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2015
Deschamps, I, Agmon G, Loewenstein Y, Grodzinsky Y.  2015.  The Processing of Polar Quantifiers, and Numerosity Perception. Cognition. 143:115-128.deschamps_et_al_cog_2015.pdf
Elyada, YM, Mizrahi A.  2015.  Becoming a mother — circuit plasticity underlying maternal behavior. Current Opinion in Neurobiology. 35:49-56.
Rothschild, G, Mizrahi A.  2015.  Global Order and Local Disorder in Brain Maps. Annual Review of Neuroscience. 38:null.
Cohen, L, Mizrahi A.  2015.  Plasticity during Motherhood: Changes in Excitatory and Inhibitory Layer 2/3 Neurons in Auditory Cortex. The Journal of Neuroscience. 35:1806-1815. Abstract
Maternal behavior can be triggered by auditory and olfactory cues originating from the newborn. Here we report how the transition to motherhood affects excitatory and inhibitory neurons in layer 2/3 (L2/3) of the mouse primary auditory cortex. We used in vivo two-photon targeted cell-attached recording to compare the response properties of parvalbumin-expressing neurons (PVNs) and pyramidal glutamatergic neurons (PyrNs). The transition to motherhood shifts the average best frequency of PVNs to higher frequency by a full octave, with no significant effect on average best frequency of PyrNs. The presence of pup odors significantly reduced the spontaneous and evoked activity of PVN. This reduction of feedforward inhibition coincides with a complimentary increase in spontaneous and evoked activity of PyrNs. The selective shift of PVN frequency tuning should render pup odor-induced disinhibition more effective for high-frequency stimuli, such as ultrasonic vocalizations. Indeed, pup odors increased neuronal responses of PyrNs to pup ultrasonic vocalizations. We conclude that plasticity in the mothers is mediated, at least in part, via modulation of the feedforward inhibition circuitry in the auditory cortex.
2014
David, A, Hagai B, Stanley F.  2014.  Redundant dopaminergic activity may enable compensatory axonal sprouting in Parkinson disease.. Neurology. 82(12):1093-8. Abstract
Neurodegenerative diseases become clinically apparent only after a substantial population of neurons is lost. This raises the possibility of compensatory mechanisms in the early phase of these diseases. The importance of understanding these mechanisms cannot be underestimated because it may guide future disease-modifying strategies. Because the anatomy and physiology of the nigrostriatal dopaminergic pathways have been well described, the study of Parkinson disease can offer insight into these early compensatory mechanisms. Collateral axonal sprouting of dopaminergic terminals into the denervated striatum is the most studied compensatory mechanism in animal (almost exclusively rodent) models of Parkinson disease and is correlated with behavioral recovery after partial lesions. This sprouting, however, does not respect the normal anatomy of the original nigrostriatal pathways and leads to aberrant neuronal networks. We suggest here that the unique physiologic property of the dopaminergic innervation of the striatum, namely redundancy of information encoding, is crucial to the efficacy of compensatory axonal sprouting in the presence of aberrant anatomical connections. Redundant information encoding results from the similarity of representation of salient and rewarding events by many dopaminergic neurons, from the wide axonal field of a single dopaminergic neuron in the striatum, and from the nonspecific spatial effect of dopamine on striatal neurons (volume conductance). Finally, we discuss the relevance of these findings in animal models to human patients with Parkinson disease.
Moustafa, AA, Bar-Gad I, Korngreen A, Bergman H.  2014.  Basal ganglia: physiological, behavioral and computational studies. Front Syst. Neurosci.. Abstract
The basal ganglia has received much attention over the last two decades, as it has been implicated in many neurological and psychiatric disorders, including Parkinson's disease (PD), Attention Deficit Hyperactivity Disorder (ADHD), Tourette's syndrome, and dystonia. Most of current basal ganglia research—in both animals and humans—attempts to understand the neural and biochemical substrates of basic motor and learning processes, and how these are affected in human patients as well as animal models of brain disorders, particularly PD. The current volume contains research articles and reviews describing basic, pre-clinical and clinical neuroscience research of the basal ganglia written by researchers of the basal ganglia and attendees of the 11th Triennial Meeting of the International Basal Ganglia Society (IBAGS) that was held on March 3–7th, 2013 at the Princess Hotel, Eilat, Israel. Specifically, articles in this volume include research reports on the biochemistry, computational theory, anatomy, and physiology of single neurons and functional circuitry of the basal ganglia networks. Below, we provide a summary of articles published in the volume. We divided the articles into 4 sections: animal studies, human studies, computational modeling, and reviews.
