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2016
Rubin, J, Ulanovsky N, Nelken I, Tishby N.  2016.  The Representation of Prediction Error in Auditory Cortex.. PLoS computational biology. 12(8):e1005058. Abstract
To survive, organisms must extract information from the past that is relevant for their future. How this process is expressed at the neural level remains unclear. We address this problem by developing a novel approach from first principles. We show here how to generate low-complexity representations of the past that produce optimal predictions of future events. We then illustrate this framework by studying the coding of 'oddball' sequences in auditory cortex. We find that for many neurons in primary auditory cortex, trial-by-trial fluctuations of neuronal responses correlate with the theoretical prediction error calculated from the short-term past of the stimulation sequence, under constraints on the complexity of the representation of this past sequence. In some neurons, the effect of prediction error accounted for more than 50% of response variability. Reliable predictions often depended on a representation of the sequence of the last ten or more stimuli, although the representation kept only few details of that sequence.
Rubin, J, Ulanovsky N, Nelken I, Tishby N.  2016.  The Representation of Prediction Error in Auditory Cortex.. PLoS Comput Biol. 12(8): e1005058. Abstract
To survive, organisms must extract information from the past that is relevant for their future. How this process is expressed at the neural level remains unclear. We address this problem by developing a novel approach from first principles. We show here how to generate low-complexity representations of the past that produce optimal predictions of future events. We then illustrate this framework by studying the coding of 'oddball' sequences in auditory cortex. We find that for many neurons in primary auditory cortex, trial-by-trial fluctuations of neuronal responses correlate with the theoretical prediction error calculated from the short-term past of the stimulation sequence, under constraints on the complexity of the representation of this past sequence. In some neurons, the effect of prediction error accounted for more than 50% of response variability. Reliable predictions often depended on a representation of the sequence of the last ten or more stimuli, although the representation kept only few details of that sequence.
Gokhman, D, Meshorer E, Carmel L.  2016.  Epigenetics: It's Getting Old. Past Meets Future in Paleoepigenetics.. Trends in ecology & evolution. 31(4):290-300. Abstract
Recent years have witnessed the rise of ancient DNA (aDNA) technology, allowing comparative genomics to be carried out at unprecedented time resolution. While it is relatively straightforward to use aDNA to identify recent genomic changes, it is much less clear how to utilize it to study changes in epigenetic regulation. Here we review recent works demonstrating that highly degraded aDNA still contains sufficient information to allow reconstruction of epigenetic signals, including DNA methylation and nucleosome positioning maps. We discuss challenges arising from the tissue specificity of epigenetics, and show how some of them might in fact turn into advantages. Finally, we introduce a method to infer methylation states in tissues that do not tend to be preserved over time.
Pfeiffer, T, Heinze N, Frysch R, Deouell LY, Schoenfeld MA, Knight RT, Rose G.  2016.  Extracting duration information in a picture category decoding task using hidden Markov Models.. Journal of neural engineering. 13(2):026010. Abstract
Adapting classifiers for the purpose of brain signal decoding is a major challenge in brain-computer-interface (BCI) research. In a previous study we showed in principle that hidden Markov models (HMM) are a suitable alternative to the well-studied static classifiers. However, since we investigated a rather straightforward task, advantages from modeling of the signal could not be assessed.
Nitzan, E, Avraham O, Kahane N, Ofek S, Kumar D, Kalcheim C.  2016.  Dynamics of BMP and Hes1/Hairy1 signaling in the dorsal neural tube underlies the transition from neural crest to definitive roof plate.. BMC biology. 14:23. Abstract
The dorsal midline region of the neural tube that results from closure of the neural folds is generally termed the roof plate (RP). However, this domain is highly dynamic and complex, and is first transiently inhabited by prospective neural crest (NC) cells that sequentially emigrate from the neuroepithelium. It only later becomes the definitive RP, the dorsal midline cells of the spinal cord. We previously showed that at the trunk level of the axis, prospective RP progenitors originate ventral to the premigratory NC and progressively reach the dorsal midline following NC emigration. However, the molecular mechanisms underlying the end of NC production and formation of the definitive RP remain virtually unknown.
