Structural and functional map for forelimb movement phases between cortex and medulla

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A midbrain-thalamus-cortex circuit reorganizes cortical dynamics to initiate movement

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Regulation of motor circuit assembly by spatial and temporal mechanisms

Precision of synaptic connections in neuronal circuits is the product of an orderly assembly process during development. Circuits controlling motor behavior have been studied extensively in many animal species, allowing an assessment of evolutionarily conserved organizational principles that underlie neuronal subtype specification, connectivity and function. Across phylogenetically distant species, motor circuit assembly is based on spatial organization of interconnected circuit elements. Developmental molecular coordinate systems demarcate dendritic and axonal targeting territories, thereby regulating convergence of synaptic partners. Additional mechanisms subsequently control fine synaptic connection specificity within these domains. Spatial organization often correlates with the orderly sequence of neurogenesis contributing to the generation of distinct postmitotic neuronal subpopulations, a developmental strategy implemented far beyond motor circuits.     

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.     

Metrics for cortical map organization and lateralization

Cerebral lateralization refers to the poorly understood fact that some functions are better controlled by one side of the brain than the other (e.g. handedness, language). Of particular concern here are the asymmetries apparent in cortical topographic maps that can be demonstrated electrophysiologically in mirror-image locations of the cerebral cortex. In spite of great interest in issues surrounding cerebral lateralization, methods for measuring the degree of organization and asymmetry in cortical maps are currently quite limited. In this paper, several measures are developed and used to assess the degree of organization, lateralization, and mirror symmetry in topographic map formation. These measures correct for large constant displacements as well as curving of maps. The behavior of the measures is tested on several topographic maps obtained by self-organization of an initially random artificial neural network model of a bihemispheric brain, and the results are compared with subjective assessments made by humans.     

Distinct cortical and collicular mechanisms of inhibition of return revealed with S cone stimuli

Visual orienting of attention and gaze are widely considered to be mediated by shared neural pathways, with automatic phenomena such as inhibition of return (IOR)--the bias against returning to recently visited locations--being generated via the direct pathway from retina to superior colliculus (SC). Here, we show that IOR occurs without direct access to the SC, by using a technique that employs stimuli visible only to short-wave-sensitive (S) cones. We found that these stimuli, to which the SC is blind , were quite capable of eliciting IOR, measured by traditional manual responses. Critically, however, we found that S cone stimuli did not cause IOR when saccadic eye movement responses were required. This demonstrates that saccadic IOR is not the same as traditional IOR, providing support for two separate cortical and collicular mechanisms of IOR. These findings represent a clear dissociation between visual orienting of attention and gaze.     

Vision and cortical map development

Functional maps arise in developing visual cortex as response selectivities become organized into columnar patterns of population activity. Recent studies of developing orientation and direction maps indicate that both are sensitive to visual experience, but not to the same degree or duration. Direction maps have a greater dependence on early vision, while orientation maps remain sensitive to experience for a longer period of cortical maturation. There is also a darker side to experience: abnormal vision through closed lids produces severe impairments in neuronal selectivity, rendering these maps nearly undetectable. Thus, the rules that govern their formation and the construction of the underlying neural circuits are modulated-for better or worse-by early vision. Direction maps, and possibly maps of other properties that are dependent upon precise conjunctions of spatial and temporal signals, are most susceptible to the potential benefits and maladaptive consequences of early sensory experience.     

Reshaping sensory representations by task-specific brain states: Toward cortical circuit mechanisms

Perception is internally constructed by integrating brain states with external sensory inputs, a process depending on the topdown modulation of sensory representations. A wealth of earlier studies described task-dependent modulations of sensory cortex corroborating perceptual and behavioral phenomena. But only with recent technological advancements, the underlying circuit-level mechanisms began to be unveiled. We review recent progress along this line of research. It begins to be appreciated that topdown signals can encode various types of task-related information, ranging from task engagement, and category knowledge to decision execution; these signals are transferred via feedback pathways originating from distinct association cortices and interact with sensory cortical circuits. These plausible mechanisms support a broad range of computations from predictive coding to inference making, ultimately form dynamic percepts and endow behavioral flexibility.     

Multilevel monte carlo for cortical circuit models

Journal of Computational Neuroscience - Multilevel Monte Carlo (MLMC) methods aim to speed up computation of statistics from dynamical simulations. MLMC is easy to implement and is sometimes very...     

Distinct motor plans form and retrieve distinct motor memories for physically identical movements

We can adapt movements to a novel dynamic environment (e.g., tool use, microgravity, and perturbation) by acquiring an internal model of the dynamics. Although multiple environments can be learned simultaneously if each environment is experienced with different limb movement kinematics, it is controversial as to whether multiple internal models for a particular movement can be learned and flexibly retrieved according to behavioral contexts. Here, we address this issue by using a novel visuomotor task. While participants reached to each of two targets located at a clockwise or counter-clockwise position, a gradually increasing visual rotation was applied in the clockwise or counter-clockwise direction, respectively, to the on-screen cursor representing the unseen hand position. This procedure implicitly led participants to perform physically identical pointing movements irrespective of their intentions (i.e., movement plans) to move their hand toward two distinct visual targets. Surprisingly, if each identical movement was executed according to a distinct movement plan, participants could readily adapt these movements to two opposing force fields simultaneously. The results demonstrate that multiple motor memories can be learned and flexibly retrieved, even for physically identical movements, according to distinct motor plans in a visual space.     