Mizrahi, A, Shalev A, Nelken I.  2014.  Single neuron and population coding of natural sounds in auditory cortex. Current Opinion in Neurobiology. 24:103-110. 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, Wandell BA, Mezer AA.  2014.  Lifespan maturation and degeneration of human brain white matter. Nature Communications. 5 Abstract
Properties of human brain tissue change across the lifespan. Here we model these changes in the living human brain by combining quantitative magnetic resonance imaging (MRI) measurements of R1 (1/T1) with diffusion MRI and tractography (N=102, ages 7–85). The amount of R1 change during development differs between white-matter fascicles, but in each fascicle the rate of development and decline are mirror-symmetric; the rate of R1 development as the brain approaches maturity predicts the rate of R1 degeneration in aging. Quantitative measurements of macromolecule tissue volume (MTV) confirm that R1 is an accurate index of the growth of new brain tissue. In contrast to R1, diffusion development follows an asymmetric time-course with rapid childhood changes but a slow rate of decline in old age. Together, the time-courses of R1 and diffusion changes demonstrate that multiple biological processes drive changes in white-matter tissue properties over the lifespan.
Livneh, Y, Adam Y, Mizrahi A.  2014.  Odor Processing by Adult-Born Neurons. Neuron. :-. Abstract
The adult mammalian brain is continuously supplied with adult-born neurons in the olfactory bulb (OB) and hippocampus, where they are thought to be important for circuit coding and plasticity. However, direct evidence for the actual involvement of these neurons in neural processing is still lacking. We recorded the spiking activity of adult-born periglomerular neurons in the mouse OB in
Moshitch, D, Nelken I.  2014.  The Representation of Interaural Time Differences in High-Frequency Auditory Cortex.. Cerebral cortex. Abstract
Early representations of auditory features often involve neuronal populations whose tuning is substantially wider than behavioral discrimination thresholds. Although behavioral discrimination performance can be sometimes achieved by single neurons when using the appropriate part of their (wide) tuning curves, neurons that encode the resulting high-acuity representations have rarely been described. Here we demonstrate the existence of neurons with extremely narrow tuning for interaural time differences (ITDs), a major physical cue for the azimuth of sound sources. The tuning width of ITD-tuned brainstem neurons is mostly determined by the properties of their acoustic input, and may be 10-100 times wider than behavioral thresholds. In contrast, we show that tuning widths of some neurons in the primary auditory cortex in the cat high-frequency auditory cortex (measured using transposed stimulus) can be very sharp and approach behavioral thresholds. Furthermore, while best ITDs of brainstem neurons often lie outside the range of naturally encountered ITDs (the ethological range), the range of best ITDs of the narrowly tuned cortical neurons corresponds well to the ethological range. Thus, our results suggest that the auditory cortex contains a high-resolution representation of ITDs that explicitly decodes the widely tuned brainstem representations.
Goshen, I.  2014.  The optogenetic revolution in memory research.. Trends in neurosciences. 37(9):511-22. Abstract
Over the past 5 years, the incorporation of optogenetics into the study of memory has resulted in a tremendous leap in this field, initiating a revolution in our understanding of the networks underlying cognitive processes. This review will present recent breakthroughs in which optogenetics was applied to illuminate, both literally and figuratively, memory research, and describe the technical approach, together with the opportunities it offers. Specifically, a large body of literature has been generated, setting the foundation for deciphering the spatiotemporal organization of hippocampal-based memory processing and its underlying mechanisms, as well as the contribution of cortical and amygdalar regions to cognition.
