Export 1829 results:
Sort by:
Breska, A, Deouell LY.  2014.  Automatic bias of temporal expectations following temporally regular input independently of high-level temporal expectation.. Journal of cognitive neuroscience. 26(7):1555-71. Abstract
Exposure to rhythmic stimulation results in facilitated responses to events that appear in-phase with the rhythm and modulation of anticipatory and target-evoked brain activity, presumably reflecting "exogenous," unintentional temporal expectations. However, the extent to which this effect is independent from intentional processes is not clear. In two EEG experiments, we isolated the unintentional component of this effect from high-level, intentional factors. Visual targets were presented either in-phase or out-of-phase with regularly flickering colored stimuli. In different blocks, the rhythm could be predictive (i.e., high probability for in-phase target) or not, and the color could be predictive (i.e., validly cue the interval to the target) or not. Exposure to nonpredictive rhythms resulted in faster responses for in-phase targets, even when the color predicted specific out-of-phase target times. Also, the contingent negative variation, an EEG component reflecting temporal anticipation, followed the interval of the nonpredictive rhythm and not that of the predictive color. Thus, rhythmic stimulation unintentionally induced expectations, even when this was detrimental. Intentional usage of predictive rhythms to form expectations resulted in a stronger behavioral effect, and only predictive cues modulated the latency of the target-evoked P3, presumably reflecting stimulus evaluation. These findings establish the existence of unintentional temporal expectations in rhythmic contexts, dissociate them from intentional expectations, and highlight the need to distinguish between the source of expectation (exogenous-endogenous) and the level of voluntary control involved in it (unintentional-intentional).
Shenhar-Tsarfaty, S, Berliner S, Bornstein NM, Soreq H.  2014.  Cholinesterases as biomarkers for parasympathetic dysfunction and inflammation-related disease.. Journal of molecular neuroscience : MN. 53(3):298-305. Abstract
Accumulating evidence suggests parasympathetic dysfunction and elevated inflammation as underlying processes in multiple peripheral and neurological diseases. Acetylcholine, the main parasympathetic neurotransmitter and inflammation regulator, is hydrolyzed by the two closely homologous enzymes, acetylcholinesterase and butyrylcholinesterase (AChE and BChE, respectively), which are also expressed in the serum. Here, we consider the potential value of both enzymes as possible biomarkers in diseases associated with parasympathetic malfunctioning. We cover the modulations of cholinesterase activities in inflammation-related events as well as by cholinesterase-targeted microRNAs. We further discuss epigenetic control over cholinesterase gene expression and the impact of single-nucleotide polymorphisms on the corresponding physiological and pathological processes. In particular, we focus on measurements of circulation cholinesterases as a readily quantifiable readout for changes in the sympathetic/parasympathetic balance and the implications of changes in this readout in health and disease. Taken together, this cumulative know-how calls for expanding the use of cholinesterase activity measurements for both basic research and as a clinical assessment tool.
Nelken, I.  2014.  Stimulus-specific adaptation and deviance detection in the auditory system: experiments and models.. Biological cybernetics. Abstract
Stimulus-specific adaptation (SSA) is the reduction in the response to a common stimulus that does not generalize, or only partially generalizes, to other, rare stimuli. SSA has been proposed to be a correlate of 'deviance detection', an important computational task of sensory systems. SSA is ubiquitous in the auditory system: It is found both in cortex and in subcortical stations, and it has been demonstrated in many mammalian species as well as in birds. A number of models have been suggested in the literature to account for SSA in the auditory domain. In this review, the experimental literature is critically examined in relationship to these models. While current models can all account for auditory SSA to some degree, none is fully compatible with the available findings.
Moshitch, D, Nelken I.  2014.  Using Tweedie distributions for fitting spike count data.. Journal of neuroscience methods. 225C:13-28. Abstract
The nature of spike count distributions is of great practical concern for the analysis of neural data. These distributions often have a tendency for 'failures' and a long tail of large counts, and may show a strong dependence of variance on the mean. Furthermore, spike count distributions often show multiplicative rather than additive effects of covariates. We analyzed the responses of neurons in primary auditory cortex to transposed stimuli as a function of interaural time differences (ITD). In more than half of the cases, the variance of neuronal responses showed a supralinear dependence on the mean spike count.
