Discovering pathways by orienting edges in protein interaction networks

Modern experimental technology enables the identification of the sensory proteins that interact with the cells' environment or various pathogens. Expression and knockdown studies can determine the downstream effects of these interactions. However, when attempting to reconstruct the signaling networks and pathways between these sources and targets, one faces a substantial challenge. Although pathways are directed, high-throughput protein interaction data are undirected. In order to utilize the available data, we need methods that can orient protein interaction edges and discover high-confidence pathways that explain the observed experimental outcomes. We formalize the orientation problem in weighted protein interaction graphs as an optimization problem and present three approximation algorithms based on either weighted Boolean satisfiability solvers or probabilistic assignments. We use these algorithms to identify pathways in yeast. Our approach recovers twice as many known signaling cascades as a recent unoriented signaling pathway prediction technique and over 13 times as many as an existing network orientation algorithm. The discovered paths match several known signaling pathways and suggest new mechanisms that are not currently present in signaling databases. For some pathways, including the pheromone signaling pathway and the high-osmolarity glycerol pathway, our method suggests interesting and novel components that extend current annotations.     

Motifs in brain networks

Complex brains have evolved a highly efficient network architecture whose structural connectivity is capable of generating a large repertoire of functional states. We detect characteristic network building blocks (structural and functional motifs) in neuroanatomical data sets and identify a small set of structural motifs that occur in significantly increased numbers. Our analysis suggests the hypothesis that brain networks maximize both the number and the diversity of functional motifs, while the repertoire of structural motifs remains small. Using functional motif number as a cost function in an optimization algorithm, we obtain network topologies that resemble real brain networks across a broad spectrum of structural measures, including small-world attributes. These results are consistent with the hypothesis that highly evolved neural architectures are organized to maximize functional repertoires and to support highly efficient integration of information.     

Disintegrating brain networks: from syndromes to molecular nexopathies

In this issue of Neuron, Raj et?al. (2012) and Zhou et?al. (2012) use graph theory to suggest that neurodegenerative diseases spread diffusively via intrinsic brain networks. These studies provide a powerful model for understanding and predicting disease-specific profiles of neurodegeneration.     

Responses to novelty in staggerer mutant mice

Responses to novelty in normal C57BL/6 and staggerer mutant mice were recorded. The normal mice confronted a novel object in their familiar environment showed avoidance and burying responses while the staggerer mutant mice contacted it. When given the opportunity to move around freely in simultaneously presented novel and familiar environments, the mutant mice more quickly entered the novel areas than normal animals. these data reveal a significant decrease in the neophobic components of the neotic behaviour in the staggerer mice. However, since the mutant mice did not show a locomotor deficit, the impairment of neophobia seems not to be due to the gait abnormalities of these animals. The results support the view that the cerebellum may contribute to the organization of complex behaviours.     

Physostigmine effects on activity and reactions to novelty

Effects of 4 doses of physostigmine on reactions to novelty, rearing and ambulation in rats were observed in an exploration box which allowed free choice of novel and familiar halves. All 3 responses tended towards decreases with higher doses but, whereas this trend was significant for rearing and ambulation, it was only suggestive for reactions to novelty. The results were discussed in the light of views on cholinergically controlled habituation processes.     

Toxoplasma infection and response to novelty in mice

Three groups of mice were infected with Toxoplasma and used for behavioral testing using a Y-maze. One group was infected when adult and two groups congenitally, one of these born to dams infected during gestation, the other to dams chronically infected prior to mating. In an initial habituation period each mouse was exposed to a black arm and stem of the maze, entrance to a white arm being blocked by a transparent door. In a subsequent free-choice trial both arms were black and the mouse was free to explore all parts of the maze. During both periods infected mice were more active than controls. Infected mice engaged in less grooming behavior indicative of less approach-avoidance conflict than controls prior to entry into a choice arm at the beginning of the free-choice trial. Infected mice spent more time in the familiar than in the novel (previously blocked) arm during the free-choice trial; conversely, uninfected mice spent more time in the novel than in the familiar arm. It is suggested that the reported behavioural changes would lead to dissemination of the infection in the environment by ultimately making infected mouse intermediate hosts more susceptible to predation by domestic cats, the definitive hosts of Toxoplasma.     

Environmental enrichment decreases responding for visual novelty

Previous research has demonstrated that rats reared in an enriched condition (EC) with novel objects and social partners self-administer less amphetamine compared to rats raised in an isolated condition (IC). However, it is unclear if the enrichment-induced decrease in stimulant self-administration generalizes to non-drug rewards such as those provided by novel environmental stimuli. In the current study, EC, IC, and social condition (SC) rats were raised from 21 to 51 days of age before being tested in a two-lever operant conditioning chamber in which responding on one lever (active lever) resulted in illumination of a cue light. In Experiment 1, rats were initially assessed for baseline responding (no contingency) and then the contingent light was introduced. EC rats responded less than IC rats for the contingent light stimulus; however, EC rats also displayed a lower rate of baseline responding. In Experiment 2, rats were trained initially to lever press for a sucrose reward to decrease differences in baseline responding. While sucrose pretraining decreased baseline response differences between groups, EC rats still responded less for the contingent light stimulus than IC or SC rats. These results suggest that environmental enrichment decreases the incentive value of visual novelty.     

The frustrated brain: from dynamics on motifs to communities and networks

Cognitive function depends on an adaptive balance between flexible dynamics and integrative processes in distributed cortical networks. Patterns of zero-lag synchrony likely underpin numerous perceptual and cognitive functions. Synchronization fulfils integration by reducing entropy, while adaptive function mandates that a broad variety of stable states be readily accessible. Here, we elucidate two complementary influences on patterns of zero-lag synchrony that derive from basic properties of brain networks. First, mutually coupled pairs of neuronal subsystems—resonance pairs—promote stable zero-lag synchrony among the small motifs in which they are embedded, and whose effects can propagate along connected chains. Second, frustrated closed-loop motifs disrupt synchronous dynamics, enabling metastable configurations of zero-lag synchrony to coexist. We document these two complementary influences in small motifs and illustrate how these effects underpin stable versus metastable phase-synchronization patterns in prototypical modular networks and in large-scale cortical networks of the macaque (CoCoMac). We find that the variability of synchronization patterns depends on the inter-node time delay, increases with the network size and is maximized for intermediate coupling strengths. We hypothesize that the dialectic influences of resonance versus frustration may form a dynamic substrate for flexible neuronal integration, an essential platform across diverse cognitive processes.