Gudes, S, Barkai O, Caspi Y, Katz B, Lev S, Binshtok AM.  2014.  The Role of Slow and Persistent TTX-resistant Sodium Currents in Acute Tumor Necrosis Factor α - Mediated Increase in Nociceptors Excitability.. Journal of Neurophysiology. :jn.00652.2014. Abstract
Tetrodotoxin (TTX)-resistant sodium channels are key players in determining the input-output properties of peripheral nociceptive neurons. Changes in gating kinetics or in expression of these channels by proinflammatory mediators are likely to cause the hyperexcitability of nociceptivors and pain hypersensitivity observed during inflammation. Proinflammatory mediator, tumor necrosis factor α (TNFα), is secreted during inflammation and is associated with the early onset, as well as long lasting, inflammation-mediated increase in excitability of peripheral nociceptive neurons. Here we studied the underlying mechanisms of the rapid component of TNFα-mediated nociceptive hyperexcitability and acute pain hypersensitivity. We showed that TNFα leads to rapid onset, cyclooxygenase-independent pain hypersensitivity in adult rats. Furthermore, TNFα rapidly and substantially increases nociceptive excitability in-vitro, by decreasing action potential threshold, increasing neuronal gain and decreasing accommodation. We extended on previous studies entailing p38 MAPK-dependent, increase in TTX-resistant sodium currents by showing that TNFα via p38 MAPK, leads to increased availability of TTX-r sodium channels by partial relief of voltage dependence of their slow inactivation, thereby contributing to increase in neuronal gain. Moreover, we showed that TNFα also in a p38 MAPK-dependent manner, increases persistent TTX-r current by shifting the voltage dependence of activation to a hyperpolarized direction, thus producing an increase in inward current at functionally critical subthreshold voltages. Our results suggest that rapid modulation of the gating of TTX-r sodium channels plays a major role in TNFα's-mediated nociceptive hyperexcitability during acute inflammation and may lead to development of effective treatments for inflammatory pain, without modulating the inflammation-induced healing processes.
Blumberg, A, Sailaja B S, Kundaje A, Levin L, Dadon S, Shmorak S, Shaulian E, Meshorer E, Mishmar D.  2014.  Transcription factors bind negatively selected sites within human mtDNA genes.. Genome biology and evolution. 6(10):2634-46. Abstract
Transcription of mitochondrial DNA (mtDNA)-encoded genes is thought to be regulated by a handful of dedicated transcription factors (TFs), suggesting that mtDNA genes are separately regulated from the nucleus. However, several TFs, with known nuclear activities, were found to bind mtDNA and regulate mitochondrial transcription. Additionally, mtDNA transcriptional regulatory elements, which were proved important in vitro, were harbored by a deletion that normally segregated among healthy individuals. Hence, mtDNA transcriptional regulation is more complex than once thought. Here, by analyzing ENCODE chromatin immunoprecipitation sequencing (ChIP-seq) data, we identified strong binding sites of three bona fide nuclear TFs (c-Jun, Jun-D, and CEBPb) within human mtDNA protein-coding genes. We validated the binding of two TFs by ChIP-quantitative polymerase chain reaction (c-Jun and Jun-D) and showed their mitochondrial localization by electron microscopy and subcellular fractionation. As a step toward investigating the functionality of these TF-binding sites (TFBS), we assessed signatures of selection. By analyzing 9,868 human mtDNA sequences encompassing all major global populations, we recorded genetic variants in tips and nodes of mtDNA phylogeny within the TFBS. We next calculated the effects of variants on binding motif prediction scores. Finally, the mtDNA variation pattern in predicted TFBS, occurring within ChIP-seq negative-binding sites, was compared with ChIP-seq positive-TFBS (CPR). Motifs within CPRs of c-Jun, Jun-D, and CEBPb harbored either only tip variants or their nodal variants retained high motif prediction scores. This reflects negative selection within mtDNA CPRs, thus supporting their functionality. Hence, human mtDNA-coding sequences may have dual roles, namely coding for genes yet possibly also possessing regulatory potential.