Siuda-Krzywicka, K, Bola Ł, Paplińska M, Sumera E, Jednoróg K, Marchewka A, Śliwińska MW, Amedi A, Szwed M.  2016.  Massive cortical reorganization in sighted Braille readers.. eLife. 5:e10762. Abstract
The brain is capable of large-scale reorganization in blindness or after massive injury. Such reorganization crosses the division into separate sensory cortices (visual, somatosensory...). As its result, the visual cortex of the blind becomes active during tactile Braille reading. Although the possibility of such reorganization in the normal, adult brain has been raised, definitive evidence has been lacking. Here, we demonstrate such extensive reorganization in normal, sighted adults who learned Braille while their brain activity was investigated with fMRI and transcranial magnetic stimulation (TMS). Subjects showed enhanced activity for tactile reading in the visual cortex, including the visual word form area (VWFA) that was modulated by their Braille reading speed and strengthened resting-state connectivity between visual and somatosensory cortices. Moreover, TMS disruption of VWFA activity decreased their tactile reading accuracy. Our results indicate that large-scale reorganization is a viable mechanism recruited when learning complex skills.
Cohen, E, Malka D, Shemer A, Shahmoon A, Zalevsky Z, London M.  2016.  Neural networks within multi-core optic fibers. Nature Publishing Group. Scientific Reports. 6:29080. Abstract
Hardware implementation of artificial neural networks facilitates real-time parallel processing of massive data sets. Optical neural networks offer low-volume 3D connectivity together with large bandwidth and minimal heat production in contrast to electronic implementation. Here, we present a conceptual design for in-fiber optical neural networks. Neurons and synapses are realized as individual silica cores in a multi-core fiber. Optical signals are transferred transversely between cores by means of optical coupling. Pump driven amplification in erbium-doped cores mimics synaptic interactions. We simulated three-layered feed-forward neural networks and explored their capabilities. Simulations suggest that networks can differentiate between given inputs depending on specific configurations of amplification; this implies classification and learning capabilities. Finally, we tested experimentally our basic neuronal elements using fibers, couplers, and amplifiers, and demonstrated that this configuration implements a neuron-like function. Therefore, devices similar to our proposed multi-core fiber could potentially serve as building blocks for future large-scale small-volume optical artificial neural networks.
Daadi, MM, Klausner JQ, Bajar B, Goshen I, Lee-Messer C, Lee S Y, Winge MCG, Ramakrishnan C, Lo M, Sun G et al..  2016.  Optogenetic Stimulation of Neural Grafts Enhances Neurotransmission and Downregulates the Inflammatory Response in Experimental Stroke Model.. Cell transplantation. 25(7):1371-80. Abstract
Compelling evidence suggests that transplantation of neural stem cells (NSCs) from multiple sources ameliorates motor deficits after stroke. However, it is currently unknown to what extent the electrophysiological activity of grafted NSC progeny participates in the improvement of motor deficits and whether excitatory phenotypes of the grafted cells are beneficial or deleterious to sensorimotor performances. To address this question, we used optogenetic tools to drive the excitatory outputs of the grafted NSCs and assess the impact on local circuitry and sensorimotor performance. We genetically engineered NSCs to express the Channelrhodopsin-2 (ChR2), a light-gated cation channel that evokes neuronal depolarization and initiation of action potentials with precise temporal control to light stimulation. To test the function of these cells in a stroke model, rats were subjected to an ischemic stroke and grafted with ChR2-NSCs. The grafted NSCs identified with a human-specific nuclear marker survived in the peri-infarct tissue and coexpressed the ChR2 transgene with the neuronal markers TuJ1 and NeuN. Gene expression analysis in stimulated versus vehicle-treated animals showed a differential upregulation of transcripts involved in neurotransmission, neuronal differentiation, regeneration, axonal guidance, and synaptic plasticity. Interestingly, genes involved in the inflammatory response were significantly downregulated. Behavioral analysis demonstrated that chronic optogenetic stimulation of the ChR2-NSCs enhanced forelimb use on the stroke-affected side and motor activity in an open field test. Together these data suggest that excitatory stimulation of grafted NSCs elicits beneficial effects in experimental stroke model through cell replacement and non-cell replacement, anti-inflammatory/neurotrophic effects.
