Learning and recall in a dynamic theory of coordination patterns

A dynamic theory of learning and recall of coordination patterns is developed in the context of relative timing skills. Characterizing the coordination patterns in such skills by the collective variable, relative phase, we choose a model system in which the intrinsic pattern dynamics as well as the influence of environmental and memorized information are well understood from previous experimental and theoretical work. To describe learning we endow memorized information with dynamics which is determined by a phenomenological strategy. Similarly, additional degrees of freedom must be introduced to understand recall. As such recall variables we choose the relative strengths with which each memorized pattern acts on the pattern dynamics and model their dynamics phenomenologically. The resulting dynamical system that resembles models used in pattern recognition theory is shown to adequately describe the learning and recall processes. Moreover, due to the operational character of the theory, several predictions emerge that are open to experimental test. In particular, we show under which conditions phase transitions occur in the dynamics of the coordination patterns during learning and during recall. Considering different time scales and their relations we demonstrate how these phase transitions can be identified and observed. Other predictions include the influence of the intrinsic pattern dynamics on the recall process and the existence of history and hysteresis effects in recall. We discuss different forms of forgetting and differentiation of memorized information. The results show how a new theoretical view of learning and recall as change of behavioral dynamics can lead to a different understanding of these processes by providing testable predictions.     

Multifrequency behavioral patterns and the phase attractive circle map

With relative phase as a collective variable or order parameter, phase attractive dynamics can capture the temporally coherent behavior of a large number of different experimental systems. We present results from multifrequency coordination experiments in humans showing: a) that phase attraction persists especially for low order frequency ratios; b) that short-term jumps from one phase relation to another occur within a frequency ratio; c) that the most stable frequency-ratios are low order; and d) that transitions frequently occur from higher order (e.g. 52, 43) to lower order (21, 11) frequency ratios. We study a modified sine circle map with built-in phase attractive dynamics that qualitatively accounts for these results. In this phase-attractive map, patterns arise from competition between external driving and intrinsic phase attractive dynamics. The relative strength of extrinsic and intrinsic parameters determines the width of Arnol'd tongues, thereby influencing the delay or acceleration of irregular behavior. Behavioral complexity is inversely proportional to tongue width, thus accounting for the relative difficulty of performing different multifrequency behaviors and why errors in such behavior are often seen to occur.     

A theoretical model of phase transitions in human hand movements

Earlier experimental studies by one of us (Kelso, 1981a, 1984) have shown that abrupt phase transitions occur in human hand movements under the influence of scalar changes in cycling frequency. Beyond a critical frequency the originally prepared out-of-phase, antisymmetric mode is replaced by a symmetrical, in-phase mode involving simultaneous activation of homologous muscle groups. Qualitavely, these phase transitions are analogous to gait shifts in animal locomotion as well as phenomena common to other physical and biological systems in which new modes or spatiotemporal patterns arise when the system is parametrically scaled beyond its equilibrium state (Haken, 1983). In this paper a theoretical model, using concepts central to the interdisciplinary field of synergetics and nonlinear oscillator theory, is developed, which reproduces (among other features) the dramatic change in coordinative pattern observed between the hands.     

Individual changes underlie age-specific pattern of laying date and egg-size in female common terns Sterna hirundo

It has been suggested that breeding performance differs between young and old birds due to the appearance and disappearance of phenotypes through differential survival (selection hypothesis) or differential recruitment (delayed breeding hypothesis) of high-quality individuals, but each bird may show constant breeding performance over its life. We tested constant egg-volume and laying date by modelling their variability on the basis of the 109 known-age females of common tern Sterna hirundo with data available from 1 to 9 years. Longitudinal analyses showed a significant advancement of laying date, as well as a steady increase in egg-volume, in young age classes from 2 to 5–7 years old, indicating individual intrinsic changes in performance with age. In our model, female effect accounted for 74% and 8% of variance in egg-volume and laying date, respectively, suggesting that if correlation between breeding performance and survival or recruitment exists, population patterns of age-specific performance may emerge. However, we found no evidence that birds that did not return to breed during young age classes laid later or smaller eggs than returned breeders. Likewise, we found no evidence that recruiting birds laid earlier or larger eggs than same aged birds recruited in preceding years. Thus, this study shows that age-specific patterns in timing of breeding and egg-size in common terns result from individuals intrinsic changes, and we reject the selection and the delayed breeding hypotheses as a major factor shaping age-specific patterns at population level.Communicated by F. Bairlein     