Chaisanguanthum, KS, Joshua M, Medina JF, Bialek W, Lisberger SG.  2014.  The Neural Code for Motor Control in the Cerebellum and Oculomotor Brainstem.. eNeuro. 1(1) Abstract
A single extra spike makes a difference. Here, the size of the eye velocity in the initiation of smooth eye movements in the right panel depends on whether a cerebellar Purkinje cell discharges 3 (red), 4 (green), 5 (blue), or 6 (black) spikes in the 40-ms window indicated by the gray shading in the rasters on the left. Spike trains are rich in information that can be extracted to guide behaviors at millisecond time resolution or across longer time intervals. In sensory systems, the information usually is defined with respect to the stimulus. Especially in motor systems, however, it is equally critical to understand how spike trains predict behavior. Thus, our goal was to compare systematically spike trains in the oculomotor system with eye movement behavior on single movements. We analyzed the discharge of Purkinje cells in the floccular complex of the cerebellum, floccular target neurons in the brainstem, other vestibular neurons, and abducens neurons. We find that an extra spike in a brief analysis window predicts a substantial fraction of the trial-by-trial variation in the initiation of smooth pursuit eye movements. For Purkinje cells, a single extra spike in a 40 ms analysis window predicts, on average, 0.5 SDs of the variation in behavior. An optimal linear estimator predicts behavioral variation slightly better than do spike counts in brief windows. Simulations reveal that the ability of single spikes to predict a fraction of behavior also emerges from model spike trains that have the same statistics as the real spike trains, as long as they are driven by shared sensory inputs. We think that the shared sensory estimates in their inputs create correlations in neural spiking across time and across each population. As a result, one or a small number of spikes in a brief time interval can predict a substantial fraction of behavioral variation.
Nelken, I, Bizley J, Shamma SA, Wang X.  2014.  Auditory cortical processing in real-world listening: the auditory system going real.. J Neurosci. 34(46):15135-8. Abstract
The auditory sense of humans transforms intrinsically senseless pressure waveforms into spectacularly rich perceptual phenomena: the music of Bach or the Beatles, the poetry of Li Bai or Omar Khayyam, or more prosaically the sense of the world filled with objects emitting sounds that is so important for those of us lucky enough to have hearing. Whereas the early representations of sounds in the auditory system are based on their physical structure, higher auditory centers are thought to represent sounds in terms of their perceptual attributes. In this symposium, we will illustrate the current research into this process, using four case studies. We will illustrate how the spectral and temporal properties of sounds are used to bind together, segregate, categorize, and interpret sound patterns on their way to acquire meaning, with important lessons to other sensory systems as well.
Main, KL, Pestilli F, Mezer A, Yeatman J, Martin R, Phipps S, Wandell B.  2014.  Speed discrimination predicts word but not pseudo-word reading rate in adults and children.. Brain and language. 138:27-37. Abstract
Visual processing in the magnocellular pathway is a reputed influence on word recognition and reading performance. However, the mechanisms behind this relationship are still unclear. To explore this concept, we measured reading rate, speed-discrimination, and contrast detection thresholds in adults and children with a wide range of reading abilities. We found that speed discrimination thresholds are higher in children than in adults and are correlated with age. Speed discrimination thresholds are also correlated with reading rates but only for real words, not pseudo-words. Conversely, we found no correlations between contrast detection thresholds and the reading rates. We also found no correlations between speed discrimination or contrast detection and WASI subtest scores. These findings indicate that familiarity is a factor in magnocellular operations that may influence reading rate. We suggest this effect supports the idea that the magnocellular pathway contributes to word reading through an analysis of letter position.
Faria, C, Sadowsky O, Bicho E, Ferrigno G, Joskowicz L, Shoham M, Vivanti R, De Momi E.  2014.  Validation of a stereo camera system to quantify brain deformation due to breathing and pulsatility.. Medical physics. 41(11):113502. Abstract
A new stereo vision system is presented to quantify brain shift and pulsatility in open-skull neurosurgeries.
Weizman, L, Ben Sira L, Joskowicz L, Rubin DL, Yeom KW, Constantini S, Shofty B, Ben Bashat D.  2014.  Semiautomatic segmentation and follow-up of multicomponent low-grade tumors in longitudinal brain MRI studies.. Medical physics. 41(5):052303. Abstract
Tracking the progression of low grade tumors (LGTs) is a challenging task, due to their slow growth rate and associated complex internal tumor components, such as heterogeneous enhancement, hemorrhage, and cysts. In this paper, the authors show a semiautomatic method to reliably track the volume of LGTs and the evolution of their internal components in longitudinal MRI scans.
