Selective Interruption of Auditory Interhemispheric Cross Talk Impairs Discrimination Learning of Frequency-Modulated Tone Direction But Not Gap Detection and Discrimination.

Functional hemispheric lateralization is a basic principle of brain organization. In the auditory domain, the right auditory cortex (AC) determines the pitch direction of continuous auditory stimuli whereas the left AC discriminates gaps in these stimuli. The involved functional interactions between the two sides, mediated by commissural connections, are poorly understood. Here, we selectively disrupted the interhemispheric cross talk from the left to the right primary AC and vice versa using chromophore-targeted laser-induced apoptosis of the respective projection neurons, which make up 6-17% of all AC neurons in Layers III, V, and VI. Following photolysis, male gerbils were trained in a first experimental set to discriminate between rising and falling frequency-modulated (FM) tone sweeps. The acquisition of the task was significantly delayed in lesioned animals of either lesion direction. However, the final discrimination performance and hit rate was lowest for animals with left-side lesioned commissural neurons, demonstrating that also information from the left AC is relevant for FM direction learning. Photolysis after successful learning did not affect the retrieval of the learned task, indicating that the disruption during learning was not because of a general functional impairment. In a second experimental set, the gerbil's ability to detect and discriminate small silent gaps of varying length within FM sweeps was tested. This ability was also preserved after interhemispheric disruption. Taken together, interhemispheric communication between the left and right AC is important for the acquisition of FM tone direction learning but not for its retrieval and for gap detection and gap duration discrimination.SIGNIFICANCE STATEMENT Hemispheric lateralization of neuronal functions such as speech and music processing in humans are common throughout the brain; however, the involved interhemispheric interactions are ill-defined. Here, we show that the selective photolytic disruption of auditory cortical commissural connections in rodents impairs the acquisition but not retrieval of a frequency-modulated tone direction discrimination task. The final discrimination performance and hit rate was lowest for animals with lesioned left-to-right-side projections; thus, although right auditory cortex is dominant, left auditory cortex is also relevant for learning this task. The detection and discrimination of small gaps within the tone sweeps remain intact, suggesting a pathway for the processing of these temporal structures, which could be independent from the lesioned interhemispheric cross talk.

Ketamine anaesthesia induces gain enhancement via recurrent excitation in granular input layers of the auditory cortex.

KEY POINTS: Ketamine is a common anaesthetic agent used in research and more recently as medication in treatment of depression. It has known effects on inhibition of interneurons and cortical stimulus-locked responses, but the underlying functional network mechanisms are still elusive. Analysing population activity across all layers within the auditory cortex, we found that doses of this anaesthetic induce a stronger activation and stimulus-locked response to pure-tone stimuli. This cortical response is driven by gain enhancement of thalamocortical input processing selectively within granular layers due to an increased recurrent excitation. Time-frequency analysis indicates a higher broadband magnitude response and prolonged phase coherence in granular layers, possibly pointing to disinhibition of this recurrent excitation. These results further the understanding of ketamine's functional mechanisms, which will improve the ability to interpret physiological studies moving from anaesthetized to awake paradigms and may lead to the development of better ketamine-based depression treatments with lower side effects. ABSTRACT: Ketamine is commonly used as an anaesthetic agent and has more recently gained attention as an antidepressant. It has been linked to increased stimulus-locked excitability, inhibition of interneurons and modulation of intrinsic neuronal oscillations. However, the functional network mechanisms are still elusive. A better understanding of these anaesthetic network effects may improve upon previous interpretations of seminal studies conducted under anaesthesia and have widespread relevance for neuroscience with awake and anaesthetized subjects as well as in medicine. Here, we investigated the effects of anaesthetic doses of ketamine (15 mg kg-1  h-1 i.p.) on the network activity after pure-tone stimulation within the auditory cortex of male Mongolian gerbils (Meriones unguiculatus). We used laminar current source density (CSD) analysis and subsequent layer-specific continuous wavelet analysis to investigate spatiotemporal response dynamics on cortical columnar processing in awake and ketamine-anaesthetized animals. We found thalamocortical input processing within granular layers III/IV to be significantly increased under ketamine. This layer-dependent gain enhancement under ketamine was not due to changes in cross-trial phase coherence but was rather attributed to a broadband increase in magnitude reflecting an increase in recurrent excitation. A time-frequency analysis was indicative of a prolonged period of stimulus-induced excitation possibly due to a reduced coupling of excitation and inhibition in granular input circuits - in line with the common hypothesis of cortical disinhibition via suppression of GABAergic interneurons.

