Dynamic behaviour restructuring mediates dopamine-dependent credit assignment.

Animals exhibit a diverse behavioural repertoire when exploring new environments and can learn which actions or action sequences produce positive outcomes. Dopamine release after encountering a reward is critical for reinforcing reward-producing actions1-3. However, it has been challenging to understand how credit is assigned to the exact action that produced the dopamine release during continuous behaviour. Here we investigated this problem in mice using a self-stimulation paradigm in which specific spontaneous movements triggered optogenetic stimulation of dopaminergic neurons. Dopamine self-stimulation rapidly and dynamically changes the structure of the entire behavioural repertoire. Initial stimulations reinforced not only the stimulation-producing target action, but also actions similar to the target action and actions that occurred a few seconds before stimulation. Repeated pairings led to a gradual refinement of the behavioural repertoire to home in on the target action. Reinforcement of action sequences revealed further temporal dependencies of refinement. Action pairs spontaneously separated by long time intervals promoted a stepwise credit assignment, with early refinement of actions most proximal to stimulation and subsequent refinement of more distal actions. Thus, a retrospective reinforcement mechanism promotes not only reinforcement, but also gradual refinement of the entire behavioural repertoire to assign credit to specific actions and action sequences that lead to dopamine release.

What, If, and When to Move: Basal Ganglia Circuits and Self-Paced Action Initiation.

Deciding what to do and when to move is vital to our survival. Clinical and fundamental studies have identified basal ganglia circuits as critical for this process. The main input nucleus of the basal ganglia, the striatum, receives inputs from frontal, sensory, and motor cortices and interconnected thalamic areas that provide information about potential goals, context, and actions and directly or indirectly modulates basal ganglia outputs. The striatum also receives dopaminergic inputs that can signal reward prediction errors and also behavioral transitions and movement initiation. Here we review studies and models of how direct and indirect pathways can modulate basal ganglia outputs to facilitate movement initiation, and we discuss the role of cortical and dopaminergic inputs to the striatum in determining what to do and if and when to do it. Complex but exciting scenarios emerge that shed new light on how basal ganglia circuits modulate self-paced movement initiation.

Altered avalanche dynamics in a developmental NMDAR hypofunction model of cognitive impairment.

Disturbed activity patterns in cortical networks contribute to the pathophysiology of schizophrenia (SZ). Several lines of evidence implicate NMDA receptor hypofunction in SZ, and blocking NMDA receptor signaling during early neurodevelopment produces cognitive deficits in rodent models that resemble those seen in schizophrenic patients. However, the altered network dynamics underlying these cognitive impairments largely remain to be characterized, especially at the cellular level. Here, we use in vivo two-photon calcium imaging to describe pathological dynamics, occurring in parallel with cognitive dysfunction, in a developmental NMDA receptor hypofunction model. We observed increased synchrony and specific alterations in spatiotemporal activity propagation, which could be causally linked to a previously unidentified persistent bursting phenotype. This phenotype was rescued by acute treatment with the NMDA receptor co-agonist D-serine or the GABAB receptor agonist baclofen, which similarly rescued working memory performance. It was not reproduced by optogenetic inhibition of fast-spiking interneurons. These results provide novel insight into network-level abnormalities mediating the cognitive impairment induced by NMDA receptor hypofunction.

Toxoplasma-induced changes in host risk behaviour are independent of parasite-derived AaaH2 tyrosine hydroxylase.

Toxoplasma gondii infects a broad range of hosts and can establish chronic infections with the formation of brain cysts. Infected animals show altered risk behaviour which has been suggested to increase capture probability of hosts, and thus enhance parasite transmission. It has been proposed that the ability of Toxoplasma cysts to secrete tyrosine hydroxylase could mediate these behavioural alterations. We tested the involvement of secreted tyrosine hydroxylase, coded by the parasite AaaH2 gene, in the development of alterations in mouse behaviour, by generating an AaaH2 deletion mutant parasite strain and testing its influence on behaviour. We found that both mice infected with wild type or AaaH2 mutant strains showed changes in risk behaviour. We confirmed these findings using factor analysis of the behaviour, which revealed that behavioural changes happened along a single dimension, and were observed in both infected groups. Furthermore, we developed a new behavioural paradigm in which animals are unpredictably trapped, and observed that both groups of infected animals perceive trapping but fail to adjust their behaviour to avoid further trapping. These results demonstrate that parasite-secreted AaaH2 TH is neither necessary for the generation of risky behaviour nor for the increased trappability observed during chronic Toxoplasma infection.

