Inactivation of PTEN and ZFHX3 in Mammary Epithelial Cells Alters Patterns of Collective Cell Migration.

Whole exome sequencing of invasive mammary carcinomas revealed the association of mutations in PTEN and ZFHX3 tumor suppressor genes (TSGs). We generated single and combined PTEN and ZFHX3 knock-outs (KOs) in the immortalized mammary epithelial cell line MCF10A to study the role of these genes and their potential synergy in migration regulation. Inactivation of PTEN, but not ZFHX3, induced the formation of large colonies in soft agar. ZFHX3 inactivation in PTEN KO, however, increased colony numbers and normalized their size. Cell migration was affected in different ways upon PTEN and ZFHX3 KO. Inactivation of PTEN enhanced coordinated cell motility and thus, the collective migration of epithelial islets and wound healing. In contrast, ZFHX3 knockout resulted in the acquisition of uncoordinated cell movement associated with the appearance of immature adhesive junctions (AJs) and the increased expression of the mesenchymal marker vimentin. Inactivation of the two TSGs thus induces different stages of partial epithelial-to-mesenchymal transitions (EMT). Upon double KO (DKO), cells displayed still another motile state, characterized by a decreased coordination in collective migration and high levels of vimentin but a restoration of mature linear AJs. This study illustrates the plasticity of migration modes of mammary cells transformed by a combination of cancer-associated genes.

Activity Stabilization in a Population Model of Working Memory by Sinusoidal and Noisy Inputs.

According to mechanistic theories of working memory (WM), information is retained as stimulus-dependent persistent spiking activity of cortical neural networks. Yet, how this activity is related to changes in the oscillatory profile observed during WM tasks remains a largely open issue. We explore joint effects of input gamma-band oscillations and noise on the dynamics of several firing rate models of WM. The considered models have a metastable active regime, i.e., they demonstrate long-lasting transient post-stimulus firing rate elevation. We start from a single excitatory-inhibitory circuit and demonstrate that either gamma-band or noise input could stabilize the active regime, thus supporting WM retention. We then consider a system of two circuits with excitatory intercoupling. We find that fast coupling allows for better stabilization by common noise compared to independent noise and stronger amplification of this effect by in-phase gamma inputs compared to anti-phase inputs. Finally, we consider a multi-circuit system comprised of two clusters, each containing a group of circuits receiving a common noise input and a group of circuits receiving independent noise. Each cluster is associated with its own local gamma generator, so all its circuits receive gamma-band input in the same phase. We find that gamma-band input differentially stabilizes the activity of the "common-noise" groups compared to the "independent-noise" groups. If the inter-cluster connections are fast, this effect is more pronounced when the gamma-band input is delivered to the clusters in the same phase rather than in the anti-phase. Assuming that the common noise comes from a large-scale distributed WM representation, our results demonstrate that local gamma oscillations can stabilize the activity of the corresponding parts of this representation, with stronger effect for fast long-range connections and synchronized gamma oscillations.

Mutational drivers of cancer cell migration and invasion.

Genomic instability and mutations underlie the hallmarks of cancer-genetic alterations determine cancer cell fate by affecting cell proliferation, apoptosis and immune response, and increasing data show that mutations are involved in metastasis, a crucial event in cancer progression and a life-threatening problem in cancer patients. Invasion is the first step in the metastatic cascade, when tumour cells acquire the ability to move, penetrate into the surrounding tissue and enter lymphatic and blood vessels in order to disseminate. A role for genetic alterations in invasion is not universally accepted, with sceptics arguing that cellular motility is related only to external factors such as hypoxia, chemoattractants and the rigidity of the extracellular matrix. However, increasing evidence shows that mutations might trigger and accelerate the migration and invasion of different types of cancer cells. In this review, we summarise data from published literature on the effect of chromosomal instability and genetic mutations on cancer cell migration and invasion.

The Activity of KIF14, Mieap, and EZR in a New Type of the Invasive Component, Torpedo-Like Structures, Predetermines the Metastatic Potential of Breast Cancer.

Intratumor morphological heterogeneity reflects patterns of invasive growth and is an indicator of the metastatic potential of breast cancer. In this study, we used this heterogeneity to identify molecules associated with breast cancer invasion and metastasis. The gene expression microarray data were used to identify genes differentially expressed between solid, trabecular, and other morphological arrangements of tumor cells. Immunohistochemistry was applied to evaluate the association of the selected proteins with metastasis. RNA-sequencing was performed to analyze the molecular makeup of metastatic tumor cells. High frequency of metastases and decreased metastasis-free survival were detected in patients either with positive expression of KIF14 or Mieap or negative expression of EZR at the tips of the torpedo-like structures in breast cancers. KIF14- and Mieap-positive and EZR-negative cells were mainly detected in the torpedo-like structures of the same breast tumors; however, their transcriptomic features differed. KIF14-positive cells showed a significant upregulation of genes involved in ether lipid metabolism. Mieap-positive cells were enriched in genes involved in mitophagy. EZR-negative cells displayed upregulated genes associated with phagocytosis and the chemokine-mediated signaling pathway. In conclusion, the positive expression of KIF14 and Mieap and negative expression of EZR at the tips of the torpedo-like structures are associated with breast cancer metastasis.