Dopaminergic neuromodulation of high gamma stimulus phase-locking in gerbil primary auditory cortex mediated by D1/D5-receptors.

Cortical release of the neurotransmitter dopamine has been implied in adapting cortical processing with respect to various functions including coding of stimulus salience, expectancy, error prediction, behavioral relevance and learning. Dopamine agonists have been shown to modulate recurrent cortico-thalamic feedback, and should therefore also affect synchronization and amplitude of thalamo-cortical oscillations. In this study, we have used multitaper spectral and time-frequency analysis of stimulus-evoked and spontaneous current source density patterns in primary auditory cortex of Mongolian gerbils to characterize dopaminergic neuromodulation of the oscillatory structure of current sources and sinks. We systemically applied D1/D5-receptor agonist SKF-38393 followed by competitive D1/D5-receptor antagonist SCH-23390. Our results reveal an increase in stimulus phase-locking in the high gamma-band (88-97 Hz) by SKF-38393, specifically in layers III/IV at the best frequency, which occurred at 20 ms after tone onset, and was reversed by SCH-23390. However, changes in induced oscillatory power after SKF-38393 treatment occurred stimulus-independently in the background activity in different layers than phase-locking effects and were not reversed by SCH-23390. These effects might either reflect longer-lasting changes in neural background noise, non-specific changes due to ketamine anesthesia, or an interaction of both. Without concomitant stimulus-induced power increase, increased stimulus phase-locking in layers III/IV indicates enhanced phase-resetting of neural oscillations by the stimulus after D1/D5-receptor activation. The frequency characteristics, together with the demonstrated stimulus specificity and layer specificity, suggest that changes in phase-resetting originate from dopaminergic neuromodulation of thalamo-cortical interactions. Enhanced phase-resetting might be a key step in the recruitment of cortical activity modes interpreting sensory input.

Ultrastructure of giant thalamic terminals in the auditory cortex.

The auditory system comprises some very large axonal terminals like the endbulb and calyx of Held and "giant" corticothalamic synapses. Previously, we described a hitherto unknown population of giant thalamocortical boutons arising from the medial division of the medial geniculate body (MGm) in the Mongolian gerbil, which terminate over a wide cortical range but in a columnar manner particularly in the extragranular layers of the auditory cortex. As a first step towards an understanding of their potential functional role, we here describe their ultrastructure combining anterograde tract-tracing with biocytin and electron microscopy. Quantitative ultrastructural analyses revealed that biocytin-labelled MGm boutons reach much larger sizes than other, non-labelled boutons. Also, mitochondria occupy more space within labelled boutons whereas synapses are of similar size. Labelled boutons are very heterogeneous in size but homogeneous with respect to their ultrastructural characteristics, with asymmetric synapses containing clear, round vesicles and targeting dendritic spines. Functionally, the ultrastructure of the MGm terminals indicates that they form excitatory contacts, which may transmit their information in a rapid, powerful and high-fidelity manner onto strategically advantageous compartments of their cortical target cells.

ß-adrenergic modulation of discrimination learning and memory in the auditory cortex.