Grodzinsky, Y, Nelken I.  2014.  The neural code that makes us human.. Science. 343(6174):978-9.
Hershenhoren, I, Taaseh N, Antunes FM, Nelken I.  2014.  Intracellular correlates of stimulus-specific adaptation.. J Neurosci.. 34(9):3303-19. Abstract
Stimulus-specific adaptation (SSA) is the reduction in response to a common stimulus that does not generalize, or only partially generalizes, to rare stimuli. SSA is strong and widespread in primary auditory cortex (A1) of rats, but is weak or absent in the main input station to A1, the ventral division of the medial geniculate body. To study SSA in A1, we recorded neural activity in A1 intracellularly using sharp electrodes. We studied the responses to tone pips of the same frequency in different contexts: as Standard and Deviants in Oddball sequences; in equiprobable sequences; in sequences consisting of rare tone presentations; and in sequences composed of many different frequencies, each of which was rare. SSA was found both in subthreshold membrane potential fluctuations and in spiking responses of A1 neurons. SSA for changes in frequency was large at a frequency difference of 44% between Standard and Deviant, and clearly present with tones separated by as little as 4%, near the behavioral frequency difference limen in rats. When using equivalent measures, SSA in spiking responses was generally larger than the SSA at the level of the membrane potential. This effect can be traced to the nonlinearity of the transformation between membrane potential to spikes. Using the responses to the same tone in different contexts made it possible to demonstrate that cortical SSA could not be fully explained by adaptation in narrow frequency channels, even at the level of the membrane potential. We conclude that local processing significantly contributes to the generation of cortical SSA.
Tavor, I, Yablonski M, Mezer A, Rom S, Assaf Y, Yovel G.  2014.  Separate parts of occipito-temporal white matter fibers are associated with recognition of faces and places.. NeuroImage. 86:123-30. Abstract
A central finding of functional MRI studies is the highly selective response of distinct brain areas in the occipital temporal cortex to faces and places. However, little is known about the association of white matter fibers with the processing of these object categories. In the current study we used DTI-based tractography to reconstruct two main fibers that connect the occipital lobe with the anterior temporal lobe (inferior longitudinal fasciculus-ILF) and with the frontal lobe (inferior fronto-occipital fasciculus-IFOF) in normal individuals. In addition to MRI scans subjects performed face, scene and body recognition tasks outside the scanner. Results show that recognition of faces and scenes were selectively associated with separate parts of the ILF. In particular, face recognition was highly associated with the fractional anisotropy (FA) of the anterior part of the ILF in the right hemisphere. In contrast, scene recognition was strongly correlated with the FA of the posterior and middle but not the anterior part of the ILF bilaterally. Our findings provide the first demonstration that faces and places are not only associated with distinct brain areas but also with separate parts of white matter fibers.
Weiss, AH, Granot RY, Ahissar M.  2014.  The enigma of dyslexic musicians.. Neuropsychologia. 54:28-40. Abstractweiss_granot_ahissar_-_2014_-_the_enigma_of_dyslexic_musicians._-_neuropsychologia.pdf
Musicians are known to have exceptional sensitivity to sounds, whereas poor phonological representations (or access to these representations) are considered a main characteristic of dyslexic individuals. Though these two characteristics refer to different abilities that are related to non-verbal and verbal skills respectively, the recent literature suggests that they are tightly related. However, there are informal reports of dyslexic musicians. To better understand this enigma, two groups of musicians were recruited, with and without a history of reading difficulties. The pattern of reading difficulties found among musicians was similar to that reported for non-musician dyslexics, though its magnitude was less severe. In contrast to non-musician dyslexics, their performance in pitch and interval discrimination, synchronous tapping and speech perception tasks, did not differ from the performance of their musician peers, and was superior to that of the general population. However, the auditory working memory scores of dyslexic musicians were consistently poor, including memory for rhythm, melody and speech sounds. Moreover, these abilities were inter-correlated, and highly correlated with their reading accuracy. These results point to a discrepancy between their perceptual and working memory skills rather than between sensitivity to speech and non-speech sounds. The results further suggest that in spite of intensive musical training, auditory working memory remains a bottleneck to the reading accuracy of dyslexic musicians.
