Detecting pairwise correlations in spike trains: an objective comparison of methods and application to the study of retinal waves.

Correlations in neuronal spike times are thought to be key to processing in many neural systems. Many measures have been proposed to summarise these correlations and of these the correlation index is widely used and is the standard in studies of spontaneous retinal activity. We show that this measure has two undesirable properties: it is unbounded above and confounded by firing rate. We list properties needed for a measure to fairly quantify and compare correlations. We propose a novel measure of correlation – the tiling coefficient. This coefficient, the correlation index and 33 other measures of correlation of spike times are blindly tested for the required properties on synthetic and experimental data. On the basis of this, we propose a measure to replace the correlation index. To demonstrate the benefits of this measure, we re-analyse data from six key studies investigating the role of spontaneous retinal activity on map formation which used the correlation index to draw their conclusions. We re-analyse data from β2KO and β2(TG) mutants, mutants lacking connexin isoforms and also the age-dependent changes in wild type correlations. Re-analysis of the data using this new measure can significantly change the conclusions. It leads to better quantification of correlations and therefore better inference from the data. We hope that this new measure will have wide applications, and will help clarify the role of activity in retinotopic map formation.

Preparation of Synaptosomes from Postmortem Human Prefrontal Cortex

Synaptosomes are a popular type of isolated synaptic fraction intensively used in neuroscience and cell biology. They are prepared by layering on density gradients and thought to consist largely of axonal endings with attached postsynaptic structures (Morgan, 1976), in contrast to synaptoneurosomes (Hollingsworth et al, 1985) which are prepared by filtration and are thought to consist largely of pinched-off dendritic spines with attached presynaptic structures. Although most studies of synaptosomes have utilized rodent or primate tissue, a score of studies have employed human samples derived from surgical specimens or postmortem brain. We recently described the isolation of synaptosomes from human postmortem prefrontal cortex to study the expression of synaptic microRNAs and other small RNAs in depression, schizophrenia and bipolar disorder (Smalheiser et al, 2014). This protocol alluded to methods and modifications that are scattered among several publications, and did not explain the reasons for the procedures chosen. Because our protocol differs from other published human synaptosome protocols in a variety of respects, we present here a detailed description of synaptosome preparation that should facilitate the use of this standardized synaptic fraction by other workers.

Combining genome-scale Drosophila 3D neuroanatomical data by bridging template brains

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The stereotyped structure of mammalian and invertebrate brains is a crucial determinant of their circuit organization. Thus large scale efforts to map circuit organization using 3D image data are underway in a number of model systems, including flies and mice. Many of these studies use registration of sample images to a standard template brain to enable co-visualization and spatial querying. However, studies often use distinct template brains, resulting in large islands of data which cannot be directly compared. To enable this comparison, we have constructed bridging registrations between template brains accounting for the vast majority of Drosophila melanogaster 3D neuroanatomical data. Furthermore, we solve the related problem of mapping data between the left and right brain hemispheres via the construction of mirroring registrations. Finally, we extend our approach across species to demonstrate its potential use in evolutionary studies of neural circuit structure and provide bridging registrations that link a new set of template brains generated for four Drosophila species that are divergent over 40 million years of evolution. We describe our strategy, document the freely available anatomical data and open source com- puter tools that we have generated and provide numerous examples of their use. This effort has unified data from over 30,000 publicly available images, with resources including the 3D atlas embodying the new standard Drosophila anatomical nomenclature and the largest single neuron databank yet available in any species. Over 20,000 registered images have been contributed to the Virtual Fly Brain project and can be viewed online at

Optimizing Real Time fMRI Neurofeedback for Therapeutic Discovery and Development

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While reducing the burden of brain disorders remains a top priority of organizations like the World Health Organization and National Institutes of Health (BRAIN, 2013), the development of novel, safe and effective treatments for brain disorders has been slow. In this paper, we describe the state of the science for an emerging technology, real time functional magnetic resonance imaging (rtfMRI) neurofeedback, in clinical neurotherapeutics. We review the scientific potential of rtfMRI and outline research strategies to optimize the development and application of rtfMRI neurofeedback as a next generation therapeutic tool. We propose that rtfMRI can be used to address a broad range of clinical problems by improving our understanding of brain-behavior relationships in order to develop more specific and effective interventions for individuals with brain disorders. We focus on the use of rtfMRI neurofeedback as a clinical neurotherapeutic tool to drive plasticity in brain function, cognition, and behavior. Our overall goal is for rtfMRI to advance personalized assessment and intervention approaches to enhance resilience and reduce morbidity by correcting maladaptive patterns of brain function in those with brain disorders.