Despite vast literature on catecholaminergic neuromodulation of auditory cortex functioning in general, knowledge about its role for long-term memory formation is scarce. Our previous pharmacological studies on cortex-dependent frequency-modulated tone-sweep discrimination learning of Mongolian gerbils showed that auditory-cortical D1/5 -dopamine receptor activity facilitates memory consolidation and anterograde memory formation. Considering overlapping functions of D1/5 -dopamine receptors and ß-adrenoceptors, we hypothesised a role of ß-adrenergic signalling in the auditory cortex for sweep discrimination learning and memory. Supporting this hypothesis, the ß1/2 -adrenoceptor antagonist propranolol bilaterally applied to the gerbil auditory cortex after task acquisition prevented the discrimination increment that was normally monitored 1 day later. The increment in the total number of hurdle crossings performed in response to the sweeps per se was normal. Propranolol infusion after the seventh training session suppressed the previously established sweep discrimination. The suppressive effect required antagonist injection in a narrow post-session time window. When applied to the auditory cortex 1 day before initial conditioning, ß1 -adrenoceptor-antagonising and ß1 -adrenoceptor-stimulating agents retarded and facilitated, respectively, sweep discrimination learning, whereas ß2 -selective drugs were ineffective. In contrast, single-sweep detection learning was normal after propranolol infusion. By immunohistochemistry, ß1 - and ß2 -adrenoceptors were identified on the neuropil and somata of pyramidal and non-pyramidal neurons of the gerbil auditory cortex. The present findings suggest that ß-adrenergic signalling in the auditory cortex has task-related importance for discrimination learning of complex sounds: as previously shown for D1/5 -dopamine receptor signalling, ß-adrenoceptor activity supports long-term memory consolidation and reconsolidation; additionally, tonic input through ß1 -adrenoceptors may control mechanisms permissive for memory acquisition.

A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis.

Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia.

A Role for Auditory Corticothalamic Feedback in the Perception of Complex Sounds.

Feedback signals from the primary auditory cortex (A1) can shape the receptive field properties of neurons in the ventral division of the medial geniculate body (MGBv). However, the behavioral significance of corticothalamic modulation is unknown. The aim of this study was to elucidate the role of this descending pathway in the perception of complex sounds. We tested the ability of adult female ferrets to detect the presence of a mistuned harmonic in a complex tone using a positive conditioned go/no-go behavioral paradigm before and after the input from layer VI in A1 to MGBv was bilaterally and selectively eliminated using chromophore-targeted laser photolysis. MGBv neurons were identified by their short latencies and sharp tuning curves. They responded robustly to harmonic complex tones and exhibited an increase in firing rate and temporal pattern changes when one frequency component in the complex tone was mistuned. Injections of fluorescent microbeads conjugated with a light-sensitive chromophore were made in MGBv, and, following retrograde transport to the cortical cell bodies, apoptosis was induced by infrared laser illumination of A1. This resulted in a selective loss of ∼60% of layer VI A1-MGBv neurons. After the lesion, mistuning detection was impaired, as indicated by decreased d' values, a shift of the psychometric curves toward higher mistuning values, and increased thresholds, whereas discrimination performance was unaffected when level cues were also available. Our results suggest that A1-MGBv corticothalamic feedback contributes to the detection of harmonicity, one of the most important grouping cues in the perception of complex sounds.SIGNIFICANCE STATEMENT Perception of a complex auditory scene is based on the ability of the brain to group those sound components that belong to the same source and to segregate them from those belonging to different sources. Because two people talking simultaneously may differ in their voice pitch, perceiving the harmonic structure of sounds is very important for auditory scene analysis. Here we demonstrate mistuning sensitivity in the thalamus and that feedback from the primary auditory cortex is required for the normal ability of ferrets to detect a mistuned harmonic within a complex sound. These results provide novel insight into the function of descending sensory pathways in the brain and suggest that this corticothalamic circuit plays an important role in scene analysis.

Comodulation masking release in the inferior colliculus by combined signal enhancement and masker reduction.

Auditory signals that contain coherent level fluctuations of a masker in different frequency regions enhance the detectability of an embedded sinusoidal target signal, an effect commonly known as comodulation masking release (CMR). Neural correlates have been proposed at different stages of the auditory system. While later stages seem to suppress the response to the masker, earlier stages are more likely to enhance their response to the signal when the masker is comodulated. Using a flanking band masking paradigm, the present study investigates how CMR is represented at the level of the inferior colliculus of the Mongolian gerbil. The responses to a target signal at various sound pressure levels in three different masking conditions were compared. In one condition the masker was a 10-Hz amplitude modulated sinusoid centered at the signal frequency while in the other two conditions six off-frequency carriers (flanking bands) were added. From 81 units 26 showed a change that enhanced the detectability of the signal if the temporal modulation of the added flanking bands was identical to that of the masker at the signal frequency compared to the other two masking conditions. This study shows that the response characteristics of these neurons represent an intermediate stage between the representation in the cochlear nucleus and the auditory cortex. This means that the response is increased during the signal intervals but is also decreased for the following masker portions.

Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex.

During brain maturation, the occurrence of the extracellular matrix (ECM) terminates juvenile plasticity by mediating structural stability. Interestingly, enzymatic removal of the ECM restores juvenile forms of plasticity, as for instance demonstrated by topographical reconnectivity in sensory pathways. However, to which degree the mature ECM is a compromise between stability and flexibility in the adult brain impacting synaptic plasticity as a fundamental basis for learning, lifelong memory formation, and higher cognitive functions is largely unknown. In this study, we removed the ECM in the auditory cortex of adult Mongolian gerbils during specific phases of cortex-dependent auditory relearning, which was induced by the contingency reversal of a frequency-modulated tone discrimination, a task requiring high behavioral flexibility. We found that ECM removal promoted a significant increase in relearning performance, without erasing already established-that is, learned-capacities when continuing discrimination training. The cognitive flexibility required for reversal learning of previously acquired behavioral habits, commonly understood to mainly rely on frontostriatal circuits, was enhanced by promoting synaptic plasticity via ECM removal within the sensory cortex. Our findings further suggest experimental modulation of the cortical ECM as a tool to open short-term windows of enhanced activity-dependent reorganization allowing for guided neuroplasticity.

Proteome rearrangements after auditory learning: high-resolution profiling of synapse-enriched protein fractions from mouse brain.

Learning and memory processes are accompanied by rearrangements of synaptic protein networks. While various studies have demonstrated the regulation of individual synaptic proteins during these processes, much less is known about the complex regulation of synaptic proteomes. Recently, we reported that auditory discrimination learning in mice is associated with a relative down-regulation of proteins involved in the structural organization of synapses in various brain regions. Aiming at the identification of biological processes and signaling pathways involved in auditory memory formation, here, a label-free quantification approach was utilized to identify regulated synaptic junctional proteins and phosphoproteins in the auditory cortex, frontal cortex, hippocampus, and striatum of mice 24 h after the learning experiment. Twenty proteins, including postsynaptic scaffolds, actin-remodeling proteins, and RNA-binding proteins, were regulated in at least three brain regions pointing to common, cross-regional mechanisms. Most of the detected synaptic proteome changes were, however, restricted to individual brain regions. For example, several members of the Septin family of cytoskeletal proteins were up-regulated only in the hippocampus, while Septin-9 was down-regulated in the hippocampus, the frontal cortex, and the striatum. Meta analyses utilizing several databases were employed to identify underlying cellular functions and biological pathways. Data are available via ProteomeExchange with identifier PXD003089. How does the protein composition of synapses change in different brain areas upon auditory learning? We unravel discrete proteome changes in mouse auditory cortex, frontal cortex, hippocampus, and striatum functionally implicated in the learning process. We identify not only common but also area-specific biological pathways and cellular processes modulated 24 h after training, indicating individual contributions of the regions to memory processing.

Dopamine-modulated recurrent corticoefferent feedback in primary sensory cortex promotes detection of behaviorally relevant stimuli.

Dopaminergic neurotransmission in primary auditory cortex (AI) has been shown to be involved in learning and memory functions. Moreover, dopaminergic projections and D1/D5 receptor distributions display a layer-dependent organization, suggesting specific functions in the cortical circuitry. However, the circuit effects of dopaminergic neurotransmission in sensory cortex and their possible roles in perception, learning, and memory are largely unknown. Here, we investigated layer-specific circuit effects of dopaminergic neuromodulation using current source density (CSD) analysis in AI of Mongolian gerbils. Pharmacological stimulation of D1/D5 receptors increased auditory-evoked synaptic currents in infragranular layers, prolonging local thalamocortical input via positive feedback between infragranular output and granular input. Subsequently, dopamine promoted sustained cortical activation by prolonged recruitment of long-range corticocortical networks. A detailed circuit analysis combining layer-specific intracortical microstimulation (ICMS), CSD analysis, and pharmacological cortical silencing revealed that cross-laminar feedback enhanced by dopamine relied on a positive, fast-acting recurrent corticoefferent loop, most likely relayed via local thalamic circuits. Behavioral signal detection analysis further showed that activation of corticoefferent output by infragranular ICMS, which mimicked auditory activation under dopaminergic influence, was most effective in eliciting a behaviorally detectable signal. Our results show that D1/D5-mediated dopaminergic modulation in sensory cortex regulates positive recurrent corticoefferent feedback, which enhances states of high, persistent activity in sensory cortex evoked by behaviorally relevant stimuli. In boosting horizontal network interactions, this potentially promotes the readout of task-related information from cortical synapses and improves behavioral stimulus detection.