Joshua, M, Lisberger SG.  2014.  A framework for using signal, noise, and variation to determine whether the brain controls movement synergies or single muscles.. Journal of neurophysiology. 111(4):733-45. Abstract
We have used an analysis of signal and variation in motor behavior to elucidate the organization of the cerebellar and brain stem circuits that control smooth pursuit eye movements. We recorded from the abducens nucleus and identified floccular target neurons (FTNs) and other, non-FTN vestibular neurons. First, we assessed neuron-behavior correlations, defined as the trial-by-trial correlation between the variation in neural firing and eye movement, in brain stem neurons. In agreement with prior data from the cerebellum, neuron-behavior correlations during pursuit initiation were large in all neurons. Second, we asked whether movement variation arises upstream from, in parallel to, or downstream from a given site of recording. We developed a model that highlighted two measures: the ratio of the SDs of neural firing rate and eye movement ("SDratio") and the neuron-behavior correlation. The relationship between these measures defines possible sources of variation. During pursuit initiation, SDratio was approximately equal to neuron-behavior correlation, meaning that the source of signal and variation is upstream from the brain stem. During steady-state pursuit, neuron-behavior correlation became somewhat smaller than SDratio for FTNs, meaning that some variation may arise downstream in the brain stem. The data contradicted the model's predictions for sources of variation in pathways that run parallel to the site of recording. Because signal and noise are tightly linked in motor control, we take the source of variation as a proxy for the source of signal, leading us to conclude that the brain controls movement synergies rather than single muscles for eye movements.
Mizrahi, A, Shalev A, Nelken I.  2014.  Single neuron and population coding of natural sounds in auditory cortex.. Current opinion in neurobiology. 24C:103-110. Abstract
The auditory system drives behavior using information extracted from sounds. Early in the auditory hierarchy, circuits are highly specialized for detecting basic sound features. However, already at the level of the auditory cortex the functional organization of the circuits and the underlying coding principles become different. Here, we review some recent progress in our understanding of single neuron and population coding in primary auditory cortex, focusing on natural sounds. We discuss possible mechanisms explaining why single neuron responses to simple sounds cannot predict responses to natural stimuli. We describe recent work suggesting that structural features like local subnetworks rather than smoothly mapped tonotopy are essential components of population coding. Finally, we suggest a synthesis of how single neurons and subnetworks may be involved in coding natural sounds.
Yeatman, JD, Weiner KS, Pestilli F, Rokem A, Mezer A, Wandell BA.  2014.  The vertical occipital fasciculus: a century of controversy resolved by in vivo measurements.. Proceedings of the National Academy of Sciences of the United States of America. 111(48):E5214-23. Abstract
The vertical occipital fasciculus (VOF) is the only major fiber bundle connecting dorsolateral and ventrolateral visual cortex. Only a handful of studies have examined the anatomy of the VOF or its role in cognition in the living human brain. Here, we trace the contentious history of the VOF, beginning with its original discovery in monkey by Wernicke (1881) and in human by Obersteiner (1888), to its disappearance from the literature, and recent reemergence a century later. We introduce an algorithm to identify the VOF in vivo using diffusion-weighted imaging and tractography, and show that the VOF can be found in every hemisphere (n = 74). Quantitative T1 measurements demonstrate that tissue properties, such as myelination, in the VOF differ from neighboring white-matter tracts. The terminations of the VOF are in consistent positions relative to cortical folding patterns in the dorsal and ventral visual streams. Recent findings demonstrate that these same anatomical locations also mark cytoarchitectonic and functional transitions in dorsal and ventral visual cortex. We conclude that the VOF is likely to serve a unique role in the communication of signals between regions on the ventral surface that are important for the perception of visual categories (e.g., words, faces, bodies, etc.) and regions on the dorsal surface involved in the control of eye movements, attention, and motion perception.