Maidenbaum, S, Buchs G, Abboud S, Lavi-Rotbain O, Amedi A.  2016.  Perception of Graphical Virtual Environments by Blind Users via Sensory Substitution.. PloS one. 11(2):e0147501. Abstract
Graphical virtual environments are currently far from accessible to blind users as their content is mostly visual. This is especially unfortunate as these environments hold great potential for this population for purposes such as safe orientation, education, and entertainment. Previous tools have increased accessibility but there is still a long way to go. Visual-to-audio Sensory-Substitution-Devices (SSDs) can increase accessibility generically by sonifying on-screen content regardless of the specific environment and offer increased accessibility without the use of expensive dedicated peripherals like electrode/vibrator arrays. Using SSDs virtually utilizes similar skills as when using them in the real world, enabling both training on the device and training on environments virtually before real-world visits. This could enable more complex, standardized and autonomous SSD training and new insights into multisensory interaction and the visually-deprived brain. However, whether congenitally blind users, who have never experienced virtual environments, will be able to use this information for successful perception and interaction within them is currently unclear.We tested this using the EyeMusic SSD, which conveys whole-scene visual information, to perform virtual tasks otherwise impossible without vision. Congenitally blind users had to navigate virtual environments and find doors, differentiate between them based on their features (Experiment1:task1) and surroundings (Experiment1:task2) and walk through them; these tasks were accomplished with a 95% and 97% success rate, respectively. We further explored the reactions of congenitally blind users during their first interaction with a more complex virtual environment than in the previous tasks-walking down a virtual street, recognizing different features of houses and trees, navigating to cross-walks, etc. Users reacted enthusiastically and reported feeling immersed within the environment. They highlighted the potential usefulness of such environments for understanding what visual scenes are supposed to look like and their potential for complex training and suggested many future environments they wished to experience.
Porat, Y, Zohary E.  2016.  Practice Improves Peri-saccadic Shape Judgment but does not Diminish Target Mislocalization.. Proc Natl Acad Sci U S A. 113:46. Abstract
Visual sensitivity is markedly reduced during an eye movement. Peri-saccadic vision is also characterized by a mislocalization of the briefly presented stimulus closer to the saccadic target. These features are commonly viewed as obligatory elements of peri-saccadic vision. However, practice improves performance in many perceptual tasks performed at threshold conditions. We wondered if this could also be the case with peri-saccadic perception. To test this, we used a paradigm in which subjects reported the orientation (or location) of an ellipse briefly presented during a saccade. Practice on peri-saccadic orientation discrimination led to long-lasting gains in that task but did not alter the classical mislocalization of the visual stimulus. Shape discrimination gains were largely generalized to other untrained conditions when the same stimuli were used (discrimination during a saccade in the opposite direction or at a different stimulus location than previously trained). However, performance dropped to baseline level when participants shifted to a novel Vernier discrimination task under identical saccade conditions. Furthermore, practice on the location task did not induce better stimulus localization or discrimination. These results suggest that the limited visual information available during a saccade may be better used with practice, possibly by focusing attention on the specific target features or a better readout of the available information. Saccadic mislocalization, by contrast, is robust and resistant to top-down modulations, suggesting that it involves an automatic process triggered by the upcoming execution of a saccade (e.g., an efference copy signal).