SPECT-imaging of activity-dependent changes in regional cerebral blood flow induced by electrical and optogenetic self-stimulation in mice.

Electrical and optogenetic methods for brain stimulation are widely used in rodents for manipulating behavior and analyzing functional connectivities in neuronal circuits. High-resolution in vivo imaging of the global, brain-wide, activation patterns induced by these stimulations has remained challenging, in particular in awake behaving mice. We here mapped brain activation patterns in awake, intracranially self-stimulating mice using a novel protocol for single-photon emission computed tomography (SPECT) imaging of regional cerebral blood flow (rCBF). Mice were implanted with either electrodes for electrical stimulation of the medial forebrain bundle (mfb-microstim) or with optical fibers for blue-light stimulation of channelrhodopsin-2 expressing neurons in the ventral tegmental area (vta-optostim). After training for self-stimulation by current or light application, respectively, mice were implanted with jugular vein catheters and intravenously injected with the flow tracer 99m-technetium hexamethylpropyleneamine oxime (99mTc-HMPAO) during seven to ten minutes of intracranial self-stimulation or ongoing behavior without stimulation. The 99mTc-brain distributions were mapped in anesthetized animals after stimulation using multipinhole SPECT. Upon self-stimulation rCBF strongly increased at the electrode tip in mfb-microstim mice. In vta-optostim mice peak activations were found outside the stimulation site. Partly overlapping brain-wide networks of activations and deactivations were found in both groups. When testing all self-stimulating mice against all controls highly significant activations were found in the rostromedial nucleus accumbens shell. SPECT-imaging of rCBF using intravenous tracer-injection during ongoing behavior is a new tool for imaging regional brain activation patterns in awake behaving rodents providing higher spatial and temporal resolutions than 18F-2-fluoro-2-dexoyglucose positron emission tomography.

Inhibiting presynaptic calcium channel motility in the auditory cortex suppresses synchronized input processing.

Introduction: The emergent coherent population activity from thousands of stochastic neurons in the brain is believed to constitute a key neuronal mechanism for salient processing of external stimuli and its link to internal states like attention and perception. In the sensory cortex, functional cell assemblies are formed by recurrent excitation and inhibitory influences. The stochastic dynamics of each cell involved is largely orchestrated by presynaptic CAV2.1 voltage-gated calcium channels (VGCCs). Cav2.1 VGCCs initiate the release of neurotransmitters from the presynaptic compartment and are therefore able to add variability into synaptic transmission which can be partly explained by their mobile organization around docked vesicles. Methods: To investigate the relevance of Cav2.1 channel surface motility for the input processing in the primary auditory cortex (A1) in vivo, we make use of a new optogenetic system which allows for acute, reversable cross-linking Cav2.1 VGCCs via a photo-cross-linkable cryptochrome mutant, CRY2olig. In order to map neuronal activity across all cortical layers of the A1, we performed laminar current-source density (CSD) recordings with varying auditory stimulus sets in transgenic mice with a citrine tag on the N-terminus of the VGCCs. Results: Clustering VGCCs suppresses overall sensory-evoked population activity, particularly when stimuli lead to a highly synchronized distribution of synaptic inputs. Discussion: Our findings reveal the importance of membrane dynamics of presynaptic calcium channels for sensory encoding by dynamically adjusting network activity across a wide range of synaptic input strength.

Neural basis of multisensory looming signals.