Raviv, O, Lieder I, Loewenstein Y, Ahissar M.  2014.  Contradictory behavioral biases result from the influence of past stimuli on perception.. PLoS computational biology. 10(12):e1003948. Abstractraviv_et_al._-_2014_-_contradictory_behavioral_biases_result_from_the_influence_of_past_stimuli_on_perception._-_plos_computational_biol.pdfjournal.pcbi_.1003948.pdf
Biases such as the preference of a particular response for no obvious reason, are an integral part of psychophysics. Such biases have been reported in the common two-alternative forced choice (2AFC) experiments, where participants are instructed to compare two consecutively presented stimuli. However, the principles underlying these biases are largely unknown and previous studies have typically used ad-hoc explanations to account for them. Here we consider human performance in the 2AFC tone frequency discrimination task, utilizing two standard protocols. In both protocols, each trial contains a reference stimulus. In one (Reference-Lower protocol), the frequency of the reference stimulus is always lower than that of the comparison stimulus, whereas in the other (Reference protocol), the frequency of the reference stimulus is either lower or higher than that of the comparison stimulus. We find substantial interval biases. Namely, participants perform better when the reference is in a specific interval. Surprisingly, the biases in the two experiments are opposite: performance is better when the reference is in the first interval in the Reference protocol, but is better when the reference is second in the Reference-Lower protocol. This inconsistency refutes previous accounts of the interval bias, and is resolved when experiments statistics is considered. Viewing perception as incorporation of sensory input with prior knowledge accumulated during the experiment accounts for the seemingly contradictory biases both qualitatively and quantitatively. The success of this account implies that even simple discriminations reflect a combination of sensory limitations, memory limitations, and the ability to utilize stimuli statistics.
Fuhrmann Alpert, G, Manor R, Spanier AB, Deouell LY, Geva AB.  2014.  Spatiotemporal representations of rapid visual target detection: a single-trial EEG classification algorithm.. IEEE transactions on bio-medical engineering. 61(8):2290-303. Abstract
Brain computer interface applications, developed for both healthy and clinical populations, critically depend on decoding brain activity in single trials. The goal of the present study was to detect distinctive spatiotemporal brain patterns within a set of event related responses. We introduce a novel classification algorithm, the spatially weighted FLD-PCA (SWFP), which is based on a two-step linear classification of event-related responses, using fisher linear discriminant (FLD) classifier and principal component analysis (PCA) for dimensionality reduction. As a benchmark algorithm, we consider the hierarchical discriminant component Analysis (HDCA), introduced by Parra, et al. 2007. We also consider a modified version of the HDCA, namely the hierarchical discriminant principal component analysis algorithm (HDPCA). We compare single-trial classification accuracies of all the three algorithms, each applied to detect target images within a rapid serial visual presentation (RSVP, 10 Hz) of images from five different object categories, based on single-trial brain responses. We find a systematic superiority of our classification algorithm in the tested paradigm. Additionally, HDPCA significantly increases classification accuracies compared to the HDCA. Finally, we show that presenting several repetitions of the same image exemplars improve accuracy, and thus may be important in cases where high accuracy is crucial.
Hanin, G, Shenhar-Tsarfaty S, Yayon N, Hoe Y Y, Bennett ER, Sklan EH, Rao DC, Rankinen T, Bouchard C, Geifman-Shochat S et al..  2014.  Competing targets of microRNA-608 affect anxiety and hypertension.. Human molecular genetics. Abstract
MicroRNAs (miRNAs) can repress multiple targets, but how a single de-balanced interaction affects others remained unclear. We found that changing a single miRNA-target interaction can simultaneously affect multiple other miRNA-target interactions and modify physiological phenotype. We show that miR-608 targets acetylcholinesterase (AChE) and demonstrate weakened miR-608 interaction with the rs17228616 AChE allele having a single-nucleotide polymorphism (SNP) in the 3'-untranslated region (3'UTR). In cultured cells, this weakened interaction potentiated miR-608-mediated suppression of other targets, including CDC42 and interleukin-6 (IL6). Postmortem human cortices homozygote for the minor rs17228616 allele showed AChE elevation and CDC42/IL6 decreases compared with major allele homozygotes. Additionally, minor allele heterozygote and homozygote subjects showed reduced cortisol and elevated blood pressure, predicting risk of anxiety and hypertension. Parallel suppression of the conserved brain CDC42 activity by intracerebroventricular ML141 injection caused acute anxiety in mice. We demonstrate that SNPs in miRNA-binding regions could cause expanded downstream effects changing important biological pathways.