Wholemount immunohistochemistry for revealing complex brain topography

The repeated and well-understood cellular architecture of the cerebellum make it an ideal model system for exploring brain topography. Underlying its relatively uniform cytoarchitecture is a complex array of parasagittal domains of gene and protein expression. The molecular compartmentalization of the cerebellum is mirrored by the anatomical and functional organization of afferent fibers. To fully appreciate the complexity of cerebellar organization we previously refined a wholemount staining approach for high throughput analysis of patterning defects in the mouse cerebellum. This protocol describes in detail the reagents, tools, and practical steps that are useful to successfully reveal protein expression patterns in the adult mouse cerebellum by using wholemount immunostaining. The steps highlighted here demonstrate the utility of this method using the expression of zebrinII/aldolaseC as an example of how the fine topography of the brain can be revealed in its native three-dimensional conformation. Also described are adaptations to the protocol that allow for the visualization of protein expression in afferent projections and large cerebella for comparative studies of molecular topography. To illustrate these applications, data from afferent staining of the rat cerebellum are included.     

Distinct mechanisms of neurodegeneration induced by chronic complex I inhibition in dopaminergic and non-dopaminergic cells

Chronic mitochondrial dysfunction, in particular of complex I, has been strongly implicated in the dopaminergic neurodegeneration in Parkinson's disease. To elucidate the mechanisms of chronic complex I disruption-induced neurodegeneration, we induced differentiation of immortalized midbrain dopaminergic (MN9D) and non-dopaminergic (MN9X) neuronal cells, to maintain them in culture without significant cell proliferation and compared their survivals following chronic exposure to nanomolar rotenone, an irreversible complex I inhibitor. Rotenone killed more dopaminergic MN9D cells than non-dopaminergic MN9X cells. Oxidative stress played an important role in rotenone-induced neurodegeneration of MN9X cells, but not MN9D cells: rotenone oxidatively modified proteins more in MN9X cells than in MN9D cells and antioxidants decreased rotenone toxicity only in MN9X cells. MN9X cells were also more sensitive to exogenous oxidants than MN9D cells. In contrast, disruption of bioenergetics played a more important role in MN9D cells: rotenone decreased mitochondrial membrane protential and ATP levels in MN9D cells more than in MN9X cells. Supplementation of cellular energy with a ketone body, D-beta-hydroxybutyrate, decreased rotenone toxicity in MN9D cells, but not in MN9X cells. MN9D cells were also more susceptible to disruption of oxidative phosphorylation or glycolysis than MN9X cells. These findings indicate that, during chronic rotenone exposure, MN9D cells die primarily through mitochondrial energy disruption, whereas MN9X cells die primarily via oxidative stress. Thus, intrinsic properties of individual cell types play important roles in determining the predominant mechanism of complex I inhibition-induced neurodegeneration.     

Distinct mechanisms for Ctr1-mediated copper and cisplatin transport

The Ctr1 family of integral membrane proteins is necessary for high affinity copper uptake in eukaryotes. Ctr1 is also involved in cellular accumulation of cisplatin, a platinum-based anticancer drug. Although the physiological role of Ctr1 has been revealed, the mechanism of action of Ctr1 remains to be elucidated. To gain a better understanding of Ctr1-mediated copper and cisplatin transport, we have monitored molecular dynamics and transport activities of yeast Saccharomyces cerevisiae Ctr1 and its mutant alleles. Co-expression of functional Ctr1 monomers fused with either cyan or yellow fluorescent protein resulted in fluorescence resonance energy transfer (FRET), which is consistent with multimer assembly of Ctr1. Copper near the K(m) value of Ctr1 enhanced FRET in a manner that correlated with cellular copper transport. In vitro cross-linking of Ctr1 confirmed that copper-induced FRET reflects conformational changes within pre-existing Ctr1 complexes. FRET assays in membrane-disrupted cells and protein extracts showed that intact cell structure is necessary for Ctr1 activity. Despite Ctr1-dependent cellular accumulation, cisplatin did not change Ctr1 FRET nor did it attenuate copper-induced FRET. A Ctr1 allele defective in copper transport enhanced cellular cisplatin accumulation. N-terminal methionine-rich motifs that are dispensable for copper transport play a critical role for cisplatin uptake. Taken together, our data reveal functional roles for structural remodeling of the Ctr1 multimeric complex in copper transport and suggest distinct mechanisms employed by Ctr1 for copper and cisplatin transport.     

Distinct mechanisms mediate visual detection and identification

A core organizing principle for studies of the brain is that distinct neural pathways mediate distinct behavioral tasks [1, 2]. When two related tasks are mediated by a common pathway, studies of one are likely to generalize to the other. Here, we test whether performance on two laboratory tasks that model object detection and identification are mediated by common mechanisms of visual adaptation. Although both tasks rely on the luminance pattern in images, their demands on visual processing are quite different. Object detection requires discriminating image luminance differences associated with the light reflected from adjacent objects. To encode these differences reliably, neurons adapt their limited dynamic range to prevailing viewing conditions [3-6]. Object identification, on the other hand, demands a fixed response to light reflected from an object independent of illumination [7]. We compared performance in discrimination and identification tasks for simulated surfaces. In striking contrast to studies with less structured contexts, we found clear evidence that distinct processes mediate judgments in the two tasks. These results challenge models that account for perceived lightness entirely through the action of image-encoding mechanisms.     

Distinct mechanisms of tumor invasion and metastasis

Most cancer deaths are caused by metastasis rather than the primary tumor. Cancer cells invade normal tissue as epithelial sheets or single cells by inducing expression of programs characteristic of developmental processes. Depending on their tissue of origin, cancer cells subsequently spread to distinct target organs where they seed secondary tumors (metastasis). Recent experimental evidence suggests that metastasis requires changes not only in cancer cells but also in the tumor microenvironment and in the metastatic target site. For example, a premetastatic niche is formed in target organs that attract cancer cells. Understanding the distinct mechanisms used by cancer cells to form metastasis will enable better patient evaluation and the design of innovative therapeutic approaches.