A computational mechanism for unified gain and timing control in the cerebellum

Precise gain and timing control is the goal of cerebellar motor learning. Because the basic neural circuitry of the cerebellum is homogeneous throughout the cerebellar cortex, a single computational mechanism may be used for simultaneous gain and timing control. Although many computational models of the cerebellum have been proposed for either gain or timing control, few models have aimed to unify them. In this paper, we hypothesize that gain and timing control can be unified by learning of the complete waveform of the desired movement profile instructed by climbing fiber signals. To justify our hypothesis, we adopted a large-scale spiking network model of the cerebellum, which was originally developed for cerebellar timing mechanisms to explain the experimental data of Pavlovian delay eyeblink conditioning, to the gain adaptation of optokinetic response (OKR) eye movements. By conducting large-scale computer simulations, we could reproduce some features of OKR adaptation, such as the learning-related change of simple spike firing of model Purkinje cells and vestibular nuclear neurons, simulated gain increase, and frequency-dependent gain increase. These results suggest that the cerebellum may use a single computational mechanism to control gain and timing simultaneously.     

Active touch, exploratory movements, and sensory prediction

The relation between somatosensory input and motor output is asymmetric. Somatosensation is associated with every movement an animal makes, but movement is not required for somatosensation. This symposium paper proposes a classification scheme for movement, in which movements are placed along a continuum that describes the role that somatosensory information plays during the movement. Fine sensorimotor control-manipulation and exploration-are found to fall to one extreme of the spectrum, and exploratory movements in particular are shown to possess characteristics that clearly distinguish them from other varieties of movement. Specifically, the exploratory process must permit animals to extract an object's features independently of the sequence of movements executed to explore the object. Based in part on our work on the rat vibrissal system, we suggest that exploration of objects may consist of two complementary levels of sensorimotor prediction operating in parallel. At the cognitive level, the animal might move so as to perform hypothesis testing about the identity or nature of the object. The particular hypothesis tests chosen by the animal might be implemented through sequences of control-level predictions that could be generated at the level of the brainstem and cerebellum.     

An hypothesis concerning the role of the Golgi apparatus in the phenomenon of memory

The hypothesis considers the anatomy and physiology of the memory-storing neuron from the viewpoint that an eccentrically placed nucleus with a Golgi Apparatus situated between it and the proximate cell membrane could be the mechanism for the storage and retrieval of experience and thought processes. Metabolites which enter the Golgi Apparatus are filtered and refined before being discharged from the surface which faces the cell membrane. They travel by the shortest route to a special location on the nearest part of the cell membrane. At this "favoured spot" the action potential is reactivated before the metabolites reach other parts of the membrane. Afferent impulses arriving via the synapses at the "favoured spot" and its tributary dendrites have priority controls the specific polarity of the cell, enabling it to record, store and reproduce the memory of its initial stimulus. Reinforcing stimuli cause the eccentric nucleus and Golgi Apparatus to move nearer to the favoured spot. This mechanism could be the basis of memory. The hypothesis may be applied to other observed phenomenon of brain function and might be submitted to experiment confirmation.     

An internal model architecture for novelty detection: implications for cerebellar and collicular roles in sensory processing

The cerebellum is thought to implement internal models for sensory prediction, but details of the underlying circuitry are currently obscure. We therefore investigated a specific example of internal-model based sensory prediction, namely detection of whisker contacts during whisking. Inputs from the vibrissae in rats can be affected by signals generated by whisker movement, a phenomenon also observable in whisking robots. Robot novelty-detection can be improved by adaptive noise-cancellation, in which an adaptive filter learns a forward model of the whisker plant that allows the sensory effects of whisking to be predicted and thus subtracted from the noisy sensory input. However, the forward model only uses information from an efference copy of the whisking commands. Here we show that the addition of sensory information from the whiskers allows the adaptive filter to learn a more complex internal model that performs more robustly than the forward model, particularly when the whisking-induced interference has a periodic structure. We then propose a neural equivalent of the circuitry required for adaptive novelty-detection in the robot, in which the role of the adaptive filter is carried out by the cerebellum, with the comparison of its output (an estimate of the self-induced interference) and the original vibrissal signal occurring in the superior colliculus, a structure noted for its central role in novelty detection. This proposal makes a specific prediction concerning the whisker-related functions of a region in cerebellar cortical zone A(2) that in rats receives climbing fibre input from the superior colliculus (via the inferior olive). This region has not been observed in non-whisking animals such as cats and primates, and its functional role in vibrissal processing has hitherto remained mysterious. Further investigation of this system may throw light on how cerebellar-based internal models could be used in broader sensory, motor and cognitive contexts.     