Memmesheimer, R-M, Rubin R, Olveczky BP, Sompolinsky H.  2014.  Learning Precisely Timed Spikes.. Neuron. Abstract
To signal the onset of salient sensory features or execute well-timed motor sequences, neuronal circuits must transform streams of incoming spike trains into precisely timed firing. To address the efficiency and fidelity with which neurons can perform such computations, we developed a theory to characterize the capacity of feedforward networks to generate desired spike sequences. We find the maximum number of desired output spikes a neuron can implement to be 0.1-0.3 per synapse. We further present a biologically plausible learning rule that allows feedforward and recurrent networks to learn multiple mappings between inputs and desired spike sequences. We apply this framework to reconstruct synaptic weights from spiking activity and study the precision with which the temporal structure of ongoing behavior can be inferred from the spiking of premotor neurons. This work provides a powerful approach for characterizing the computational and learning capacities of single neurons and neuronal circuits.
Woolley, SC, Rajan R, Joshua M, Doupe AJ.  2014.  Emergence of context-dependent variability across a basal ganglia network.. Neuron. 82(1):208-23. Abstract
Context dependence is a key feature of cortical-basal ganglia circuit activity, and in songbirds the cortical outflow of a basal ganglia circuit specialized for song, LMAN, shows striking increases in trial-by-trial variability and bursting when birds sing alone rather than to females. To reveal where this variability and its social regulation emerge, we recorded stepwise from corticostriatal (HVC) neurons and their target spiny and pallidal neurons in Area X. We find that corticostriatal and spiny neurons both show precise singing-related firing across both social settings. Pallidal neurons, in contrast, exhibit markedly increased trial-by-trial variation when birds sing alone, created by highly variable pauses in firing. This variability persists even when recurrent inputs from LMAN are ablated. These data indicate that variability and its context sensitivity emerge within the basal ganglia network, suggest a network mechanism for this emergence, and highlight variability generation and regulation as basal ganglia functions.
Orlov, T, Porat Y, Makin TR, Zohary E.  2014.  Hands in motion: an upper-limb-selective area in the occipitotemporal cortex shows sensitivity to viewed hand kinematics.. J neuroscience. 34(14):4882-95. Abstract
Regions in the occipitotemporal cortex (OTC) show clear selectivity to static images of human body parts, and upper limbs in particular, with respect to other object categories. Such selectivity was previously attributed to shape aspects, which presumably vary across categories. Alternatively, it has been proposed that functional selectivity for upper limbs is driven by processing of their distinctive motion features. In the present study we show that selectivity to static upper-limb images and motion processing go hand in hand. Using resting-state and task-based functional MRI, we demonstrate that OTC voxels showing greater preference to static images of arms and hands also show stronger functional connectivity with motion coding regions within the human middle temporal complex (hMT+), but not with shape-selective midtier areas, such as hV4 or LO-1, suggesting a tight link between upper-limb selectivity and motion processing. To test this directly, we created a set of natural arm-movement videos where kinematic patterns were parametrically manipulated, while keeping shape information constant. Using multivariate pattern analysis, we show that the degree of (dis)similarity in arm-velocity profiles across the video set predicts, to a significant extent, the degree of (dis)similarity in multivoxel activation patterns in both upper-limb-selective OTC regions and the hMT+. Together, these results suggest that the functional specificity of upper-limb-selective regions may be partially determined by their involvement in the processing of upper-limb dynamics. We propose that the selectivity to static upper-limb images in the OTC may be a result of experience-dependent association between shape elements, which characterize upper limbs, and upper-limb-specific motion patterns.