The Spatiotemporal Organization of the Striatum Encodes Action Space.

Activity in striatal direct- and indirect-pathway spiny projection neurons (SPNs) is critical for proper movement. However, little is known about the spatiotemporal organization of this activity. We investigated the spatiotemporal organization of SPN ensemble activity in mice during self-paced, natural movements using microendoscopic imaging. Activity in both pathways showed predominantly local but also some long-range correlations. Using a novel approach to cluster and quantify behaviors based on continuous accelerometer and video data, we found that SPN ensembles active during specific actions were spatially closer and more correlated overall. Furthermore, similarity between different actions corresponded to the similarity between SPN ensemble patterns, irrespective of movement speed. Consistently, the accuracy of decoding behavior from SPN ensemble patterns was directly related to the dissimilarity between behavioral clusters. These results identify a predominantly local, but not spatially compact, organization of direct- and indirect-pathway SPN activity that maps action space independently of movement speed.

The Interplay between Long- and Short-Range Temporal Correlations Shapes Cortex Dynamics across Vigilance States.

Increasing evidence suggests that cortical dynamics during wake exhibits long-range temporal correlations suitable to integrate inputs over extended periods of time to increase the signal-to-noise ratio in decision making and working memory tasks. Accordingly, sleep has been suggested as a state characterized by a breakdown of long-range correlations. However, detailed measurements of neuronal timescales that support this view have so far been lacking. Here, we show that the cortical timescales measured at the individual neuron level in freely behaving male rats change as a function of vigilance state and time awake. Although quiet wake and rapid eye movement (REM) sleep are characterized by similar, long timescales, these long timescales are abrogated in non-REM sleep. We observe that cortex dynamics exhibits rapid transitions between long-timescale states and sleep-like states governed by short timescales even during wake. This becomes particularly evident during sleep deprivation, when the interplay between these states can lead to an increasing disruption of long timescales that are restored after sleep. Experiments and modeling identify the intrusion of neuronal offline periods as a mechanism that disrupts the long timescales arising from reverberating cortical network activity. Our results provide novel mechanistic and functional links among behavioral manifestations of sleep, wake, and sleep deprivation and specific measurable changes in the network dynamics relevant for characterizing the brain's changing information-processing capabilities. They suggest a network-level function of sleep to reorganize cortical networks toward states governed by long timescales to ensure efficient information integration for the time awake.SIGNIFICANCE STATEMENT Lack of sleep deteriorates several key cognitive functions, yet the neuronal underpinnings of these deficits have remained elusive. Cognitive capabilities are generally believed to benefit from a neural circuit's ability to reliably integrate information. Persistent network activity characterized by long timescales may provide the basis for this integration in cortex. Here, we show that long-range temporal correlations indicated by slowly decaying autocorrelation functions in neuronal activity are dependent on vigilance states. Although wake and rapid eye movement (REM) sleep exhibit long timescales, these long-range correlations break down during non-REM sleep. Our findings thus suggest two distinct states in terms of timescale dynamics. During extended wake, the rapid switching to sleep-like states with short timescales can lead to an overall decline in cortical timescales.

A Low-Correlation Resting State of the Striatum during Cortical Avalanches and Its Role in Movement Suppression.

During quiet resting behavior, involuntary movements are suppressed. Such movement control is attributed to cortico-basal ganglia loops, yet population dynamics within these loops during resting and their relation to involuntary movements are not well characterized. Here, we show by recording cortical and striatal ongoing population activity in awake rats during quiet resting that intrastriatal inhibition maintains a low-correlation striatal resting state in the presence of cortical neuronal avalanches. Involuntary movements arise from disturbed striatal resting activity through two different population dynamics. Nonselectively reducing intrastriatal γ-aminobutyric acid (GABA) receptor-A inhibition synchronizes striatal dynamics, leading to involuntary movements at low rate. In contrast, reducing striatal interneuron (IN)-mediated inhibition maintains decorrelation and induces intermittent involuntary movements at high rate. This latter scenario was highly effective in modulating cortical dynamics at a subsecond timescale. To distinguish intrastriatal processing from loop dynamics, cortex-striatum-midbrain cultures, which lack feedback to cortex, were used. Cortical avalanches in vitro were accompanied by low-correlated resting activity in the striatum and nonselective reduction in striatal inhibition synchronized striatal neurons similar to in vivo. Importantly, reduction of inhibition from striatal INs maintained low correlations in the striatum while reorganizing functional connectivities among striatal neurons. Our results demonstrate the importance of two major striatal microcircuits in distinctly regulating striatal and cortical resting state dynamics. These findings suggest that specific functional connectivities of the striatum that are maintained by local inhibition are important in movement control.