Evolution of a predictive internal model in an embodied and situated agent

We show how simulated robots evolved for the ability to display a context-dependent periodic behavior can spontaneously develop an internal model and rely on it to fulfill their task when sensory stimulation is temporarily unavailable. The analysis of some of the best evolved agents indicates that their internal model operates by anticipating sensory stimuli. More precisely, it anticipates functional properties of the next sensory state rather than the exact state that sensors will assume. The characteristics of the states that are anticipated and of the sensorimotor rules that determine how the agents react to the experienced states, however, ensure that they produce very similar behaviour during normal and blind phases in which sensory stimulation is available or is self-generated by the agent, respectively. Agents’ internal models also ensure an effective transition during the phases in which agents’ internal dynamics is decoupled and re-coupled with the sensorimotor flow. Our results suggest that internal models might have arisen for behavioral reasons and successively exapted for other cognitive functions. Moreover, the obtained results suggest that self-generated internal states should not necessarily match in detail the corresponding sensory states and might rather encode more abstract and motor-oriented information.     

Modelling the control of interceptive actions

In recent years, several phenomenological dynamical models have been formulated that describe how perceptual variables are incorporated in the control of motor variables. We call these short-route models as they do not address how perception-action patterns might be constrained by the dynamical properties of the sensory, neural and musculoskeletal subsystems of the human action system. As an alternative, we advocate a long-route modelling approach in which the dynamics of these subsystems are explicitly addressed and integrated to reproduce interceptive actions. The approach is exemplified through a discussion of a recently developed model for interceptive actions consisting of a neural network architecture for the online generation of motor outflow commands, based on time-to-contact information and information about the relative positions and velocities of hand and ball. This network is shown to be consistent with both behavioural and neurophysiological data. Finally, some problems are discussed with regard to the question of how the motor outflow commands (i.e. the intended movement) might be modulated in view of the musculoskeletal dynamics.     

陆地碳循环的动态非平衡假说

生态系统维持物质与能量的动态平衡是地球系统孕育与维持生物多样性的重要基础。自工业革命以来, 人类活动导致陆地生态系统的碳循环转变为动态非平衡,进而使陆地生态系统的结构与功能出现许多难以预测的变化动态。本文阐释了陆地生态系统碳循环的动态非平衡假说。该假说构建于陆地碳循环内部过程的四点基本特征和五类外部驱动因素。基于这些内部特征与外部因素, 本文归纳了陆地生态系统碳循环动态非平衡在不同时间与空间尺度的表达现象, 并从观测、实验与模型的角度讨论了其检测方法。陆地生态系统碳循环的动态非平衡假说不仅有助于我们理解复杂的陆地碳循环现象, 也为预测未来陆地碳汇动态提供了新的理论框架。     

Moving, sensing and learning with cerebellar damage

The cerebellum is a subcortical brain structure that is essential for learning and controlling movement. Recent work shows that the cerebellum also plays a role in certain perceptual abilities, beyond what would be expected secondary to poor movement control. This review covers these and other recent advances, focusing on how cerebellar damage affects human abilities ranging from sensory perception to movement control and motor learning.     

Reduction of a biochemical model with preservation of its basic dynamic properties

The complexity of full-scale metabolic models is a major obstacle for their effective use in computational systems biology. The aim of model reduction is to circumvent this problem by eliminating parts of a model that are unimportant for the properties of interest. The choice of reduction method is influenced both by the type of model complexity and by the objective of the reduction; therefore, no single method is superior in all cases. In this study we present a comparative study of two different methods applied to a 20D model of yeast glycolytic oscillations. Our objective is to obtain biochemically meaningful reduced models, which reproduce the dynamic properties of the 20D model. The first method uses lumping and subsequent constrained parameter optimization. The second method is a novel approach that eliminates variables not essential for the dynamics. The applications of the two methods result in models of eight (lumping), six (elimination) and three (lumping followed by elimination) dimensions. All models have similar dynamic properties and pin-point the same interactions as being crucial for generation of the oscillations. The advantage of the novel method is that it is algorithmic, and does not require input in the form of biochemical knowledge. The lumping approach, however, is better at preserving biochemical properties, as we show through extensive analyses of the models.     

