How strong are correlations in strongly recurrent neuronal networks?

Cross-correlations in the activity in neural networks are commonly used to characterize their dynamical states and their anatomical and functional organizations. Yet, how these latter network features affect the spatiotemporal structure of the correlations in recurrent networks is not fully understood. Here, we develop a general theory for the emergence of correlated neuronal activity from the dynamics in strongly recurrent networks consisting of several populations of binary neurons. We apply this theory to the case in which the connectivity depends on the anatomical or functional distance between the neurons. We establish the architectural conditions under which the system settles into a dynamical state where correlations are strong, highly robust and spatially modulated. We show that such strong correlations arise if the network exhibits an effective feedforward structure. We establish how this feedforward structure determines the way correlations scale with the network size and the degree of the connectivity. In networks lacking an effective feedforward structure correlations are extremely small and only weakly depend on the number of connections per neuron. Our work shows how strong correlations can be consistent with highly irregular activity in recurrent networks, two key features of neuronal dynamics in the central nervous system

Short-term plasticity explains irregular persistent activity in working memory tasks

Persistent activity in cortex is the neural correlate of working memory (WM). In persistent activity, spike trains are highly irregular, even more than in baseline. This seemingly innocuous feature challenges our current understanding of the synaptic mechanisms underlying WM. Here we argue that in WM the prefrontal cortex (PFC) operates in a regime of balanced excitation and inhibition and that the observed temporal irregularity reflects this regime. We show that this requires that nonlinearities underlying the persistent activity are primarily in the neuronal interactions between PFC neurons. We also show that short-term synaptic facilitation can be the physiological substrate of these nonlinearities and that the resulting mechanism of balanced persistent activity is robust, in particular with respect to changes in the connectivity. As an example, we put forward a computational model of the PFC circuit involved in oculomotor delayed response task. The novelty of this model is that recurrent excitatory synapses are facilitating. We demonstrate that this model displays direction-selective persistent activity. We find that, even though the memory eventually degrades because of the heterogeneities, it can be stored for several seconds for plausible network size and connectivity. This model accounts for a large number of experimental findings, such as the findings that have shown that firing is more irregular during the persistent state than during baseline, that the neuronal responses are very diverse, and that the preferred directions during cue and delay periods are strongly correlated but tuning widths are not.Fil: Hansel, David. University Paris Descartes. Laboratory of Neurophysics and Physiology; Francia. University Paris Descartes. Institute of Neuroscience and Cognition; FranciaFil: Mato, German. Comision Nacional de Energia Atomica. Gerencia del Area de Investigaciones y Aplicaciones no Nucleares. Gerencia de Fisica (CAB); Argentina. Comisión Nacional de Energía Atómica. Gerencia del Area de Energía Nuclear. Instituto Balseiro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Emergent Orientation Selectivity from Random Networks in Mouse Visual Cortex

The connectivity principles underlying the emergence of orientation selectivity in primary visual cortex (V1) of mammals lacking an orientation map (such as rodents and lagomorphs) are poorly understood. We present a computational model in which random connectivity gives rise to orientation selectivity that matches experimental observations. The model predicts that mouse V1 neurons should exhibit intricate receptive fields in the two-dimensional frequency domain, causing a shift in orientation preferences with spatial frequency. We find evidence for these features in mouse V1 using calcium imaging and intracellular whole-cell recordings. Pattadkal et al. show that orientation selectivity can emerge from random connectivity, and offer a distinct perspective for how computations occur in the neocortex. They propose that a random convergence of inputs can provide signals for orientation preference in contrast with the dominant model that requires a precise arrangement.Fil: Pattadkal, Jagruti J.. University of Texas at Austin; Estados UnidosFil: Mato, German. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: van Vreeswijk, Carl. Centre National de la Recherche Scientifique; FranciaFil: Priebe, Nicholas J.. University of Texas at Austin; Estados UnidosFil: Hansel, David. Centre National de la Recherche Scientifique; Franci

Small Molecule Inhibitor Design for Anaplastic Lymphoma Kinase Inhibition

The Anaplastic Lymphoma Kinase (ALK) gene has been linked to tumorigenesis in a number of human cancers, including anaplastic large cell lymphoma (ALCL) and neuroblastoma. While ALK mutations in ALCL and many other cancers occur as a result of gene fusions with wild type kinase domains, those in neuroblastoma stem from single nucleotide polymorphisms (SNPs) in the kinase domain. These lead to autophosphorylation and constitutive signaling by ALK for cell growth and division, ultimately causing cancer. Crizotinib, an ATP-competitive ALK inhibitor, has proven to be an effective inhibitor of both ALKWT and ALKMutant kinase domains, and is in the middle of clinical trials for neuroblastoma treatment. This review used the PyMOL and AutoDock Vina computational biology programs to predict the binding affinities of Crizotinib, Ceritinib (LDK378), and PF-922 to three different ALK kinase mutations in order to determine the most effective inhibitor. The EGFR inhibitors gefitinib and erlotinib were also analyzed in complex with ALK as negative controls to verify the specificity of the ALK inhibitors. The crystalline complexes were then qualitatively analyzed to uncover the mechanics behind the docking results. Based on the results generated by Vina, PF-922, representative of the second generation of ALK inhibitors, is predicted to be the most effective out of the tested compounds. These results may be used to predict the inhibitor that will require the lowest dosage to achieve the greatest inhibitory effect, hopefully leading to fewer side effects from treatment