Mudrik, L, Shalgi S, Lamy D, Deouell LY.  2014.  Synchronous contextual irregularities affect early scene processing: replication and extension.. Neuropsychologia. 56:447-58. Abstract
Whether contextual regularities facilitate perceptual stages of scene processing is widely debated, and empirical evidence is still inconclusive. Specifically, it was recently suggested that contextual violations affect early processing of a scene only when the incongruent object and the scene are presented a-synchronously, creating expectations. We compared event-related potentials (ERPs) evoked by scenes that depicted a person performing an action using either a congruent or an incongruent object (e.g., a man shaving with a razor or with a fork) when scene and object were presented simultaneously. We also explored the role of attention in contextual processing by using a pre-cue to direct subjects׳ attention towards or away from the congruent/incongruent object. Subjects׳ task was to determine how many hands the person in the picture used in order to perform the action. We replicated our previous findings of frontocentral negativity for incongruent scenes that started ~ 210 ms post stimulus presentation, even earlier than previously found. Surprisingly, this incongruency ERP effect was negatively correlated with the reaction times cost on incongruent scenes. The results did not allow us to draw conclusions about the role of attention in detecting the regularity, due to a weak attention manipulation. By replicating the 200-300 ms incongruity effect with a new group of subjects at even earlier latencies than previously reported, the results strengthen the evidence for contextual processing during this time window even when simultaneous presentation of the scene and object prevent the formation of prior expectations. We discuss possible methodological limitations that may account for previous failures to find this an effect, and conclude that contextual information affects object model selection processes prior to full object identification, with semantic knowledge activation stages unfolding only later on.
Xu, X, Yu X, He J, Nelken I.  2014.  Across-ear stimulus-specific adaptation in the auditory cortex.. Frontiers in neural circuits. 8:89. Abstract
The ability to detect unexpected or deviant events in natural scenes is critical for survival. In the auditory system, neurons from the midbrain to cortex adapt quickly to repeated stimuli but this adaptation does not fully generalize to other rare stimuli, a phenomenon called stimulus-specific adaptation (SSA). Most studies of SSA were conducted with pure tones of different frequencies, and it is by now well-established that SSA to tone frequency is strong and robust in auditory cortex. Here we tested SSA in the auditory cortex to the ear of stimulation using broadband noise. We show that cortical neurons adapt specifically to the ear of stimulation, and that the contrast between the responses to stimulation of the same ear when rare and when common depends on the binaural interaction class of the neurons.
Arbel, Y, Shenhar-Tsarfaty S, Waiskopf N, Finkelstein A, Halkin A, Revivo M, Berliner S, Herz I, Shapira I, Keren G et al..  2014.  Decline in serum cholinesterase activities predicts 2-year major adverse cardiac events.. Molecular medicine (Cambridge, Mass.). 20:38-45. Abstract
Parasympathetic activity influences long-term outcome in patients with cardiovascular disease, but the underlying mechanism(s) linking parasympathetic activity and the occurrence of major adverse cardiovascular events (MACEs) are incompletely understood. The aim of this pilot study was to evaluate the association between serum cholinesterase activities as parasympathetic biomarkers and the risk for the occurrence of MACEs. Cholinergic status was determined by measuring the cumulative capacity of serum acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) to hydrolyze the AChE substrate acetylthiocholine. Cholinergic status was evaluated in randomly selected patients undergoing cardiac catheterization. The patients were divided into two groups of 100 patients in each group, with or without occurrence of MACEs during a follow-up period of 40 months. Cox regression models adjusted for potential clinical, metabolic and inflammatory confounders served to evaluate association with clinical outcome. We found that patients with MACE presented lower cholinergic status and AChE values at catheterization (1,127 ± 422 and 359 ± 153 nmol substrate hydrolyzed per minute per milliliter, respectively) than no-MACE patients (1,760 ± 546 and 508 ± 183 nmol substrate hydrolyzed per minute per milliliter, p < 0.001 and p < 0.001, respectively), whose levels were comparable to those of matched healthy controls (1,622 ± 303 and 504 ± 126 nmol substrate hydrolyzed per minute per milliliter, respectively). In a multivariate analysis, patients with AChE or total cholinergic status values below median showed conspicuously elevated risk for MACE (hazard ratio 1.85 [95% confidence interval [CI] 1.09-3.15, p = 0.02] and 2.21 [95% CI 1.22-4.00, p = 0.009]) compared with those above median, even after adjusting for potential confounders. We conclude that parasympathetic dysfunction expressed as reduced serum AChE and AChE activities in patients compared to healthy controls can together reflect impaired parasympathetic activity. This impairment predicts the risk of MACE up to 40 months in such patients. Monitoring these parasympathetic parameters might help in the risk stratification of patients with cardiovascular disease.