Simultaneous calcium fluorescence imaging and MR of ex vivo organotypic cortical cultures: a new test bed for functional MRI.

Recently, several new functional (f)MRI contrast mechanisms including diffusion, phase imaging, proton density, etc. have been proposed to measure neuronal activity more directly and accurately than blood-oxygen-level dependent (BOLD) fMRI. However, these approaches have proved difficult to reproduce, mainly because of the dearth of reliable and robust test systems to vet and validate them. Here we describe the development and testing of such a test bed for non-BOLD fMRI. Organotypic cortical cultures were used as a stable and reproducible biological model of neuronal activity that shows spontaneous activity similar to that of in vivo brain cortex without any hemodynamic confounds. An open-access, single-sided magnetic resonance (MR) "profiler" consisting of four permanent magnets with magnetic field of 0.32 T was used in this study to perform MR acquisition. A fluorescence microscope with long working distance objective was mounted on the top of a custom-designed chamber that keeps the organotypic culture vital, and the MR system was mounted on the bottom of the chamber to achieve real-time simultaneous calcium fluorescence optical imaging and MR acquisition on the same specimen. In this study, the reliability and performance of the proposed test bed were demonstrated by a conventional CPMG MR sequence acquired simultaneously with calcium imaging, which is a well-characterized measurement of neuronal activity. This experimental design will make it possible to correlate directly the other candidate functional MR signals to the optical indicia of neuronal activity in the future.

Irregular spiking of pyramidal neurons organizes as scale-invariant neuronal avalanches in the awake state.

Spontaneous fluctuations in neuronal activity emerge at many spatial and temporal scales in cortex. Population measures found these fluctuations to organize as scale-invariant neuronal avalanches, suggesting cortical dynamics to be critical. Macroscopic dynamics, though, depend on physiological states and are ambiguous as to their cellular composition, spatiotemporal origin, and contributions from synaptic input or action potential (AP) output. Here, we study spontaneous firing in pyramidal neurons (PNs) from rat superficial cortical layers in vivo and in vitro using 2-photon imaging. As the animal transitions from the anesthetized to awake state, spontaneous single neuron firing increases in irregularity and assembles into scale-invariant avalanches at the group level. In vitro spike avalanches emerged naturally yet required balanced excitation and inhibition. This demonstrates that neuronal avalanches are linked to the global physiological state of wakefulness and that cortical resting activity organizes as avalanches from firing of local PN groups to global population activity.

Critical slowing down governs the transition to neuron spiking.

Many complex systems have been found to exhibit critical transitions, or so-called tipping points, which are sudden changes to a qualitatively different system state. These changes can profoundly impact the functioning of a system ranging from controlled state switching to a catastrophic break-down; signals that predict critical transitions are therefore highly desirable. To this end, research efforts have focused on utilizing qualitative changes in markers related to a system's tendency to recover more slowly from a perturbation the closer it gets to the transition--a phenomenon called critical slowing down. The recently studied scaling of critical slowing down offers a refined path to understand critical transitions: to identify the transition mechanism and improve transition prediction using scaling laws. Here, we outline and apply this strategy for the first time in a real-world system by studying the transition to spiking in neurons of the mammalian cortex. The dynamical system approach has identified two robust mechanisms for the transition from subthreshold activity to spiking, saddle-node and Hopf bifurcation. Although theory provides precise predictions on signatures of critical slowing down near the bifurcation to spiking, quantitative experimental evidence has been lacking. Using whole-cell patch-clamp recordings from pyramidal neurons and fast-spiking interneurons, we show that 1) the transition to spiking dynamically corresponds to a critical transition exhibiting slowing down, 2) the scaling laws suggest a saddle-node bifurcation governing slowing down, and 3) these precise scaling laws can be used to predict the bifurcation point from a limited window of observation. To our knowledge this is the first report of scaling laws of critical slowing down in an experiment. They present a missing link for a broad class of neuroscience modeling and suggest improved estimation of tipping points by incorporating scaling laws of critical slowing down as a strategy applicable to other complex systems.