Role of synaptic nonlinearity in persistent firing rate shifts caused by external periodic forcing.

Information storage and processing in the brain largely relies on the neural population coding principle. In this framework, information is reflected in the population firing rate that reflects asynchronous irregular spiking of its constituent neurons. Periodic modulations of neural activity can lead to neural activity oscillations. Data indicate that such oscillations are ubiquitous in brain activity and are modulated, in frequency and amplitude, in a functionally meaningful manner. The relationship between oscillations and the population rate code remains an open issue. While ample works show how changes in the mean firing rate may alter neural oscillations, the reverse connection is unclear. One notable possibility is that oscillatory activity impinging on a neural population modulates its mean firing rate, thereby impacting information processing. We suggest that such modulation requires nonlinearities and propose nonlinear excitatory coupling via slow N-methyl-D-aspartate (NMDA) receptors as the prevalent mechanism. The aim of our paper is to theoretically explore to what extent the NMDA-related mechanism could account for oscillation-induced mean firing rate changes. We consider a mean-field model of a neural circuit containing an excitatory and an inhibitory population with linear transfer functions. Along with NMDA excitation, the model included fast recurrent excitatory and inhibitory connectivity. To explicitly study the effects of impinging oscillation on the rate dynamics, we subjected the circuit to a sinusoidal input signal imitating an input from distant brain regions or from a larger network into which the circuit is embedded. Using time-scale separation and time-averaging techniques, we developed a geometric method to determine the oscillation-induced mean firing rate shifts and validated it by numeric simulations of the model. Our results indicate that a large-amplitude stable firing rate shift requires nonlinear NMDA synapses on both the excitatory and the inhibitory populations. Our results delineate specific neural synaptic properties that enable neural oscillations to act as flexible modulators of the population rate code.

Markers of Cancer Cell Invasion: Are They Good Enough?

Invasion, or directed migration of tumor cells into adjacent tissues, is one of the hallmarks of cancer and the first step towards metastasis. Penetrating to adjacent tissues, tumor cells form the so-called invasive front/edge. The cellular plasticity afforded by different kinds of phenotypic transitions (epithelial-mesenchymal, collective-amoeboid, mesenchymal-amoeboid, and vice versa) significantly contributes to the diversity of cancer cell invasion patterns and mechanisms. Nevertheless, despite the advances in the understanding of invasion, it is problematic to identify tumor cells with the motile phenotype in cancer tissue specimens due to the absence of reliable and acceptable molecular markers. In this review, we summarize the current information about molecules such as extracellular matrix components, factors of epithelial-mesenchymal transition, proteases, cell adhesion, and actin cytoskeleton proteins involved in cell migration and invasion that could be used as invasive markers and discuss their advantages and limitations. Based on the reviewed data, we conclude that future studies focused on the identification of specific invasive markers should use new models one of which may be the intratumor morphological heterogeneity in breast cancer reflecting different patterns of cancer cell invasion.

Enhanced Theta-Band Coherence Between Midfrontal and Posterior Parietal Areas Reflects Post-feedback Adjustments in the State of Outcome Uncertainty.

Medial frontal cortex is currently viewed as the main hub of the performance monitoring system; upon detection of an error committed, it establishes functional connections with brain regions involved in task performance, thus leading to neural adjustments in them. Previous research has identified targets of such adjustments in the dorsolateral prefrontal cortex, posterior cortical regions, motor cortical areas, and subthalamic nucleus. Yet most of such studies involved visual tasks with relatively moderate cognitive load and strong dependence on motor inhibition - thus highlighting sensory, executive and motor effects while underestimating sensorimotor transformation and related aspects of decision making. Currently there is ample evidence that posterior parietal cortical areas are involved in task-specific neural processes of decision making (including evidence accumulation, sensorimotor transformation, attention, etc.) - yet, to our knowledge, no EEG studies have demonstrated post-error increase in functional connectivity in the theta-band between midfrontal and posterior parietal areas during performance on non-visual tasks. In the present study, we recorded EEG while subjects were performing an auditory version of the cognitively demanding attentional condensation task; this task involves rather non-straightforward stimulus-to-response mapping rules, thus, creating increased load on sensorimotor transformation. We observed strong pre-response alpha-band suppression in the left parietal area, which presumably reflected involvement of the posterior parietal cortex in task-specific decision-making processes. Negative feedback was followed by increased midfrontal theta-band power and increased functional coupling in the theta band between midfrontal and left parietal regions. This could be interpreted as activation of the performance monitoring system and top-down influence of this system on the posterior parietal regions involved in decision making, respectively. This inter-site coupling related to negative feedback was stronger for subjects who tended to commit errors with slower response times. Generally, current findings support the idea that slower errors are related to the state of outcome uncertainty caused by failures of task-specific processes, associated with posterior parietal regions.

Power of Feedback-Induced Beta Oscillations Reflect Omission of Rewards: Evidence From an EEG Gambling Study.

