Circumstantial evidence and explanatory models for synapses in large-scale spike recordings

Whether, when, and how causal interactions between neurons can be meaningfully studied from observations of neural activity alone are vital questions in neural data analysis. Here we aim to better outline the concept of functional connectivity for the specific situation where systems neuroscientists aim to study synapses using spike train recordings. In some cases, cross-correlations between the spikes of two neurons are such that, although we may not be able to say that a relationship is causal without experimental manipulations, models based on synaptic connections provide precise explanations of the data. Additionally, there is often strong circumstantial evidence that pairs of neurons are monosynaptically connected. Here we illustrate how circumstantial evidence for or against synapses can be systematically assessed and show how models of synaptic effects can provide testable predictions for pair-wise spike statistics. We use case studies from large-scale multi-electrode spike recordings to illustrate key points and to demonstrate how modeling synaptic effects using large-scale spike recordings opens a wide range of data analytic questions

On the Similarity of Functional Connectivity between Neurons Estimated across Timescales

A central objective in neuroscience is to understand how neurons interact. Such functional interactions have been estimated using signals recorded with different techniques and, consequently, different temporal resolutions. For example, spike data often have sub-millisecond resolution while some imaging techniques may have a resolution of many seconds. Here we use multi-electrode spike recordings to ask how similar functional connectivity inferred from slower timescale signals is to the one inferred from fast timescale signals. We find that functional connectivity is relatively robust to low-pass filtering—dropping by about 10% when low pass filtering at 10 hz and about 50% when low pass filtering down to about 1 Hz—and that estimates are robust to high levels of additive noise. Moreover, there is a weak correlation for physiological filters such as hemodynamic or Ca2+ impulse responses and filters based on local field potentials. We address the origin of these correlations using simulation techniques and find evidence that the similarity between functional connectivity estimated across timescales is due to processes that do not depend on fast pair-wise interactions alone. Rather, it appears that connectivity on multiple timescales or common-input related to stimuli or movement drives the observed correlations. Despite this qualification, our results suggest that techniques with intermediate temporal resolution may yield good estimates of the functional connections between individual neurons

Spatially distributed local fields in the hippocampus encode rat position

Although neuronal spikes can be readily detected from extracellular recordings, synaptic and subthreshold activity remains undifferentiated within the local field potential (LFP). In the hippocampus, neurons discharge selectively when the rat is at certain locations, while LFPs at single anatomical sites exhibit no such place-tuning. Nonetheless, because the representation of position is sparse and distributed, we hypothesized that spatial information can be recovered from multiple-site LFP recordings. Using high-density sampling of LFP and computational methods, we show that the spatiotemporal structure of the theta rhythm can encode position as robustly as neuronal spiking populations. Because our approach exploits the rhythmicity and sparse structure of neural activity, features found in many brain regions, it is useful as a general tool for discovering distributed LFP codes

Decreasing survival benefit from cardiac transplantation for outpatients as the waiting list lengthens

AbstractMany patients are accepted for cardiac transplantation during a period of clinical instability associated with a high risk of death, even though most can be discharged home to await transplantation. As the waiting lists lengthen, priority is awarded solely on the basis of the waiting time of outpatients, who now usually undergo transplantation after they have already survived a major period of jeopardy. To determine the impact of the current waiting times and priority system on the previously expected benefit offered by transplantation, 1-year actuarial survival without transplantation was recalculated after each month without transplantation for 214 potential candidates with an ejection fraction of 0.17 ± 0.05 discharged on tailored medical therapy after evaluation. These data were compared with the 1-year survival data of 88 outpatients who underwent transplantation.Actuarial survival after 1 year was 67% on tailored therapy compared with 88% after transplantation (p = 0.009). Death without transplantation was sudden in 43 of 51 patients, resulting from hemodynamic decompensation in 8. For outpatients already surviving 6 months without transplantation, actuarial survival over the next 12 months was 83% without transplantation. Thus, the expected improvement in survival after transplantation would be only 5% over the subsequent year for patients waiting 6 months, which is the waiting time for many outpatients. Such patients should be reevaluated to determine whether transplantation remains indicated during the next year

Rewiring Neural Interactions by Micro-Stimulation

Plasticity is a crucial component of normal brain function and a critical mechanism for recovery from injury. In vitro, associative pairing of presynaptic spiking and stimulus-induced postsynaptic depolarization causes changes in the synaptic efficacy of the presynaptic neuron, when activated by extrinsic stimulation. In vivo, such paradigms can alter the responses of whole groups of neurons to stimulation. Here, we used in vivo spike-triggered stimulation to drive plastic changes in rat forelimb sensorimotor cortex, which we monitored using a statistical measure of functional connectivity inferred from the spiking statistics of the neurons during normal, spontaneous behavior. These induced plastic changes in inferred functional connectivity depended on the latency between trigger spike and stimulation, and appear to reflect a robust reorganization of the network. Such targeted connectivity changes might provide a tool for rerouting the flow of information through a network, with implications for both rehabilitation and brain–machine interface applications

Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase

Objectives To evaluate the efficacy of two novel compounds against mycobacteria and determine the molecular basis of their action on DNA gyrase using structural and mechanistic approaches. Methods Redx03863 and Redx04739 were tested in antibacterial assays, and also against their target, DNA gyrase, using DNA supercoiling and ATPase assays. X-ray crystallography was used to determine the structure of the gyrase B protein ATPase sub-domain from Mycobacterium smegmatis complexed with the aminocoumarin drug novobiocin, and structures of the same domain from Mycobacterium thermoresistibile complexed with novobiocin, and also with Redx03863. Results Both compounds, Redx03863 and Redx04739, were active against selected Gram-positive and Gram-negative species, with Redx03863 being the more potent, and Redx04739 showing selectivity against M. smegmatis. Both compounds were potent inhibitors of the supercoiling and ATPase reactions of DNA gyrase, but did not appreciably affect the ATP-independent relaxation reaction. The structure of Redx03863 bound to the gyrase B protein ATPase sub-domain from M. thermoresistibile shows that it binds at a site adjacent to the ATP- and novobiocin-binding sites. We found that most of the mutations that we made in the Redx03863-binding pocket, based on the structure, rendered gyrase inactive. Conclusions Redx03863 and Redx04739 inhibit gyrase by preventing the binding of ATP. The fact that the Redx03863-binding pocket is distinct from that of novobiocin, coupled with the lack of activity of resistant mutants, suggests that such compounds could have potential to be further exploited as antibiotics

The Science Case for an Extended Spitzer Mission

Although the final observations of the Spitzer Warm Mission are currently scheduled for March 2019, it can continue operations through the end of the decade with no loss of photometric precision. As we will show, there is a strong science case for extending the current Warm Mission to December 2020. Spitzer has already made major impacts in the fields of exoplanets (including microlensing events), characterizing near Earth objects, enhancing our knowledge of nearby stars and brown dwarfs, understanding the properties and structure of our Milky Way galaxy, and deep wide-field extragalactic surveys to study galaxy birth and evolution. By extending Spitzer through 2020, it can continue to make ground-breaking discoveries in those fields, and provide crucial support to the NASA flagship missions JWST and WFIRST, as well as the upcoming TESS mission, and it will complement ground-based observations by LSST and the new large telescopes of the next decade. This scientific program addresses NASA's Science Mission Directive's objectives in astrophysics, which include discovering how the universe works, exploring how it began and evolved, and searching for life on planets around other stars.Comment: 75 pages. See page 3 for Table of Contents and page 4 for Executive Summar

A Novel Cre Recombinase Imaging System for Tracking Lymphotropic Virus Infection In Vivo

BACKGROUND:Detection, isolation, and identification of individual virus infected cells during long term infection are critical to advance our understanding of mechanisms of pathogenesis for latent/persistent viruses. However, current approaches to study these viruses in vivo have been hampered by low sensitivity and effects of cell-type on expression of viral encoded reporter genes. We have designed a novel Cre recombinase (Cre)-based murine system to overcome these problems, and thereby enable tracking and isolation of individual in vivo infected cells. METHODOLOGY/PRINCIPAL FINDINGS:Murine gammaherpesvirus 68 (MHV-68) was used as a prototypic persistent model virus. A Cre expressing recombinant virus was constructed and characterised. The virus is attenuated both in lytic virus replication, producing ten-fold lower lung virus titres than wild type virus, and in the establishment of latency. However, despite this limitation, when the sEGFP7 mouse line containing a Cre-activated enhanced green fluorescent protein (EGFP) was infected with the Cre expressing virus, sites of latent and persistent virus infection could be identified within B cells and macrophages of the lymphoid system on the basis of EGFP expression. Importantly, the use of the sEGFP7 mouse line which expresses high levels of EGFP allowed individual virus positive cells to be purified by FACSorting. Virus gene expression could be detected in these cells. Low numbers of EGFP positive cells could also be detected in the bone marrow. CONCLUSIONS/SIGNIFICANCE:The use of this novel Cre-based virus/mouse system allowed identification of individual latently infected cells in vivo and may be useful for the study and long-term monitoring of other latent/persistent virus infections