Rapid transcriptional response to physiological neuronal activity in vivo revealed by transcriptome sequencing

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Neuronal activity serves as a gateway between external stimulus from environment and the brain, often inducing gene expression changes. Alternative splicing (AS) is a widespread mechanism of increasing the number of transcripts produced from a single gene and has been shown to alter properties of neuronal genes, such as ion channels and neurotransmitter receptors. Patterns of neural tissue-specific AS have been identified, often regulated by neuron-specific splicing factors that are essential for survival, demonstrating the importance of AS in neurons. In vitro studies of neuronal activity found AS changes in response to neuronal activity in addition to transcriptional ones, raising the question of whether such changes are recapitulated in vivo on behaviorally relevant timescales. We developed a paradigm for studying physiological neuronal activity through controlled stimulation of the olfactory bulb, and performed RNA-Seq transcriptome analysis of olfactory bulbs from odor-deprived and stimulated mice. We found that physiological stimulation induces large, rapid and reproducible changes in transcription in vivo, and that the activation of a core set of activity-regulated factors is recapitulated in an in vitro model of neuronal stimulation. However, physiological activity did not induce global changes in post-transcriptional mRNA processing, such as AS or alternative cleavage and polyadenylation. In contrast, analysis of RNA-Seq from in vitro stimulation models showed rapid activity-dependent changes in both transcription and mRNA processing. Our results provide the first genome-wide look at neuronal activity-dependent mRNA processing and suggest that rapid changes in AS might not be the dominant form of transcriptome alterations that take place during olfactory rodent behavior.

Untangling cross-frequency coupling in neuroscience

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Cross-frequency coupling (CFC) has been proposed to coordinate neural dynamics across spatial and temporal scales. Despite its potential relevance for understanding healthy and pathological brain function, critical evaluation of the available methods for CFC analysis has been lacking. Here we aim to unravel several fundamental problems with the current standard analysis for CFC that make it non-specific and difficult to interpret physiologically. We show that apparent CFC can arise because of spectral correlations due to common non-stationarities and non-linear effects that might be unrelated to a true interaction between frequency components. After reviewing common problems in CFC analysis, we discuss how different statistical/modeling approaches to CFC can be conceptually organized according to their biophysical interpretability and statistical inference approach. This classification provides a possible road-map towards mechanistic understanding of cross-frequency coupling. We end with a list of practical recommendations to avoid common errors and enhance the interpretability of the analysis.

Boymaw, Overexpressed in Brains with Major Psychiatric Disorders, May Encode a Small Protein to Inhibit Mitochondrial Function and Protein Translation

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The t(1,11) chromosome translocation co-segregates with major psychiatric disorders in a large Scottish family. The translocation disrupts the DISC1and Boymaw (DISC1FP1) genes on chromosomes 1 and 11, respectively. After translocation, two fusion genes are generated. Our recent studies found that the DISC1-Boymaw fusion protein is localized in mitochondria and inhibits oxidoreductase activity, rRNA expression, and protein translation. Mice carrying the DISC1-Boymaw fusion genes display intermediate behavioral phenotypes related to major psychiatric disorders. Here, we report that the Boymaw gene encodes a small protein predominantly localized in mitochondria. The Boymaw protein inhibits oxidoreductase activity, rRNA expression, and protein translation in the same way as the DISC1-Boymaw fusion protein. Interestingly, Boymaw expression is up-regulated by different stressors at RNA and/or protein translational levels. In addition, we found that Boymaw RNA expression is significantly increased in the postmortem brains of patients with major psychiatric disorders. Our studies therefore suggest that the Boymaw gene is a potential susceptibility gene for major psychiatric disorders in both the Scottish t(1,11) family and the general population of patients.