Representation of Coarse-grained Potentials for Polymer Simulations

In order to be able to simulate long time and large space scale properties of polymer melts one has to resort to coarse grained models, for example by subdividing all polymers into parts and restricting attention to the center of mass positions and velocities of these parts. The dynamics of these variables is governed by Langevin equations in which the free energy obtained by integrating the remaining variables provides the potential of the conservative forces. In general this leads to many particle interactions on the coarse-grained level. Methods suggested in the literature to represent these many particle interactions by effective two body interactions are reviewed and a new method, based on the Gibbs-Bogoliubov inequality, is proposed. The reason why none of these methods is able to reproduce the pressure of the underlying atomistic model is discussed.     

When Kinesthesia Becomes Visual: A Theoretical Justification for Executing Motor Tasks in Visual Space

Several experimental studies in the literature have shown that even when performing purely kinesthetic tasks, such as reaching for a kinesthetically felt target with a hidden hand, the brain reconstructs a visual representation of the movement. In our previous studies, however, we did not observe any role of a visual representation of the movement in a purely kinesthetic task. This apparent contradiction could be related to a fundamental difference between the studied tasks. In our study subjects used the same hand to both feel the target and to perform the movement, whereas in most other studies, pointing to a kinesthetic target consisted of pointing with one hand to the finger of the other, or to some other body part. We hypothesize, therefore, that it is the necessity of performing inter-limb transformations that induces a visual representation of purely kinesthetic tasks. To test this hypothesis we asked subjects to perform the same purely kinesthetic task in two conditions: INTRA and INTER. In the former they used the right hand to both perceive the target and to reproduce its orientation. In the latter, subjects perceived the target with the left hand and responded with the right. To quantify the use of a visual representation of the movement we measured deviations induced by an imperceptible conflict that was generated between visual and kinesthetic reference frames. Our hypothesis was confirmed by the observed deviations of responses due to the conflict in the INTER, but not in the INTRA, condition. To reconcile these observations with recent theories of sensori-motor integration based on maximum likelihood estimation, we propose here a new model formulation that explicitly considers the effects of covariance between sensory signals that are directly available and internal representations that are ‘reconstructed’ from those inputs through sensori-motor transformations.     

Deformations in actin comets from rocketing beads

The mechanical and dynamical properties of the actin network are essential for many cellular processes like motility or division, and there is a growing body of evidence that they are also important for adhesion and trafficking. The leading edge of migrating cells is pushed out by the polymerization of actin networks, a process orchestrated by cross-linkers and other actin-binding proteins. In vitro physical characterizations show that these same proteins control the elastic properties of actin gels. Here we use a biomimetic system of Listeria monocytogenes, beads coated with an activator of actin polymerization, to assess the role of various actin-binding proteins in propulsion. We find that the properties of actin-based movement are clearly affected by the presence of cross-linkers. By monitoring the evolution of marked parts of the comet, we provide direct experimental evidence that the actin gel continuously undergoes deformations during the growth of the comet. Depending on the protein composition in the motility medium, deformations arise from either gel elasticity or monomer diffusion through the actin comet. Our findings demonstrate that actin-based movement is governed by the mechanical properties of the actin network, which are fine-tuned by proteins involved in actin dynamics and assembly.     

What we see is how we are: new paradigms in visual research

As most sensory modalities, the visual system needs to deal with very fast changes in the environment. Instead of processing all sensory stimuli, the brain is able to construct a perceptual experience by combining selected sensory input with an ongoing internal activity. Thus, the study of visual perception needs to be approached by examining not only the physical properties of stimuli, but also the brain's ongoing dynamical states onto which these perturbations are imposed. At least three different models account for this internal dynamics. One model is based on cardinal cells where the activity of few cells by itself constitutes the neuronal correlate of perception, while a second model is based on a population coding that states that the neuronal correlate of perception requires distributed activity throughout many areas of the brain. A third proposition, known as the temporal correlation hypothesis states that the distributed neuronal populations that correlate with perception, are also defined by synchronization of the activity on a millisecond time scale. This would serve to encode contextual information by defining relations between the features of visual objects. If temporal properties of neural activity are important to establish the neural mechanisms of perception, then the study of appropriate dynamical stimuli should be instrumental to determine how these systems operate. The use of natural stimuli and natural behaviors such as free viewing, which features fast changes of internal brain states as seen by motor markers, is proposed as a new experimental paradigm to study visual perception.     