Scale-invariant neuronal avalanche dynamics and the cut-off in size distributions.

Identification of cortical dynamics strongly benefits from the simultaneous recording of as many neurons as possible. Yet current technologies provide only incomplete access to the mammalian cortex from which adequate conclusions about dynamics need to be derived. Here, we identify constraints introduced by sub-sampling with a limited number of electrodes, i.e. spatial 'windowing', for well-characterized critical dynamics-neuronal avalanches. The local field potential (LFP) was recorded from premotor and prefrontal cortices in two awake macaque monkeys during rest using chronically implanted 96-microelectrode arrays. Negative deflections in the LFP (nLFP) were identified on the full as well as compact sub-regions of the array quantified by the number of electrodes N (10-95), i.e., the window size. Spatiotemporal nLFP clusters organized as neuronal avalanches, i.e., the probability in cluster size, p(s), invariably followed a power law with exponent -1.5 up to N, beyond which p(s) declined more steeply producing a 'cut-off' that varied with N and the LFP filter parameters. Clusters of size s≤N consisted mainly of nLFPs from unique, non-repeated cortical sites, emerged from local propagation between nearby sites, and carried spatial information about cluster organization. In contrast, clusters of size s>N were dominated by repeated site activations and carried little spatial information, reflecting greatly distorted sampling conditions. Our findings were confirmed in a neuron-electrode network model. Thus, avalanche analysis needs to be constrained to the size of the observation window to reveal the underlying scale-invariant organization produced by locally unfolding, predominantly feed-forward neuronal cascades.

[Pathophysiology and epidemiology of pain in thoracic surgery]. / Schmerztherapie in der Thoraxchirurgie - Schmerzpathophysiologie und -epidemiologie bei thorakalen Eingriffen.

Acute and chronic pain are significant problems after thoracic surgery with a multifactorial pathogenesis. On the one hand iatrogenic procedures as surgical access and complexity of treatment procedures, and on the other hand constitutional factors as psychosocial comorbidities affect individual pain threshold and the development of a Postthoracic Pain Syndrome (PTPS). Special phenomena associated with thoracic surgery like ipsitateral shoulder pain and neuropathic pain are discussed. The characterization of pathophysiological pathways wants to point out treatment options. In conclusion there is a need for well organized, multimodal pain therapy concepts to minimize the risk of perioperative and chronic pain.

Multi-electrode array recordings of neuronal avalanches in organotypic cultures.

The cortex is spontaneously active, even in the absence of any particular input or motor output. During development, this activity is important for the migration and differentiation of cortex cell types and the formation of neuronal connections. In the mature animal, ongoing activity reflects the past and the present state of an animal into which sensory stimuli are seamlessly integrated to compute future actions. Thus, a clear understanding of the organization of ongoing i.e. spontaneous activity is a prerequisite to understand cortex function. Numerous recording techniques revealed that ongoing activity in cortex is comprised of many neurons whose individual activities transiently sum to larger events that can be detected in the local field potential (LFP) with extracellular microelectrodes, or in the electroencephalogram (EEG), the magnetoencephalogram (MEG), and the BOLD signal from functional magnetic resonance imaging (fMRI). The LFP is currently the method of choice when studying neuronal population activity with high temporal and spatial resolution at the mesoscopic scale (several thousands of neurons). At the extracellular microelectrode, locally synchronized activities of spatially neighbored neurons result in rapid deflections in the LFP up to several hundreds of microvolts. When using an array of microelectrodes, the organizations of such deflections can be conveniently monitored in space and time. Neuronal avalanches describe the scale-invariant spatiotemporal organization of ongoing neuronal activity in the brain. They are specific to the superficial layers of cortex as established in vitro, in vivo in the anesthetized rat, and in the awake monkey. Importantly, both theoretical and empirical studies suggest that neuronal avalanches indicate an exquisitely balanced critical state dynamics of cortex that optimizes information transfer and information processing. In order to study the mechanisms of neuronal avalanche development, maintenance, and regulation, in vitro preparations are highly beneficial, as they allow for stable recordings of avalanche activity under precisely controlled conditions. The current protocol describes how to study neuronal avalanches in vitro by taking advantage of superficial layer development in organotypic cortex cultures, i.e. slice cultures, grown on planar, integrated microelectrode arrays (MEA).