A dynamical neural network model for motor cortical activity during movement: population coding of movement trajectories

As a dynamical model for motor cortical activity during hand movement we consider an artificial neural network that consists of extensively interconnected neuron-like units and performs the neuronal population vector operations. Local geometrical parameters of a desired curve are introduced into the network as an external input. The output of the model is a time-dependent direction and length of the neuronal population vector which is calculated as a sum of the activity of directionally tuned neurons in the ensemble. The main feature of the model is that dynamical behavior of the neuronal population vector is the result of connections between directionally tuned neurons rather than being imposed externally. The dynamics is governed by a system of coupled nonlinear differential equations. Connections between neurons are assigned in the simplest and most common way so as to fulfill basic requirements stemming from experimental findings concerning the directional tuning of individual neurons and the stabilization of the neuronal population vector, as well as from previous theoretical studies. The dynamical behavior of the model reveals a close similarity with the experimentally observed dynamics of the neuronal population vector. Specifically, in the framework of the model it is possible to describe a geometrical curve in terms of the time series of the population vector. A correlation between the dynamical behavior of the direction and the length of the population vector entails a dependence of the neural velocity on the curvature of the tracing trajectory that corresponds well to the experimentally measured covariation between tangential velocity and curvature in drawing tasks.On leave of absencefrom the Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia.     

Primary and Secondary Rewards Differentially Modulate Neural Activity Dynamics during Working Memory

Background

Cognitive control and working memory processes have been found to be influenced by changes in motivational state. Nevertheless, the impact of different motivational variables on behavior and brain activity remains unclear.

Methodology/Principal Findings

The current study examined the impact of incentive category by varying on a within-subjects basis whether performance during a working memory task was reinforced with either secondary (monetary) or primary (liquid) rewards. The temporal dynamics of motivation-cognition interactions were investigated by employing an experimental design that enabled isolation of sustained and transient effects. Performance was dramatically and equivalently enhanced in each incentive condition, whereas neural activity dynamics differed between incentive categories. The monetary reward condition was associated with a tonic activation increase in primarily right-lateralized cognitive control regions including anterior prefrontal cortex (PFC), dorsolateral PFC, and parietal cortex. In the liquid condition, the identical regions instead showed a shift in transient activation from a reactive control pattern (primary probe-based activation) during no-incentive trials to proactive control (primary cue-based activation) during rewarded trials. Additionally, liquid-specific tonic activation increases were found in subcortical regions (amygdala, dorsal striatum, nucleus accumbens), indicating an anatomical double dissociation in the locus of sustained activation.

Conclusions/Significance

These different activation patterns suggest that primary and secondary rewards may produce similar behavioral changes through distinct neural mechanisms of reinforcement. Further, our results provide new evidence for the flexibility of cognitive control, in terms of the temporal dynamics of activation.     

On synchronization in semelparous populations

Synchronization, i.e., convergence towards a dynamical state where the whole population is in one age class, is a characteristic feature of some population models with semelparity. We prove some rigorous results on this, for a simple class of nonlinear one- population models with age structure and semelparity: (i) the survival probabilities are assumed constant, and (ii) only the last age class is reproducing (semelparity), with fecundity decreasing with total population. For this model we prove: (a) The synchronized, or Single Year Class (SYC), dynamical state is always attracting. (b) The coexistence equilibrium is often unstable; we state and prove simple results on this. (c) We describe dynamical states with some, but not all, age classes populated, which we call Multiple Year Class (MYC) patterns, and we prove results extending (a) and (b) into these patterns.Acknowledgement Boris Kruglikov contributed the nonlinear part of the formulation as well as the proof of Theorem 1. The authors are grateful for critical and constructive comments by N. Davydova and O. Diekmann. E.M. is also grateful for discussions with Marius Overholt concerning problems of proving Theorem 2.     