Guffanti, A, Simchovitz A, Soreq H.  2014.  Emerging bioinformatics approaches for analysis of NGS-derived coding and non-coding RNAs in neurodegenerative diseases.. Frontiers in cellular neuroscience. 8:89. Abstract
Neurodegenerative diseases in general and specifically late-onset Alzheimer's disease (LOAD) involve a genetically complex and largely obscure ensemble of causative and risk factors accompanied by complex feedback responses. The advent of "high-throughput" transcriptome investigation technologies such as microarray and deep sequencing is increasingly being combined with sophisticated statistical and bioinformatics analysis methods complemented by knowledge-based approaches such as Bayesian Networks or network and graph analyses. Together, such "integrative" studies are beginning to identify co-regulated gene networks linked with biological pathways and potentially modulating disease predisposition, outcome, and progression. Specifically, bioinformatics analyses of integrated microarray and genotyping data in cases and controls reveal changes in gene expression of both protein-coding and small and long regulatory RNAs; highlight relevant quantitative transcriptional differences between LOAD and non-demented control brains and demonstrate reconfiguration of functionally meaningful molecular interaction structures in LOAD. These may be measured as changes in connectivity in "hub nodes" of relevant gene networks (Zhang etal., 2013). We illustrate here the open analytical questions in the transcriptome investigation of neurodegenerative disease studies, proposing "ad hoc" strategies for the evaluation of differential gene expression and hints for a simple analysis of the non-coding RNA (ncRNA) part of such datasets. We then survey the emerging role of long ncRNAs (lncRNAs) in the healthy and diseased brain transcriptome and describe the main current methods for computational modeling of gene networks. We propose accessible modular and pathway-oriented methods and guidelines for bioinformatics investigations of whole transcriptome next generation sequencing datasets. We finally present methods and databases for functional interpretations of lncRNAs and propose a simple heuristic approach to visualize and represent physical and functional interactions of the coding and non-coding components of the transcriptome. Integrating in a functional and integrated vision coding and ncRNA analyses is of utmost importance for current and future analyses of neurodegenerative transcriptomes.
Rotem, N, Sestieri E, Hounsgaard J, Yarom Y.  2014.  Excitatory and inhibitory synaptic mechanisms at the first stage of integration in the electroreception system of the shark.. Frontiers in cellular neuroscience. 8:72. Abstract
High impulse rate in afferent nerves is a common feature in many sensory systems that serve to accommodate a wide dynamic range. However, the first stage of integration should be endowed with specific properties that enable efficient handling of the incoming information. In elasmobranches, the afferent nerve originating from the ampullae of Lorenzini targets specific neurons located at the Dorsal Octavolateral Nucleus (DON), the first stage of integration in the electroreception system. Using intracellular recordings in an isolated brainstem preparation from the shark we analyze the properties of this afferent pathway. We found that stimulating the afferent nerve activates a mixture of excitatory and inhibitory synapses mediated by AMPA-like and GABAA receptors, respectively. The excitatory synapses that are extremely efficient in activating the postsynaptic neurons display unusual voltage dependence, enabling them to operate as a current source. The inhibitory input is powerful enough to completely eliminate the excitatory action of the afferent nerve but is ineffective regarding other excitatory inputs. These observations can be explained by the location and efficiency of the synapses. We conclude that the afferent nerve provides powerful and reliable excitatory input as well as a feed-forward inhibitory input, which is partially presynaptic in origin. These results question the cellular location within the DON where cancelation of expected incoming signals occurs.