Malkinson, T S, Pertzov Y, Zohary E.  2016.  Turning Symbolic: The Representation of Motion Direction in Working Memory.. Frontiers in psychology. 7:165. Abstract
What happens to the representation of a moving stimulus when it is no longer present and its motion direction has to be maintained in working memory (WM)? Is the initial, sensorial representation maintained during the delay period or is there another representation, at a higher level of abstraction? It is also feasible that multiple representations may co-exist in WM, manifesting different facets of sensory and more abstract features. To that end, we investigated the mnemonic representation of motion direction in a series of three psychophysical experiments, using a delayed motion-discrimination task (relative clockwise∖counter-clockwise judgment). First, we show that a change in the dots' contrast polarity does not hamper performance. Next, we demonstrate that performance is unaffected by relocation of the Test stimulus in either retinotopic or spatiotopic coordinate frames. Finally, we show that an arrow-shaped cue presented during the delay interval between the Sample and Test stimulus, strongly biases performance toward the direction of the arrow, although the cue itself is non-informative (it has no predictive value of the correct answer). These results indicate that the representation of motion direction in WM could be independent of the physical features of the stimulus (polarity or position) and has non-sensorial abstract qualities. It is plausible that an abstract mnemonic trace might be activated alongside a more basic, analog representation of the stimulus. We speculate that the specific sensitivity of the mnemonic representation to the arrow-shaped symbol may stem from the long term learned association between direction and the hour in the clock.
Tzour, A, Leibovich H, Barkai O, Biala Y, Lev S, Yaari Y, Binshtok AM.  2016.  KV 7/M channels as targets for lipopolysaccharide-induced inflammatory neuronal hyperexcitability.. The Journal of Physiology. Abstract
Acute brain insults and many chronic brain diseases manifest an innate inflammatory response. The hallmark of this response is glia activation, which promotes repair of damaged tissue, but also induces structural and functional changes that may lead to an increase in neuronal excitability. We have investigated the mechanisms involved in the modulation of neuronal activity by acute inflammation. Initiating inflammatory responses in hippocampal tissue rapidly led to neuronal depolarization and repetitive firing even in absence of active synaptic transmission. This action was mediated by a complex metabotropic purinergic and glutamatergic glia-to-neuron signalling cascade, leading to the blockade of neuronal KV 7/M channels by Ca(2+) released from internal stores. These channels generate the low voltage-activating, noninactivating M-type K(+) current (M-current) that controls intrinsic neuronal excitability, and its inhibition was the predominant cause of the inflammation-induced hyperexcitability. Our discovery that the ubiquitous KV 7/M channels are the downstream target of the inflammation-induced cascade, has far reaching implications for the understanding and treatment of many acute and chronic brain disorders. This article is protected by copyright. All rights reserved.
II, N, Caspi Y, Gudes S, Fishman D, Lev S, Hersfinkel M, Sekler I, Binshtok AM.  2016.  Privileged crosstalk between TRPV1 channels and mitochondrial calcium shuttling machinery controls nociception.. Molecular Cell Research. 1863(12):2868–2880. Abstract
The nociceptive noxious heat-activated receptor - TRPV1, conducts calcium and sodium, thus producing a depolarizing receptor potential, leading to activation of nociceptive neurons. TRPV1-mediated calcium and sodium influx is negatively modulated by calcium, via calcium-dependent desensitization of TRPV1 channels. A mitochondrial Ca(2+) uniporter - MCU, controls mitochondrial Ca(2+) entry while a sodium/calcium transporter - NCLX shapes calcium and sodium transients by mediating sodium entry into and removing calcium from the mitochondria. The functional interplay between TRPV1, MCU and NCLX, in controlling the cytosolic and mitochondrial calcium and sodium transients and subsequently the nociceptive excitability, is poorly understood. Here, we used cytosolic and mitochondrial fluorescent calcium and sodium imaging together with electrophysiological recordings of TRPV1-induced currents in HEK293T cells and nociceptor-like dissociated rat dorsal root ganglion neurons, while modulating NCLX or MCU expression using specific small interfering RNA (siNCLX). We show that the propagation of the TRPV1-induced cytosolic calcium and sodium fluxes into mitochondria is dependent on coordinated activity of NCLX and MCU. Thus, knocking-down of NCLX triggers down regulation of MCU dependent mitochondrial Ca(2+) uptake. This in turn decreases rate and amplitude of TRPV1-mediated cytosolic calcium, which inhibits capsaicin-induced inward current and neuronal firing. TRPV1-mediated currents were fully rescued by intracellular inclusion of the fast calcium chelator BAPTA. Finally, NCLX controls capsaicin-induced cell death, by supporting massive mitochondrial Ca(2+) shuttling. Altogether, our results suggest that NCLX, by regulating cytosolic and mitochondrial ionic transients, modulates calcium-dependent desensitization of TRPV1 channels, thereby, controlling nociceptive signaling.