Relations between visceral and behavioral function in men at bedrest

Multiple physiological measurements as well as a self-assessment of arousal was made in eight men on the first, third, and fifth days of bedrest. On the third day, additional measurements of performance on memory and dexterity tasks were made. Univariate analysis did not reveal any physiological variable to either predict subsequent performance well or to co-vary acutely with it; however, self-rating scores did prove to be useful predictors of subsequent performance. Principal components analysis suggested an "alertness" factor comprised of physiological measures as well as self-ratings which helped in predicting better performance. Although the individual patterns of correlations between variable on each of the three test days was variable, even more variability between subjects was found on the performance testing day. We believe this effect of behavioral activation may be due to the injection of common, slow temporal trends into many of the different data sets.     

Thermostability of endo-β-Xylanase from the thermophilic fungus Thermomyces lanuginosus

Summary The stability of endo--xylanase produced by the thermophilic fungus Thermomyces lanuginosus was examined at various temperatures and pH values. The enzyme was highly stable in the pH range from 6 to 9. The rate of inactivation was shown to follow first order kinetics. The half lives of enzyme activity as well as the activation energies of the inactivation at pH values between 5 and 11 were determined.     

Altered neural and behavioral dynamics in Huntington's disease: an entropy conservation approach

Background

Huntington''s disease (HD) is an inherited condition that results in neurodegeneration of the striatum, the forebrain structure that processes cortical information for behavioral output. In the R6/2 transgenic mouse model of HD, striatal neurons exhibit aberrant firing patterns that are coupled with reduced flexibility in the motor system. The aim of this study was to test the patterns of unpredictability in brain and behavior in wild-type (WT) and R6/2 mice.

Methodology/Principal Findings

Striatal local field potentials (LFP) were recorded from 18 WT and 17 R6/2 mice (aged 8–11 weeks) while the mice were exploring a plus-shaped maze. We targeted LFP activity for up to 2 s before and 2 s after each choice-point entry. Approximate Entropy (ApEn) was calculated for LFPs and Shannon Entropy was used to measure the probability of arm choice, as well as the likelihood of making consecutive 90-degree turns in the maze. We found that although the total number of choice-point crossings and entropy of arm-choice probability was similar in both groups, R6/2 mice had more predictable behavioral responses (i.e., were less likely to make 90-degree turns and perform them in alternation with running straight down the same arm), while exhibiting more unpredictable striatal activity, as indicated by higher ApEn values. In both WT and R6/2 mice, however, behavioral unpredictability was negatively correlated with LFP ApEn.

Conclusions/Significance

HD results in a perseverative exploration of the environment, occurring in concert with more unpredictable brain activity. Our results support the entropy conservation hypothesis in which unpredictable behavioral patterns are coupled with more predictable brain activation patterns, suggesting that this may be a fundamental process unaffected by HD.     

Toll-Like Receptor 9-Activation during Onset of Myocardial Ischemia Does Not Influence Infarct Extension

Aim

Myocardial infarction (MI) remains a major cause of death and disability worldwide, despite available reperfusion therapies. Inflammatory signaling is considered nodal in defining final infarct size. Activation of the innate immune receptor toll-like receptors (TLR) 9 prior to ischemia and reperfusion (I/R) reduces infarct size, but the consequence of TLR9 activation timed to the onset of ischemia is not known.