Gene profiling suggests a common evolution of bladder cancer subtypes

Abstract Background Bladder cancer exists as several distinct subtypes, including urothelial carcinoma (UCa), squamous cell carcinoma (SCCa), adenocarcinoma and small cell carcinoma. These entities, despite showing distinct morphology and clinical behavior, arise from the urothelial lining and are often accompanied by similar precursor/in situ findings. The relationship between these subtypes has not been explored in detail. Methods We compared gene expression analysis of the two most common subtypes of bladder cancer, UCa (n = 10) and SCCa (n = 9), with an additional comparison to normal urothelium from non-cancer patients (n = 8) using Affymetrix GeneChip Human genome arrays (Affymetrix, Santa Clara, CA). The results were stratified by supervised and unsupervised clustering analysis, as well as by overall fold change in gene expression. Results When compared to normal urothelium, UCa showed differential expression of 155 genes using a 5-fold cut-off. Examples of differentially regulated genes included topoisomerases, cancer-related transcription factors and cell cycle mediators. A second comparison of normal urothelium to SCCa showed differential expression of 503 genes, many of which were related to squamous-specific morphology (desmosomal complex, intermediate filaments present within squamous epithelium, squamous cornifying proteins, and molecules upregulated in squamous carcinomas from other anatomic sites). When compared, 137 genes were commonly dysregulated in both UCa and SCCa as compared to normal urothelium. All dysregulated genes in UCa were shared in common with SCCa, with the exception of only 18 genes. Supervised clustering analysis yielded correct classification of lesions in 26/27 (96%) of cases and unsupervised clustering analysis yielded correct classification in 25/27 (92.6%) of cases. Conclusions The results from this analysis suggest that bladder SCCa shares a significant number of gene expression changes with conventional UCa, but also demonstrates an additional set of alterations that is unique to this entity that defines the squamous phenotype. The similarity in deregulated gene products suggests that SCCa may be a much more closely related entity at the molecular level to conventional UCa than previously hypothesized

Mechanisms of Firing Patterns in Fast-Spiking Cortical Interneurons

Cortical fast-spiking (FS) interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequency tonic firing and rhythmic or irregular bursting (stuttering). What is the origin of this variability? In the present paper, we hypothesize that it emerges naturally if one assumes a continuous distribution of properties in a small set of active channels. To test this hypothesis, we construct a minimal, single-compartment conductance-based model of FS cells that includes transient Na+, delayed-rectifier K+, and slowly inactivating d-type K+ conductances. The model is analyzed using nonlinear dynamical system theory. For small Na+ window current, the neuron exhibits high-frequency tonic firing. At current threshold, the spike response is almost instantaneous for small d-current conductance, gd, and it is delayed for larger gd. As gd further increases, the neuron stutters. Noise substantially reduces the delay duration and induces subthreshold oscillations. In contrast, when the Na+ window current is large, the neuron always fires tonically. Near threshold, the firing rates are low, and the delay to firing is only weakly sensitive to noise; subthreshold oscillations are not observed. We propose that the variability in the response of cortical FS neurons is a consequence of heterogeneities in their gd and in the strength of their Na+ window current. We predict the existence of two types of firing patterns in FS neurons, differing in the sensitivity of the delay duration to noise, in the minimal firing rate of the tonic discharge, and in the existence of subthreshold oscillations. We report experimental results from intracellular recordings supporting this prediction

Family medicine around the world: overview by region: The Besrour Papers: a series on the state of family medicine in the world.

OBJECTIVE: To demonstrate how family medicine has been recognized and integrated into primary health care systems in contrasting contexts around the world and to provide an overview of how family physicians are trained and certified. COMPOSITION OF THE COMMITTEE: Since 2012, the College of Family Physicians of Canada has hosted the Besrour Conferences to reflect on its role in advancing the discipline of family medicine globally. The Besrour Papers Working Group, which was struck at the 2013 conference, was tasked with developing a series of papers to highlight the key issues, lessons learned, and outcomes emerging from the various activities of the Besrour collaboration. The working group comprised members of various academic departments of family medicine in Canada and abroad who attended the conferences. METHODS: An initial search was conducted in PubMed using a family medicine hedge of MeSH terms, text words, and family medicine journals, combined with text words and terms representing low- and middle-income countries and the concept of family medicine training programs. A second search was completed using only family medicine terms in the CAB Direct and World Bank databases. Subsequent PubMed searches were conducted to identify articles about specific conditions or services based on suggestions from the authors of the articles selected from the second search. Additional articles were identified through reference lists of key articles and through Google searches. We then attempted to verify and augment the information through colleagues and partners. REPORT: The scope of family medicine and the nature of family medicine training vary considerably worldwide. Challenges include limited capacity, incomplete understanding of roles, and variability of standards and recognition. Opportunities for advancement might include technology, collaboration, changes in pedagogy, flexible training methods, and system-wide support