Physiological and circuit mechanisms of postural control

The postural system maintains a specific body orientation and equilibrium during standing and during locomotion in the presence of many destabilizing factors (external and internal). Numerous studies in humans have revealed essential features of the functional organization of this system. Recent studies on different animal models have significantly supplemented human studies. They have greatly expanded our knowledge of how the control system operates, how the postural functions are distributed within different parts of CNS, and how these parts interact with each other to produce postural corrections and adjustments. This review outlines recent advances in the studies of postural control in quadrupeds, with special attention given the neuronal postural mechanisms.     

Optimal body size with respect to maximal speed for the yellow-spotted monitor lizard (Varanus panoptes; Varanidae)

Studies of locomotor performance often link variation in morphology with ecology. While maximum sprint speed is a commonly used performance variable, the absolute limits for this performance trait are not completely understood. Absolute maximal speed has often been shown to increase linearly with body size, but several comparative studies covering a large range of body sizes suggest that maximal speed does not increase indefinitely with body mass but rather reaches an optimum after which speed declines. Because of the comparative nature of these studies, it is difficult to determine whether this decrease is due to biomechanical constraints on maximal speed or is a consequence of phylogenetic inertia or perhaps relaxed selection for lower maximal speed at large body size. To explore this issue, we have examined intraspecific variations in morphology, maximal sprint speed, and kinematics for the yellow-spotted monitor lizard Varanus panoptes, which varied in body mass from 0.09 to 5.75 kg. We show a curvilinear relationship between body size and absolute maximal sprint speed with an optimal body mass with respect to speed of 1.245 kg. This excludes the phylogenetic inertia hypothesis, because this effect should be absent intraspecifically, while supporting the biomechanical constraints hypothesis. The relaxed selection hypothesis cannot be excluded if there is a size-based behavioral shift intraspecifically, but the biomechanical constraints hypothesis is better supported from kinematic analyses. Kinematic measurements of hind limb movement suggest that the distance moved by the body during the stance phase may limit maximum speed. This limit is thought to be imposed by a decreased ability of the bones and muscles to support body mass for larger lizards.     

Hill muscle model errors during movement are greatest within the physiologically relevant range of motor unit firing rates

This study evaluated the accuracy of Hill-type muscle models during movement. Hill-type models are ubiquitous in biomechanical simulations. They are attractive because of their computational simplicity and close relation to commonly measured experimental variables, but there have been surprisingly few experimental validations of these models during functionally relevant conditions. Our hypothesis was that model errors during movement are largest at the low motor unit firing rates most relevant to normal movement conditions. This hypothesis was evaluated in the cat soleus muscle activated either by electrical stimulation at physiological rates or via the crossed-extension reflex (CXR) thereby obtaining normal patterns of motor unit recruitment and rate modulation. These activation paradigms were applied during continuous movements approximately matched to locomotor length changes. The resulting muscle force was modeled using a common Hill model incorporating independent activation, tetanic length-tension and tetanic force-velocity properties. Errors for this model were greatest for stimulation rates between approximately 10-20Hz. Errors were especially large for muscles activated via the CXR, where most motor units appear to fire within this range. For large muscle excursions, such as those seen during normal locomotion, the errors for naturally activated muscle typically exceeded 50%, supporting our hypothesis and indicating that the Hill model is not appropriate for these conditions. Subsequent analysis suggested that model errors were due to the common Hill model's inability to account for the coupling between muscle activation and force-velocity properties that is most prevalent at the low motor unit firing rates relevant to normal activation.     

Role of the Kinesin Neck Region in Processive Microtubule-based Motility

Kinesin is a dimeric motor protein that can move along a microtubule for several microns without releasing (termed processive movement). The two motor domains of the dimer are thought to move in a coordinated, hand-over-hand manner. A region adjacent to kinesin's motor catalytic domain (the neck) contains a coiled coil that is sufficient for motor dimerization and has been proposed to play an essential role in processive movement. Recent models have suggested that the neck enables head-to-head communication by creating a stiff connection between the two motor domains, but also may unwind during the mechanochemical cycle to allow movement to new tubulin binding sites. To test these ideas, we mutated the neck coiled coil in a 560-amino acid (aa) dimeric kinesin construct fused to green fluorescent protein (GFP), and then assayed processivity using a fluorescence microscope that can visualize single kinesin–GFP molecules moving along a microtubule. Our results show that replacing the kinesin neck coiled coil with a 28-aa residue peptide sequence that forms a highly stable coiled coil does not greatly reduce the processivity of the motor. This result argues against models in which extensive unwinding of the coiled coil is essential for movement. Furthermore, we show that deleting the neck coiled coil decreases processivity 10-fold, but surprisingly does not abolish it. We also demonstrate that processivity is increased by threefold when the neck helix is elongated by seven residues. These results indicate that structural features of the neck coiled coil, although not essential for processivity, can tune the efficiency of single molecule motility.     