Methods and Results

The TLR9-agonist; CpG B was injected i.p. in C57BL/6 mice immediately after induction of ischemia (30 minutes). Final infarct size, as well as area-at-risk, was measured after 24 hours of reperfusion. CpG B injection resulted in a significant increase in circulating granulocytes and monocytes both in sham and I/R mice. Paradoxically, clear evidence of reduced cardiac infiltration of both monocytes and granulocytes could be demonstrated in I/R mice treated with CpG B (immunocytochemistry, myeloperoxidase activity and mRNA expression patterns). In addition, systemic TLR9 activation elicited significant alterations of cardiac inflammatory genes. Despite these biochemical and cellular changes, there was no difference in infarct size between vehicle and CpG B treated I/R mice.

Conclusion

Systemic TLR9-stimulation upon onset of ischemia and subsequent reperfusion does not alter final infarct size despite causing clear alterations of both systemic and cardiac inflammatory parameters. Our results question the clinical usefulness of TLR9 activation during cardiac I/R.     

Phenethyl isothiocyanate exhibits antileukemic activity in vitro and in vivo by inactivation of Akt and activation of JNK pathways

Effects of phenethyl isothiocyanate (PEITC) have been investigated in human leukemia cells (U937, Jurkat, and HL-60) as well as in primary human acute myeloid leukemia (AML) cells in relation to apoptosis and cell signaling events. Exposure of cells to PEITC resulted in pronounced increase in the activation of caspase-3, -8, -9, cleavage/degradation of PARP, and apoptosis in dose- and time-dependent manners. These events were accompanied by the caspase-independent downregulation of Mcl-1, inactivation of Akt, as well as activation of Jun N-terminal kinase (JNK). Inhibition of PI3K/Akt by {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 significantly enhanced PEITC-induced apoptosis. Conversely, enforced activation of Akt by a constitutively active Akt construct markedly abrogated PEITC-mediated JNK activation, Mcl-1 downregulation, caspase activation, and apoptosis, and also interruption of the JNK pathway by pharmacological or genetically (e.g., siRNA) attenuated PEITC-induced apoptosis. Finally, administration of PEITC markedly inhibited tumor growth and induced apoptosis in U937 xenograft model in association with inactivation of Akt, activation of JNK, as well as downregulation of Mcl-1. Taken together, these findings represent a novel mechanism by which agents targeting Akt/JNK/Mcl-1 pathway potentiate PEITC lethality in transformed and primary human leukemia cells and inhibitory activity of tumor growth of U937 xenograft model.     

Urinary testosterone-metabolite levels and dominance rank in male and female bonobos (<Emphasis Type="Italic">Pan paniscus</Emphasis>)

The correlation between testosterone (T) and dominance rank may vary among species, and is expected to become stronger as the importance of aggressive competition for rank increases. However, it may also vary among social situations within a species, showing a stronger correlation during socially unstable periods. Knowledge on this topic in great apes, especially in females, is scant. This study presents the first data on the relationship between T and dominance rank in both sexes of the bonobo (Pan paniscus). For each period (four socially unstable and two stable ones), linear rank orders were determined and subsequently correlated with the accompanying mean urinary T-metabolite concentrations (measured as immunoreactive 5-androstan-17-ol-3-one). No correlation between these two variables was found for either sex among individuals during socially unstable or stable periods. Also, within an individual over the six periods, no relationship of T with rank could be demonstrated. These results suggest that either the outcomes of aggressions have no influence on T levels, or such clear outcomes appear insufficiently frequent to affect T levels over longer periods. Even during the unstable periods, the rate of aggressions was not higher than during stable periods, suggesting that frequencies of aggression have little effect on rank. Further analyses indeed demonstrated no correlation between frequencies of overall aggressions or any type of aggressive behavior separately, or rank. Perhaps factors other than the frequency of displayed aggressions alone have a marked influence on a bonobos rank, for example, coalition partners. Overall, in bonobos, T apparently does not form a physiological reflection of social status.     