The functional role of high beta oscillations (20-35 Hz) during feedback processing has been suggested to reflect unexpected gains. Using a novel gambling task that separates gains and losses across blocks and directly compares reception of monetary rewards to a 'no-reward/punishment' condition with equal probability we aimed to further investigate the role of beta oscillations. When contrasting different feedback conditions across rewards, we found that a late low beta component (12-20 Hz) had increased in power during the omission of rewards relative to the reception of rewards, while no differences were observed during the loss domain. These findings may indicate that late low beta oscillations in the context of feedback processing may respond to omission of gains relative to other potential outcomes. We speculate that late low beta oscillations may operate as a learning mechanism that signals the brain to make future adequate decisions. Overall, our study provides new insights for the role of late low beta oscillations in reward processing.

Slow and Fast Responses: Two Mechanisms of Trial Outcome Processing Revealed by EEG Oscillations.

Cognitive control includes maintenance of task-specific processes related to attention, and non-specific regulation of motor threshold. Depending upon the nature of the behavioral tasks, these mechanisms may predispose to different kinds of errors, with either increased or decreased response time (RT) of erroneous responses relative to correct responses. Specifically, slow responses are related to attentional lapses and decision uncertainty, these conditions tending to delay RTs of both erroneous and correct responses. Here we studied if RT may be a valid approximation distinguishing trials with high and low levels of sustained attention and decision uncertainty. We analyzed response-related and feedback-related modulations in theta, alpha and beta band activity in the auditory version of the two-choice condensation task, which is highly demanding for sustained attention while involves no inhibition of prepotent responses. Depending upon response speed and accuracy, trials were divided into slow correct, slow erroneous, fast correct and fast erroneous. We found that error-related frontal midline theta (FMT) was present only on fast erroneous trials. The feedback-related FMT was equally strong on slow erroneous and fast erroneous trials. Late post-response posterior alpha suppression was stronger on erroneous slow trials. Feedback-related frontal beta was present only on slow correct trials. The data obtained cumulatively suggests that RT allows distinguishing the two types of trials, with fast trials related to higher levels of attention and low uncertainty, and slow trials related to lower levels of attention and higher uncertainty.

Robustness of persistent spiking to partial synchronization in a minimal model of synaptically driven self-sustained activity.

We study the behavior of a minimal model of synaptically sustained persistent activity that consists of two quadratic integrate-and-fire neurons mutually coupled via excitatory synapses. Importantly, each of the neurons is excitable, as opposed to an oscillator; hence when uncoupled it sits at a subthreshold rest state. When the constituent neurons are mutually coupled via sufficiently strong fast excitatory synapses, the system demonstrates bistability between a fixed point (quiescent background state) and a limit cycle (memory state with synaptically driven spiking activity). Previous work showed that this persistent activity can be stopped by an excitatory input that synchronizes the network. Here we analyzed how this persistent state reacts to partial synchronization. We considered three types of progressively more complex excitatory synaptic kernels: delta pulse, square, and exponential. The first two cases were treated analytically, and the latter case numerically. Using phase-plane methods, we characterized the shape of the region, such that all orbits starting within it correspond to infinite spike trains; this constitutes the persistent activity region. In the case of instant coupling, all such active orbits were neutrally stable; in the case of noninstant coupling, the activity region contained a unique stable limit cycle (so the activity region was the basin of attraction for the limit cycle). This limit cycle corresponded to purely antiphase spiking of two neurons. Increasing synchronization shifted the system toward the border of the activity region, eventually terminating spiking activity. We calculated three measures of robustness of the active state: width of the activity region in the phase plane, critical level of synchronization that can be tolerated by the persistent spiking activity, and speed of reconvergence to the limit cycle. Our analysis revealed that the self-sustained activity is more robust to synchronization when each individual neuron is closer to SNIC bifurcation (closer to being an intrinsic oscillator), the recurrent synaptic excitation is stronger, and the synaptic decay is slower, which is in agreement with the existing data on local circuits in the cortex that show sustained activity.

Theta and Alpha Band Modulations Reflect Error-Related Adjustments in the Auditory Condensation Task.

Error commission leads to adaptive adjustments in a number of brain networks that subserve goal-directed behavior, resulting in either enhanced stimulus processing or increased motor threshold depending on the nature of errors committed. Here, we studied these adjustments by analyzing post-error modulations of alpha and theta band activity in the auditory version of the two-choice condensation task, which is highly demanding for sustained attention while involves no inhibition of prepotent responses. Errors were followed by increased frontal midline theta (FMT) activity, as well as by enhanced alpha band suppression in the parietal and the left central regions; parietal alpha suppression correlated with the task performance, left central alpha suppression correlated with the post-error slowing, and FMT increase correlated with both behavioral measures. On post-error correct trials, left-central alpha band suppression started earlier before the response, and the response was followed by weaker FMT activity, as well as by enhanced alpha band suppression distributed over the entire scalp. These findings indicate that several separate neuronal networks are involved in post-error adjustments, including the midfrontal performance monitoring network, the parietal attentional network, and the sensorimotor network. Supposedly, activity within these networks is rapidly modulated after errors, resulting in optimization of their functional state on the subsequent trials, with corresponding changes in behavioral measures.