Shteingart, H, Loewenstein Y.  2016.  Heterogeneous Suppression of Sequential Effects in Random Sequence Generation, but Not in Operant Learning. PloS one. 11(8):e0157643. AbstractPDF
There is a long history of experiments in which participants are instructed to generate a long sequence of binary random numbers. The scope of this line of research has shifted over the years from identifying the basic psychological principles and/or the heuristics that lead to deviations from randomness, to one of predicting future choices. In this paper, we used generalized linear regression and the framework of Reinforcement Learning in order to address both points. In particular, we used logistic regression analysis in order to characterize the temporal sequence of participants’ choices. Surprisingly, a population analysis indicated that the contribution of the most recent trial has only a weak effect on behavior, compared to more preceding trials, a result that seems irreconcilable with standard sequential effects that decay monotonously with the delay. However, when considering each participant separately, we found that the magnitudes of the sequential effect are a monotonous decreasing function of the delay, yet these individual sequential effects are largely averaged out in a population analysis because of heterogeneity. The substantial behavioral heterogeneity in this task is further demonstrated quantitatively by considering the predictive power of the model. We show that a heterogeneous model of sequential dependencies captures the structure available in random sequence generation. Finally, we show that the results of the logistic regression analysis can be interpreted in the framework of reinforcement learning, allowing us to compare the sequential effects in the random sequence generation task to those in an operant learning task. We show that in contrast to the random sequence generation task, sequential effects in operant learning are far more homogenous across the population. These results suggest that in the random sequence generation task, different participants adopt different cognitive strategies to suppress sequential dependencies when generating the “random” sequences.
Ravid-Tannenbaum, N, Burak Y.  2016.  Shaping Neural Circuits by High Order Synaptic Interactions. PLoS Computational Biology. 12(8):e1005056.2016_ravidtannenbaum_burak.pdf
DeFelipe, J, Douglas RJ, Hill SL, Lein ES, Martin KAC, Rockland KS, Segev I, Shepherd GM, Tamás G.  2016.  Comments and General Discussion on “The Anatomical Problem Posed by Brain Complexity and Size: A Potential Solution”. Frontiers in Neuroanatomy. 10 Abstract
This article gathers together different opinions on the current status and future directions of the study of the brain, taking as a working document the article “The anatomical problem posed by brain complexity and size: a potential solution” http://journal.frontiersin.org/article/10.3389/fnana. 2015.00104/full. These commentaries are followed by a section dedicated to a general discussion of the issues raised, in which all contributors participate. The authors who have contributed to this article are listed in alphabetical order. As the reader will see, there are different points of view and of course there are many other aspects that would need further discussion that have been raised by other scientists who did not participate directly. For example, Peter Somogyi made the following comment (personal communication): [“Anatomy” is a discipline and not a biological entity that exists in nature. Hence the brain or its cells do not have anatomy; we study them with anatomical methods (usually using microscopes) while we carry out “anatomical analysis.” The brain, its nuclei, cells, and their parts are the biological entities which several disciplines study, preferably together, providing a unified description and explanation of them. We must be clear about this, and avoid terms like “anatomical properties,” “physiological properties,” or “biochemical properties” as if these somehow existed in isolation. The separate disciplines, which developed historically due to the limitation of individual human brain capacity and short life span leading to methodological and conceptual specialization, are based on sets of methods, but study the same indivisible biological entity. E.g., the synaptic current recorded by electrophysiological methods flows through the membrane that we see in the electron microscope or with the help of antibodies to synaptic ion channels in the light microscope. Accordingly, the “anatomical problem” exists because of inadequate scientific rigor in addition to methodological limitations that are often not understood, not because of “brain complexity”.] This is just an example of the many possible different points of view when dealing with the subject of the anatomy of the brain. Thus, this article is not intended to be comprehensive, and the unavoidable limitations in the selection of comments, data, and their interpretation reflect, in many cases, the personal views and interests of the authors.