Localization of importin α (Rch1) at the plasma membrane and subcellular redistribution during lymphocyte activation

Rch1 belongs to the importin subfamily and works as an adapter between karyophilic proteins and the nuclear import machinery. Its level of expression varies among species and tissues, and depends on the state of cellular metabolism. In the present study we examined the level of expression of nuclear envelope and nuclear transport proteins (Rch1, importin , lamins A/C, lamin B, gp210, p62 and transportin) after human lymphocyte activation with phytohemagglutinin. We observed that the level of Rch1 increases dramatically, especially in larger lymphocytes, in response to activation. Moreover, using immunoelectron microscopy, this nuclear transport factor was found to be localized at the plasma membrane and also in tracks from the cytoplasm through the nuclear envelope into the nucleus. Similar localization was also observed in the human melanoma cell line A375. In addition, metabolic activation led to a redistribution of Rch1 from the cytoplasm to both the plasma membrane and the nuclear interior. These results suggest that, during lymphocyte activation, Rch1 may be involved in a signal transduction pathway that involves the shuttling of karyophilic proteins from the plasma membrane to the nucleus. Edited by: U. Scheer     

The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors

Background

Platelets are involved in the thromboses that are central to myocardial infarctions and ischemic strokes. Such adverse cardiovascular events have day/night patterns with peaks in the morning (∼9AM), potentially related to endogenous circadian clock control of platelet activation. The objective was to test if the human endogenous circadian system influences (1) platelet function and (2) platelet response to standardized behavioral stressors. We also aimed to compare the magnitude of any effects on platelet function caused by the circadian system with that caused by varied standardized behavioral stressors, including mental arithmetic, passive postural tilt and mild cycling exercise.

Methodology/Principal Findings

We studied 12 healthy adults (6 female) who lived in individual laboratory suites in dim light for 240 h, with all behaviors scheduled on a 20-h recurring cycle to permit assessment of endogenous circadian function independent from environmental and behavioral effects including the sleep/wake cycle. Circadian phase was assessed from core body temperature. There were highly significant endogenous circadian rhythms in platelet surface activated glycoprotein (GP) IIb-IIIa, GPIb and P-selectin (6–17% peak-trough amplitudes; p≤0.01). These circadian peaks occurred at a circadian phase corresponding to 8–9AM. Platelet count, ATP release, aggregability, and plasma epinephrine also had significant circadian rhythms but with later peaks (corresponding to 3–8PM). The circadian effects on the platelet activation markers were always larger than that of any of the three behavioral stressors.

Conclusions/Significance

These data demonstrate robust effects of the endogenous circadian system on platelet activation in humans—independent of the sleep/wake cycle, other behavioral influences and the environment. The ∼9AM timing of the circadian peaks of the three platelet surface markers, including platelet surface activated GPIIb-IIIa, the final common pathway of platelet aggregation, suggests that endogenous circadian influences on platelet function could contribute to the morning peak in adverse cardiovascular events as seen in many epidemiological studies.     

A method for constructing data-based models of spiking neurons using a dynamic linear-static nonlinear cascade

This paper describes a general nonlinear dynamical model for neural system identification. It describes an algorithm for fitting a simple form of the model to spike train data, and reports on this algorithm's performance in identifying the structure and parameters of simulated neurons. The central element of the model is a Wiener-Bose dynamic nonlinearity that ensures that the model is able to approximate the behaviour of an arbitrary nonlinear dynamical system. Nonlinearities associated with spike generation and transmission are treated by placing the Wiener-Bose system in cascade with pulse frequency modulators and demodulators, and the static nonlinearity at the output of the Wiener-Bose system is decomposed into a rectifier and a multinomial. This simplifies the model without reducing its generality for neuronal system identification. Model elements can be characterised using standard methods of dynamical systems analysis, and the model has a simple form that can be implemented and simulated efficiently. This model bears a structural resemblance to real neurons; it may be regarded as a connectionist neuron that has been generalized in a realistic way to enable it to mimic the behaviour of an arbitrary nonlinear system, or conversely as a general nonlinear model that has been constrained to make it easy to fit to spike train data. Tests with simulated data show that the identification algorithm can accurately estimate the structure and parameters of neuron-like nonlinear dynamical systems using data sets containing only a few hundred spikes.     