Orosensory stimulation effects on human saliva proteome.

Saliva flow induced by 6-gingerol (pungent), hydroxy-α/ß-sanshools (tingling), and citric acid (sour) was measured, and the time-dependent changes in the whole saliva proteome were analyzed by means of 2D-PAGE, followed by tryptic in-gel digestion and MALDI-TOF-MS peptide mass fingerprint analysis. The proteins showing significantly decreased abundance after oral 6-gingerol stimulation were identified as glutathione S-transferase P, the heat shock protein ß-1, the heat shock 70 kDa protein 1, annexin A1, and cytoplasmic ß-actin, whereas prolactin inducible proteins (PIP), short palate, lung and nasal epithelium carcinoma-associated protein 2 (SPLUNC2), zinc-α-2-glycoproteins (Zn-α-GP), and carbonic anhydrase VI (CAVI) were found with increased abundance. As the effects of this study were observed instantaneously upon stimulation, any proteome modulation is very likely to result from the release of proteins from preformed vesicles and not from de novo synthesis. The elevated levels of SPLUNC2, Zn-α-GP, and CAVI might be interpreted to trigger innate protective mechanisms in mucosal immunity and in nonimmune mucosal defense and might play an important role during the initial stage of inflammation.

Striatal fast-spiking interneurons: from firing patterns to postsynaptic impact.

In the striatal microcircuit, fast-spiking (FS) interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS) projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo, these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity.

Statistical analyses support power law distributions found in neuronal avalanches.

The size distribution of neuronal avalanches in cortical networks has been reported to follow a power law distribution with exponent close to -1.5, which is a reflection of long-range spatial correlations in spontaneous neuronal activity. However, identifying power law scaling in empirical data can be difficult and sometimes controversial. In the present study, we tested the power law hypothesis for neuronal avalanches by using more stringent statistical analyses. In particular, we performed the following steps: (i) analysis of finite-size scaling to identify scale-free dynamics in neuronal avalanches, (ii) model parameter estimation to determine the specific exponent of the power law, and (iii) comparison of the power law to alternative model distributions. Consistent with critical state dynamics, avalanche size distributions exhibited robust scaling behavior in which the maximum avalanche size was limited only by the spatial extent of sampling ("finite size" effect). This scale-free dynamics suggests the power law as a model for the distribution of avalanche sizes. Using both the Kolmogorov-Smirnov statistic and a maximum likelihood approach, we found the slope to be close to -1.5, which is in line with previous reports. Finally, the power law model for neuronal avalanches was compared to the exponential and to various heavy-tail distributions based on the Kolmogorov-Smirnov distance and by using a log-likelihood ratio test. Both the power law distribution without and with exponential cut-off provided significantly better fits to the cluster size distributions in neuronal avalanches than the exponential, the lognormal and the gamma distribution. In summary, our findings strongly support the power law scaling in neuronal avalanches, providing further evidence for critical state dynamics in superficial layers of cortex.

Optimum spatiotemporal receptive fields for vision in dim light.

Many nocturnal insects depend on vision for daily life and have evolved different strategies to improve their visual capabilities in dim light. Neural summation of visual signals is one strategy to improve visual performance, and this is likely to be especially important for insects with apposition compound eyes. Here we develop a model to determine the optimum spatiotemporal sampling of natural scenes at gradually decreasing light levels. Image anisotropy has a strong influence on the receptive field properties predicted to be optimal at low light intensities. Spatial summation between visual channels is predicted to extend more strongly in the direction with higher correlations between the input signals. Increased spatiotemporal summation increases signal-to-noise ratio at low frequencies but sacrifices signal-to-noise ratio at higher frequencies. These results, while obtained from a model of the insect visual system, are likely to apply to visual systems in general.