Amsalem, O, Geit W V, Muller E, Markram H, Segev I.  2016.  From Neuron Biophysics to Orientation Selectivity in Electrically Coupled Networks of Neocortical L2/3 Large Basket Cells.. Cerebral Cortex Advance Access. Abstract
In the neocortex, inhibitory interneurons of the same subtype are electrically coupled with each other via dendritic gap junctions (GJs). The impact of multiple GJs on the biophysical properties of interneurons and thus on their input processing is unclear. The present experimentally based theoretical study examined GJs in L2/3 large basket cells (L2/3 LBCs) with 3 goals in mind: (1) To evaluate the errors due to GJs in estimating the cable properties of individual L2/3 LBCs and suggest ways to correct these errors when modeling these cells and the networks they form; (2) to bracket the GJ conductance value (0.05–0.25 nS) and membrane resistivity (10 000–40 000 Ω cm2) of L2/3 LBCs; these estimates are tightly constrained by in vitro input resistance (131 ± 18.5 MΩ) and the coupling coefficient (1–3.5%) of these cells; and (3) to explore the functional implications of GJs, and show that GJs: (i) dynamically modulate the effective time window for synaptic integration; (ii) improve the axon’s capability to encode rapid changes in synaptic inputs; and (iii) reduce the orientation selectivity, linearity index, and phase difference of L2/3 LBCs. Our study provides new insights into the role of GJs and calls for caution when using in vitro measurements for modeling electrically coupled neuronal networks.
Mezer, A, Rokem A, Berman S, Hastie T, Wandell BA.  2016.  Evaluating quantitative proton-density-mapping methods. Hum Brain Mapp. Abstract
Quantitative magnetic resonance imaging (qMRI) aims to quantify tissue parameters by eliminating instrumental bias. We describe qMRI theory, simulations, and software designed to estimate proton density (PD), the apparent local concentration of water protons in the living human brain. First, we show that, in the absence of noise, multichannel coil data contain enough information to separate PD and coil sensitivity, a limiting instrumental bias. Second, we show that, in the presence of noise, regularization by a constraint on the relationship between T1 and PD produces accurate coil sensitivity and PD maps. The ability to measure PD quantitatively has applications in the analysis of in-vivo human brain tissue and enables multisite comparisons between individuals and across instruments.
Stueber, T, Eberhardt MJ, Hadamitzky C, Jangra A, Schenk S, Dick F, Stoetzer C, Kistner K, Reeh PW, Binshtok AM et al..  2016.  Quaternary Lidocaine Derivative QX-314 Activates and Permeates Human TRPV1 and TRPA1 to Produce Inhibition of Sodium Channels and Cytotoxicity.. Anesthesiology. 124(5):1153-65. Abstract
The relatively membrane-impermeable lidocaine derivative QX-314 has been reported to permeate the ion channels transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential cation channel, subfamily A, member 1 (TRPA1) to induce a selective inhibition of sensory neurons. This approach is effective in rodents, but it also seems to be associated with neurotoxicity. The authors examined whether the human isoforms of TRPV1 and TRPA1 allow intracellular entry of QX-314 to mediate sodium channel inhibition and cytotoxicity.