A neural model of the dynamic activation of memory

We study an Attractor Neural Network that stores natural concepts, organized in semantic classes. The concepts are represented by distributed patterns over a space of attributes, and are related by both semantic and episodic associations. While semantic relations are expressed through an hierarchical coding over the attribute space, episodic links are realized via specific synaptic projections. Due to dynamic thresholds expressing neuronal fatigue, the network's behavior is characterized by convergence toward the concept patterns on a short time scale, and by transitions between the various patterns on a longer time scale. In its baseline, undamaged state, the network manifests semantic, episodic, and random transitions, and demonstrates the phenomen of priming. Modeling possible pathological changes, we have found that increasing the noise level or the rate of neuronal fatigue decreases the frequency of semantic transitions. When neurons characterized by large synaptic connectivity are deleted, semantic transitions decay before the episodic ones, in accordance with the findings in patients with Alzheimer's disease.     

Endogenous regulation of the acute inflammatory response

The acute inflammatory response has been triggered in rat lungs by deposition of IgG immune complexes. The inflammatory reaction triggered is highly tissue damaging and requires activation of NF-B with ensuing generation of chemokines and cytokines. Endogenous generation of IL-10 and IL-13 as well as secretory leukocyte protease inhibitor (SLPI), significantly regulates this inflammatory response. IL-10 and IL-13 attenuate NF-B activation by interfering with breakdown of IB, while SLPI likewise suppresses NF-B activation, but by interfering with breakdown of IB. Antibody induced blockade of IL-10, IL-13 or SLPI enhances NF-B activation in lung and exacerbates the lung inflammatory response and injury. These data indicate that endogenous IL-10, IL-13 and SLPI are important regulators of the inflammatory response by reducing gene activation with resultant generation of peptide mediators/cytokines and chemokines.     

Computational analysis reveals the coupling between bistability and the sign of a feedback loop in a TGF-β1 activation model

Background

Bistable behaviors are prevalent in cell signaling and can be modeled by ordinary differential equations (ODEs) with kinetic parameters. A bistable switch has recently been found to regulate the activation of transforming growth factor-β1 (TGF-β1) in the context of liver fibrosis, and an ordinary differential equation (ODE) model was published showing that the net activation of TGF-β1 depends on the balance between two antagonistic sub-pathways.

Results

Through modeling the effects of perturbations that affect both sub-pathways, we revealed that bistability is coupled with the signs of feedback loops in the model. We extended the model to include calcium and Krüppel-like factor 2 (KLF2), both regulators of Thrombospondin-1 (TSP1) and Plasmin (PLS). Increased levels of extracellular calcium, which alters the TSP1-PLS balance, would cause high levels of TGF-β1, resembling a fibrotic state. KLF2, which suppresses production of TSP1 and plasminogen activator inhibitor-1 (PAI1), would eradicate bistability and preclude the fibrotic steady-state. Finally, the loop PLS???TGF-β1???PAI1 had previously been reported as negative feedback, but the model suggested a stronger indirect effect of PLS down-regulating PAI1 to produce positive (double-negative) feedback in a fibrotic state. Further simulations showed that activation of KLF2 was able to restore negative feedback in the PLS???TGF-β1???PAI1 loop.

Conclusions

Using the TGF-β1 activation model as a case study, we showed that external factors such as calcium or KLF2 can induce or eradicate bistability, accompanied by a switch in the sign of a feedback loop (PLS???TGF-β1???PAI1) in the model. The coupling between bistability and positive/negative feedback suggests an alternative way of characterizing a dynamical system and its biological implications.