Approaching or looming signals are often related to extremely relevant environmental events (e.g. threats or collisions) making these signals critical for survival. However, the neural network underlying multisensory looming processing is not yet fully understood. Using functional magnetic resonance imaging (fMRI) we identified the neural correlates of audiovisual looming processing in humans: audiovisual looming (vs. receding) signals enhance fMRI-responses in low-level visual and auditory areas plus multisensory cortex (superior temporal sulcus; plus parietal and frontal structures). When characterizing the fMRI-response profiles for multisensory looming stimuli, we found significant enhancements relative to the mean and maximum of unisensory responses in looming-sensitive visual and auditory cortex plus STS. Superadditive enhancements were observed in visual cortex. Subject-specific region-of-interest analyses further revealed superadditive response profiles within all sensory-specific looming-sensitive structures plus bilateral STS for audiovisual looming vs. summed unisensory looming conditions. Finally, we observed enhanced connectivity of bilateral STS with low-level visual areas in the context of looming processing. This enhanced coupling of STS with unisensory regions might potentially serve to enhance the salience of unisensory stimulus features and is accompanied by superadditive fMRI-responses. We suggest that this preference in neural signaling for looming stimuli effectively informs animals to avoid potential threats or collisions.

Wave propagation of cortical population activity under urethane anesthesia is state dependent.

BACKGROUND: Propagating waves of excitation have been observed extensively in the neocortex, during both spontaneous and sensory-evoked activity, and they play a critical role in spatially organizing information processing. However, the state-dependence of these spatiotemporal propagation patterns is largely unexplored. In this report, we use voltage-sensitive dye imaging in the rat visual cortex to study the propagation of spontaneous population activity in two discrete cortical states induced by urethane anesthesia. RESULTS: While laminar current source density patterns of spontaneous population events in these two states indicate a considerable degree of similarity in laminar networks, lateral propagation in the more active desynchronized state is approximately 20% faster than in the slower synchronized state. Furthermore, trajectories of wave propagation exhibit a strong anisotropy, but the preferred direction is different depending on cortical state. CONCLUSIONS: Our results show that horizontal wave propagation of spontaneous neural activity is largely dependent on the global activity states of local cortical circuits.

Prestimulus α/ß power in temporal-order judgments: individuals differ in direction of modulation but show consistency over auditory and visual tasks.

The processing of incoming sensory information can be differentially affected by varying levels of α-power in the electroencephalogram (EEG). A prominent hypothesis is that relatively low prestimulus α-power is associated with improved perceptual performance. However, there are studies in the literature that do not fit easily into this picture, and the reasons for this are poorly understood and rarely discussed. To evaluate the robustness of previous findings and to better understand the overall mixed results, we used a spatial TOJ task in which we presented auditory and visual stimulus pairs in random order while recording EEG. For veridical and non-veridical TOJs, we calculated the power spectral density (PSD) for 3 frequencies (5 Hz steps: 10, 15, and 20 Hz). We found on the group level: (1) Veridical auditory TOJs, relative to non-veridical, were associated with higher ß-band (20 Hz) power over central electrodes. (2) Veridical visual TOJs showed higher ß-band (10, 15 Hz) power over parieto-occipital electrodes (3) Electrode site interacted with TOJ condition in the ß-band: For auditory TOJs, PSD over central electrodes was higher for veridical than non-veridical and over parieto-occipital electrodes was lower for veridical than non-veridical trials, while the latter pattern was reversed for visual TOJs. While our group-level result showed a clear direction of prestimulus modulation, the individual-level modulation pattern was variable and included activations opposite to the group mean. Interestingly, our results at the individual-level mirror the situation in the literature, where reports of group-level prestimulus modulation were found in either direction. Because the direction of individual activation of electrodes over auditory brain regions and parieto-occipital electrodes was always negatively correlated in the respective TOJ conditions, this activation opposite to the group mean cannot be easily dismissed as noise. The consistency of the individual-level data cautions against premature generalization of group-effects and suggests different strategies that participants initially adopted and then consistently followed. We discuss our results in light of probabilistic information processing and complex system properties, and suggest that a general description of brain activity must account for variability in modulation directions at both the group and individual levels.

Research Data Management and Data Sharing for Reproducible Research-Results of a Community Survey of the German National Research Data Infrastructure Initiative Neuroscience.