Amsalem, O, Pozzorini C, Chindemi G, Davison AP, Eroe C, King J, Newton TH, Nolte M, Ramaswamy S, Reimann MW et al..  2016.  Automated point-neuron simplification of data-driven microcircuit models. Abstract
A method is presented for the reduction of morphologically detailed microcircuit models to a point-neuron representation without human intervention. The simplification occurs in a modular workflow, in the neighborhood of a user specified network activity state for the reference model, the “operating point”. First, synapses are moved to the soma, correcting for dendritic filtering by low-pass filtering the delivered synaptic current. Filter parameters are computed numerically and independently for inhibitory and excitatory input on the basal and apical dendrites, respectively, in a distance dependent and post-synaptic m-type specific manner. Next, point-neuron models for each neuron in the microcircuit are fit to their respective morphologically detailed counterparts. Here, generalized integrate-and-fire point neuron models are used, leveraging a recently published fitting toolbox. The fits are constrained by currents and voltages computed in the morphologically detailed partner neurons with soma corrected synapses at three depolarizations about the user specified operating point. The result is a simplified circuit which is well constrained by the reference circuit, and can be continuously updated as the latter iteratively integrates new data. The modularity of the approach makes it applicable also for other point-neuron and synapse models. The approach is demonstrated on a recently reported reconstruction of a neocortical microcircuit around an in vivo-like working point. The resulting simplified network model is benchmarked to the reference morphologically detailed microcircuit model for a range of simulated network protocols. The simplified network is found to be slightly more sub-critical than the reference, with otherwise good agreement for both quantitative and qualitative validations.
Amsalem, O, Gevaert M, Chindemi G, Rossert C, Courcol J-D, Muller E, Schurmann F, Segev I, Markram H.  2016.  BluePyOpt: Leveraging open source software and cloud infrastructure to optimise model parameters in neuroscience. Abstract
At many scales in neuroscience, appropriate mathematical models take the form of com- plex dynamical systems. Parametrising such models to conform to the multitude of available experimental constraints is a global nonlinear optimisation problem with a complex fitness landscape, requiring numerical techniques to find suitable approximate solutions. Stochastic optimisation approaches, such as evolutionary algorithms, have been shown to be effective, but often the setting up of such optimisations and the choice of a specific search algorithm and its parameters is non-trivial, requiring domain-specific expertise. Here we describe BluePyOpt, a Python package targeted at the broad neuroscience community to simplify this task. BluePy- Opt is an extensible framework for data-driven model parameter optimisation that wraps and standardises several existing open-source tools. It simplifies the task of creating and shar- ing these optimisations, and the associated techniques and knowledge. This is achieved by abstracting the optimisation and evaluation tasks into various reusable and flexible discrete elements according to established best-practices. Further, BluePyOpt provides methods for setting up both small- and large-scale optimisations on a variety of platforms, ranging from laptops to Linux clusters and cloud-based compute infrastructures. The versatility of the BluePyOpt framework is demonstrated by working through three representative neuroscience specific use cases.
Grimm, S, Escera C, Nelken I.  2016.  Early indices of deviance detection in humans and animal models.. Biological Psychology. Volume 116 Abstract
Detecting unexpected stimuli in the environment is a critical function of the auditory system. Responses to unexpected "deviant" sounds are enhanced compared to responses to expected stimuli. At the human scalp, deviance detection is reflected in the mismatch negativity (MMN) and in an enhancement of the middle-latency response (MLR). Single neurons often respond more strongly to a stimulus when rare than when common, a phenomenon termed stimulus-specific adaptation (SSA). Here we compare stimulus-specific adaptation with scalp-recorded deviance-related responses. We conclude that early markers of deviance detection in the time range of the MLR could be a direct correlate of cortical SSA. Both occur at an early level of cortical activation, both are robust findings with low-probability stimuli, and both show properties of genuine deviance detection. Their causal relation with the later scalp-recorded MMN is a key question in this field.
