell resolution as well as whole brain analyses. This, in parallel with the recent development of fMRI cognitive tasks in awake rats and the use of high resolution fMRI in humans, holds great promises for bridging further memory in humans and animals.</p>
    • Constanze Seidenbecher
    • 2019
    • Journal of Neurochemistry
    • The energetic brain - A review from students to students
    • <p>The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia-neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the central nervous system (CNS). We cover neuronal energy consumption in neural transmission and basic ('housekeeping') cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies and medium chain fatty acids. We discuss the multifaceted role of non-neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS. This article is protected by copyright. All rights reserved.</p>
    • Alice Weiglein
    • 2019
    • Learning and Memory
    • 4
    • 109-120
    • One-trial learning in larval Drosophila
    • <p>Animals of many species are capable of "small data" learning, that is, of learning without repetition. Here we introduce larval Drosophila melanogaster as a relatively simple study case for such one-trial learning. Using odor-food associative conditioning, we first show that a sugar that is both sweet and nutritious (fructose) and sugars that are only sweet (arabinose) or only nutritious (sorbitol) all support appetitive one-trial learning. The same is the case for the optogenetic activation of a subset of dopaminergic neurons innervating the mushroom body, the memory center of the insects. In contrast, no one-trial learning is observed for an amino acid reward (aspartic acid). As regards the aversive domain, one-trial learning is demonstrated for high-concentration sodium chloride, but is not observed for a bitter tastant (quinine). Second, we provide follow-up, parametric analyses of odor-fructose learning. Specifically, we ascertain its dependency on the number and duration of training trials, the requirements for the behavioral expression of one-trial odor-fructose memory, its temporal stability, and the feasibility of one-trial differential conditioning. Our results set the stage for a neurogenetic analysis of one-trial learning and define the requirements for modeling mnemonic processes in the larva.</p>
    • http://www.scopus.com/inward/record.url?scp=85063625323&partnerID=8YFLogxK
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