Science is changing: the volume and complexity of data are increasing, the number of studies is growing and the goal of achieving reproducible results requires new solutions for scientific data management. In the field of neuroscience, the German National Research Data Infrastructure (NFDI-Neuro) initiative aims to develop sustainable solutions for research data management (RDM). To obtain an understanding of the present RDM situation in the neuroscience community, NFDI-Neuro conducted a comprehensive survey among the neuroscience community. Here, we report and analyze the results of the survey. We focused the survey and our analysis on current needs, challenges, and opinions about RDM. The German neuroscience community perceives barriers with respect to RDM and data sharing mainly linked to (1) lack of data and metadata standards, (2) lack of community adopted provenance tracking methods, (3) lack of secure and privacy preserving research infrastructure for sensitive data, (4) lack of RDM literacy, and (5) lack of resources (time, personnel, money) for proper RDM. However, an overwhelming majority of community members (91%) indicated that they would be willing to share their data with other researchers and are interested to increase their RDM skills. Taking advantage of this willingness and overcoming the existing barriers requires the systematic development of standards, tools, and infrastructure, the provision of training, education, and support, as well as additional resources for RDM to the research community and a constant dialogue with relevant stakeholders including policy makers to leverage of a culture change through adapted incentivization and regulation.

Synaptic proteome changes in mouse brain regions upon auditory discrimination learning.

Changes in synaptic efficacy underlying learning and memory processes are assumed to be associated with alterations of the protein composition of synapses. Here, we performed a quantitative proteomic screen to monitor changes in the synaptic proteome of four brain areas (auditory cortex, frontal cortex, hippocampus striatum) during auditory learning. Mice were trained in a shuttle box GO/NO-GO paradigm to discriminate between rising and falling frequency modulated tones to avoid mild electric foot shock. Control-treated mice received corresponding numbers of either the tones or the foot shocks. Six hours and 24 h later, the composition of a fraction enriched in synaptic cytomatrix-associated proteins was compared to that obtained from naïve mice by quantitative mass spectrometry. In the synaptic protein fraction obtained from trained mice, the average percentage (±SEM) of downregulated proteins (59.9 ± 0.5%) exceeded that of upregulated proteins (23.5 ± 0.8%) in the brain regions studied. This effect was significantly smaller in foot shock (42.7 ± 0.6% down, 40.7 ± 1.0% up) and tone controls (43.9 ± 1.0% down, 39.7 ± 0.9% up). These data suggest that learning processes initially induce removal and/or degradation of proteins from presynaptic and postsynaptic cytoskeletal matrices before these structures can acquire a new, postlearning organisation. In silico analysis points to a general role of insulin-like signalling in this process.

The use of thallium diethyldithiocarbamate for mapping CNS potassium metabolism and neuronal activity: Tl+ -redistribution, Tl+ -kinetics and Tl+ -equilibrium distribution.

The potassium (K(+)) analogue thallium (Tl(+)) can be used as a tracer for mapping neuronal activity. However, because of the poor blood-brain barrier (BBB) K(+) -permeability, only minute amounts of Tl(+) enter the brain after systemic injection of Tl(+) -salts like thallium acetate (TlAc). We have recently shown that it is possible to overcome this limitation by injecting animals with the lipophilic chelate complex thallium diethyldithiocarbamate (TlDDC), that crosses the BBB and releases Tl(+) prior to neuronal or glial uptake. TlDDC can thus be used for mapping CNS K(+) metabolism and neuronal activity. Here, we analyze Tl(+) -kinetics in the rodent brain both experimentally and using simple mathematical models. We systemically injected animals either with TlAc or with TlDDC. Using an autometallographic method we mapped the brain Tl(+) -distribution at various time points after injection. We show that the patterns and kinetics of Tl(+) -redistribution in the brain are essentially the same irrespective of whether animals have been injected with TlAc or TlDDC. Data from modeling and experiments indicate that transmembrane Tl(+) -fluxes in cells within the CNS in vivo equilibrate at similar rates as K(+) -fluxes in vitro. This equilibration is much faster than and largely independent of the equilibration of Tl(+) -fluxes across the BBB. The study provides further proof-of-concept for the use of TlDDC for mapping neuronal activity and CNS K(+) -metabolism. A theoretical guideline is given for the use of K(+) -analogues for imaging neuronal activity with general implications for the use of metal ions in neuroimaging.

Spectral integration in primary auditory cortex attributable to temporally precise convergence of thalamocortical and intracortical input.

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.