de Hoz, L, Nelken I.  2014.  Frequency tuning in the behaving mouse: different bandwidths for discrimination and generalization.. PloS one. 9(3):e91676. Abstract
When faced with sensory stimuli, an organism may be required to detect very small differences in a physical parameter (discrimination), while in other situations it may have to generalize over many possible values of the same physical parameter. This decision may be based both on learned information and on sensory aspects of perception. In the present study we describe frequency processing in the behaving mouse using both discrimination and generalization as two key aspects of behaviour. We used a novel naturalistic behavioural apparatus designed for mice, the Audiobox, and paradigm contingencies that were identical for both auditory discrimination and generalization, the latter measured using latent inhibition. Mice learned to discriminate between frequencies that were an octave apart in a single trial. They showed significant discrimination between tone frequencies that were as close as 4-7%, and had d' of about 1 for ΔF of around 10%. In contrast, pre-exposure frequencies that were half an octave or less below the conditioned tone elicited latent inhibition, showing a generalization bandwidth of at least half an octave. Thus, in the same apparatus and using the same general memory paradigm, mice showed generalization gradients that were considerably wider than their discrimination threshold, indicating that environmental requirements and previous experience can determine whether the same two frequencies will be considered same or different. Remarkably, generalization gradients paralleled the typical bandwidths established in the auditory periphery and midbrain, suggesting that frequencies may be considered similar when falling within the same critical band.
Shrem, T, Deouell LY.  2014.  Frequency-dependent auditory space representation in the human planum temporale.. Frontiers in human neuroscience. 8:524. Abstract
Functional magnetic resonance imaging (fMRI) findings suggest that a part of the planum temporale (PT) is involved in representing spatial properties of acoustic information. Here, we tested whether this representation of space is frequency-dependent or generalizes across spectral content, as required from high order sensory representations. Using sounds with two different spectral content and two spatial locations in individually tailored virtual acoustic environment, we compared three conditions in a sparse-fMRI experiment: Single Location, in which two sounds were both presented from one location; Fixed Mapping, in which there was one-to-one mapping between two sounds and two locations; and Mixed Mapping, in which the two sounds were equally likely to appear at either one of the two locations. We surmised that only neurons tuned to both location and frequency should be differentially adapted by the Mixed and Fixed mappings. Replicating our previous findings, we found adaptation to spatial location in the PT. Importantly, activation was higher for Mixed Mapping than for Fixed Mapping blocks, even though the two sounds and the two locations appeared equally in both conditions. These results show that spatially tuned neurons in the human PT are not invariant to the spectral content of sounds.
Greenberg, DS, Soreq H.  2014.  MicroRNA therapeutics in neurological disease.. Current pharmaceutical design. 20(38):6022-7. Abstract
Developing microRNA therapeutics for neurological diseases is both a promising opportunity and an extremely challenging topic for several reasons. The promise stems from the very small size of microRNAs, which makes them amenable for manipulation via short synthetic oligonucleotides or engineered viruses. Also, the fact that each microRNA may regulate numerous target transcripts of the same pathway predicts that such manipulations may affect an entire pathway rather than a single gene and gives reason to hope that low dose therapeutic targeting of the top microRNA in such a hierarchic pyramid would suffice to induce a focused change in the entire pyramid. However, these same features, which make microRNAs such promising targets for therapeutic manipulations also present great challenges. Thus the plethora of functional targets for each microRNA in specific cell types is yet far from being elucidated, which implies that the targets to be affected may not be those planned to be manipulated (a risk of 'off-target' effects). Also, the hierarchic order of microRNA regulation is yet unknown, which predicts a risk of complex, multi-leveled consequences following the manipulation of a single microRNA; and the delivery of oligonucleotide therapeutics into the brain is a challenge due to the blood-brain barrier. In this chapter, we briefly outline the current state of knowledge regarding microRNA regulation in different neuropathologies and sketch the emerging principles for the development of microRNA therapeutics for these diseases.We address issues such as modes of delivery and consideration of the inherited and acquired variability between individuals in the susceptibility to such treatments. We further refer in a somewhat more in-depth manner to the issue of manipulating microRNA functioning in the parasympathetic system and the pathway of cholinergic signaling. Beyond the brain and within it, cholinergic signaling controls inflammatory reactions, and microRNA changes would likely affect this function as well. Furthermore, microRNA regulation of cholinergic signaling involves the elements of complexity and hierarchy noted above, and is relevant to numerous neuropathologies and neurodegenerative syndromes. Research and translational efforts that lead to the development of microRNA therapeutics merit thorough discussion.