A family of plasmodesmal proteins with receptor-like properties for plant viral movement proteins

Plasmodesmata (PD) are essential but poorly understood structures in plant cell walls that provide symplastic continuity and intercellular communication pathways between adjacent cells and thus play fundamental roles in development and pathogenesis. Viruses encode movement proteins (MPs) that modify these tightly regulated pores to facilitate their spread from cell to cell. The most striking of these modifications is observed for groups of viruses whose MPs form tubules that assemble in PDs and through which virions are transported to neighbouring cells. The nature of the molecular interactions between viral MPs and PD components and their role in viral movement has remained essentially unknown. Here, we show that the family of PD-located proteins (PDLPs) promotes the movement of viruses that use tubule-guided movement by interacting redundantly with tubule-forming MPs within PDs. Genetic disruption of this interaction leads to reduced tubule formation, delayed infection and attenuated symptoms. Our results implicate PDLPs as PD proteins with receptor-like properties involved the assembly of viral MPs into tubules to promote viral movement.     

Gene Circuit Analysis of the Terminal Gap Gene huckebein

The early embryo of Drosophila melanogaster provides a powerful model system to study the role of genes in pattern formation. The gap gene network constitutes the first zygotic regulatory tier in the hierarchy of the segmentation genes involved in specifying the position of body segments. Here, we use an integrative, systems-level approach to investigate the regulatory effect of the terminal gap gene huckebein (hkb) on gap gene expression. We present quantitative expression data for the Hkb protein, which enable us to include hkb in gap gene circuit models. Gap gene circuits are mathematical models of gene networks used as computational tools to extract regulatory information from spatial expression data. This is achieved by fitting the model to gap gene expression patterns, in order to obtain estimates for regulatory parameters which predict a specific network topology. We show how considering variability in the data combined with analysis of parameter determinability significantly improves the biological relevance and consistency of the approach. Our models are in agreement with earlier results, which they extend in two important respects: First, we show that Hkb is involved in the regulation of the posterior hunchback (hb) domain, but does not have any other essential function. Specifically, Hkb is required for the anterior shift in the posterior border of this domain, which is now reproduced correctly in our models. Second, gap gene circuits presented here are able to reproduce mutants of terminal gap genes, while previously published models were unable to reproduce any null mutants correctly. As a consequence, our models now capture the expression dynamics of all posterior gap genes and some variational properties of the system correctly. This is an important step towards a better, quantitative understanding of the developmental and evolutionary dynamics of the gap gene network.     

From random walks to informed movement

The analysis of animal movement is a large and continuously growing field of research. Detailed knowledge about movement strategies is of crucial importance for understanding eco‐evolutionary dynamics at all scales – from individuals to (meta‐)populations. This and the availability of detailed movement and dispersal data motivated Nathan and colleagues to published their much appreciated call to base movement ecology on a more thorough mechanistic basis. So far, most movement models are based on random walks. However, even if a random walk might describe real movement patterns acceptably well, there is no reason to assume that animals move randomly. Therefore, mechanistic models of foraging strategies should be based on information use and memory in order to increase our understanding of the processes that lead to animal movement decisions. We present a mechanistic movement model of an animal with a limited perceptual range and basic information storage capacities. This ‘spatially informed forager’ constructs an internal map of its environment by using perception, memory and learned or evolutionarily acquired assumptions about landscape attributes. We analyse resulting movement patterns and search efficiencies and compare them to area restricted search strategies (ARS) and biased correlated random walks (BCRW) of omniscient individuals. We show that, in spite of their limited perceptual range, spatially informed individuals boost their foraging success and may perform much better than the best ARS. The construction of an internal map and the use of spatial information results in the emergence of a highly correlated walk between patches and a rather systematic search within resource clusters. Furthermore, the resulting movement patterns may include foray search behaviour. Our work highlights the strength of mechanistic modelling approaches and sets the stage for the development of more sophisticated models of memory use for movement decisions and dispersal.