Pinho, R, Guedes LC, Soreq L, Lobo PP, Mestre T, Coelho M, Rosa MM, Goncalves N, Wales P, Mendes T et al..  2016.  Gene Expression Differences in Peripheral Blood of Parkinson's Disease Patients with Distinct Progression Profiles. PLoS One. 11:e0157852. Abstract
The prognosis of neurodegenerative disorders is clinically challenging due to the inexistence of established biomarkers for predicting disease progression. Here, we performed an exploratory cross-sectional, case-control study aimed at determining whether gene expression differences in peripheral blood may be used as a signature of Parkinson's disease (PD) progression, thereby shedding light into potential molecular mechanisms underlying disease development. We compared transcriptional profiles in the blood from 34 PD patients who developed postural instability within ten years with those of 33 patients who did not develop postural instability within this time frame. Our study identified >200 differentially expressed genes between the two groups. The expression of several of the genes identified was previously found deregulated in animal models of PD and in PD patients. Relevant genes were selected for validation by real-time PCR in a subset of patients. The genes validated were linked to nucleic acid metabolism, mitochondria, immune response and intracellular-transport. Interestingly, we also found deregulation of these genes in a dopaminergic cell model of PD, a simple paradigm that can now be used to further dissect the role of these molecular players on dopaminergic cell loss. Altogether, our study provides preliminary evidence that expression changes in specific groups of genes and pathways, detected in peripheral blood samples, may be correlated with differential PD progression. Our exploratory study suggests that peripheral gene expression profiling may prove valuable for assisting in prediction of PD prognosis, and identifies novel culprits possibly involved in dopaminergic cell death. Given the exploratory nature of our study, further investigations using independent, well-characterized cohorts will be essential in order to validate our candidates as predictors of PD prognosis and to definitively confirm the value of gene expression analysis in aiding patient stratification and therapeutic intervention.
Lykhmus, O, Mishra N, Koval L, Kalashnyk O, Gergalova G, Uspenska K, Komisarenko S, Soreq H, Skok M.  2016.  Molecular Mechanisms Regulating LPS-Induced Inflammation in the Brain. Front Mol Neurosci. 9:19. Abstract
Neuro-inflammation, one of the pathogenic causes of neurodegenerative diseases, is regulated through the cholinergic anti-inflammatory pathway via the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR). We previously showed that either bacterial lipopolysaccharide (LPS) or immunization with the alpha7(1-208) nAChR fragment decrease alpha7 nAChRs density in the mouse brain, exacerbating chronic inflammation, beta-amyloid accumulation and episodic memory decline, which mimic the early stages of Alzheimer's disease (AD). To study the molecular mechanisms underlying the LPS and antibody effects in the brain, we employed an in vivo model of acute LPS-induced inflammation and an in vitro model of cultured glioblastoma U373 cells. Here, we report that LPS challenge decreased the levels of alpha7 nAChR RNA and protein and of acetylcholinesterase (AChE) RNA and activity in distinct mouse brain regions, sensitized brain mitochondria to the apoptogenic effect of Ca(2+) and modified brain microRNA profiles, including the cholinergic-regulatory CholinomiRs-132/212, in favor of anti-inflammatory and pro-apoptotic ones. Adding alpha7(1-208)-specific antibodies to the LPS challenge prevented elevation of both the anti-inflammatory and pro-apoptotic miRNAs while supporting the resistance of brain mitochondria to Ca(2+) and maintaining alpha7 nAChR/AChE decreases. In U373 cells, alpha7-specific antibodies and LPS both stimulated interleukin-6 production through the p38/Src-dependent pathway. Our findings demonstrate that acute LPS-induced inflammation induces the cholinergic anti-inflammatory pathway in the brain, that alpha7 nAChR down-regulation limits this pathway, and that alpha7-specific antibodies aggravate neuroinflammation by inducing the pro-inflammatory interleukin-6 and dampening anti-inflammatory miRNAs; however, these antibodies may protect brain mitochondria and decrease the levels of pro-apoptotic miRNAs, preventing LPS-induced neurodegeneration.
Grodzinsky, Y.  2016.  "Neural substrates for linguistic and musical abilities: a neurolinguist’s perspective." In Ida Toivonen, Piroska Csúri, Emile van der Zee , eds. Structures in the Mind: Essays on Language, Music, and Cognition in Honor of Ray Jackendoff.. grodzinsky_in_jackendoff_festschrift_2015.pdf