Barbash, S, Shifman S, Soreq H.  2014.  Global co-evolution of human microRNAs and their target genes.. Molecular biology and evolution. Abstract
MicroRNAs (miRNAs) have presumably contributed to the emergence of the novel expression patterns, higher brain functions and skills underlying human evolution. However, it is incompletely understood how new miRNAs have evolved in the human lineage since their initial emergence predictably entailed deleterious consequences due to their powerful multi-target effects. Here, we report genetic variation and conservation parameters for miRNAs and their predicted targets in the genomes of 1092 humans and 58 additional organisms. We show that miRNAs were evolutionarily more conserved than their predicted binding sites, which were inversely subject to the accumulation of single nucleotide variations over short evolutionary timescales. Moreover, the predictably 'younger' human-specific miRNAs presented lower genetic variation than other miRNAs; their targets displayed higher genetic variation compared to other miRNA targets in diverse human populations; and neuronal miRNAs showed yet lower levels of genetic variation and were found to target more protein-coding genes than non-neuronal miRNAs. Furthermore, enrichment analysis indicated that targets of human-specific miRNAs primarily perform neuronal functions. Specifically, the genomic regions harboring the vertebrate-conserved neuronal miRNA-132 presented considerably higher conservation scores than those of its target genes throughout evolution, whereas both the recently evolved human miRNA-941 and its acquired targets showed relatively low conservation. Our findings demonstrate inversely correlated genetic variation around miRNAs and their targets, consistent with theories of co-evolution of these elements and the predicted role attributed to miRNAs in recent human evolution.
Mudrik, L, Shalgi S, Lamy D, Deouell LY.  2014.  Synchronous contextual irregularities affect early scene processing: Replication and extension.. Neuropsychologia. 56C:447-458. 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 ~210ms 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 200-300ms 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.
Lefler, Y, Yarom Y, Uusisaari M Y.  2014.  Cerebellar inhibitory input to the inferior olive decreases electrical coupling and blocks subthreshold oscillations.. Neuron. 81(6):1389-400. Abstract
GABAergic projection neurons in the cerebellar nuclei (CN) innervate the inferior olive (IO) that in turn is the source of climbing fibers targeting Purkinje neurons in the cerebellar cortex. Anatomical evidence suggests that CN synapses modulate electrical coupling between IO neurons. In vivo studies indicate that they are also involved in controlling synchrony and rhythmicity of IO neurons. Here, we demonstrate using virally targeted channelrhodopsin in the cerebellar nucleo-olivary neurons that synaptic input can indeed modulate both the strength and symmetry of electrical coupling between IO neurons and alter network activity. Similar synaptic modifications of electrical coupling are likely to occur in other brain regions, where rapid modification of the spatiotemporal features of the coupled networks is needed to adequately respond to behavioral demands.
Lefler, Y, Yarom Y, Uusisaari M Y.  2014.  Cerebellar inhibitory input to the inferior olive decreases electrical coupling and blocks subthreshold oscillations.. Neuron. 81(6):1389-400. Abstract
GABAergic projection neurons in the cerebellar nuclei (CN) innervate the inferior olive (IO) that in turn is the source of climbing fibers targeting Purkinje neurons in the cerebellar cortex. Anatomical evidence suggests that CN synapses modulate electrical coupling between IO neurons. In vivo studies indicate that they are also involved in controlling synchrony and rhythmicity of IO neurons. Here, we demonstrate using virally targeted channelrhodopsin in the cerebellar nucleo-olivary neurons that synaptic input can indeed modulate both the strength and symmetry of electrical coupling between IO neurons and alter network activity. Similar synaptic modifications of electrical coupling are likely to occur in other brain regions, where rapid modification of the spatiotemporal features of the coupled networks is needed to adequately respond to behavioral demands.
Soreq, L, Guffanti A, Salomonis N, Simchovitz A, Israel Z, Bergman H, Soreq H.  2014.  Long non-coding RNA and alternative splicing modulations in Parkinson's leukocytes identified by RNA sequencing.. PLoS computational biology. 10(3) Abstract
The continuously prolonged human lifespan is accompanied by increase in neurodegenerative diseases incidence, calling for the development of inexpensive blood-based diagnostics. Analyzing blood cell transcripts by RNA-Seq is a robust means to identify novel biomarkers that rapidly becomes a commonplace. However, there is lack of tools to discover novel exons, junctions and splicing events and to precisely and sensitively assess differential splicing through RNA-Seq data analysis and across RNA-Seq platforms. Here, we present a new and comprehensive computational workflow for whole-transcriptome RNA-Seq analysis, using an updated version of the software AltAnalyze, to identify both known and novel high-confidence alternative splicing events, and to integrate them with both protein-domains and microRNA binding annotations. We applied the novel workflow on RNA-Seq data from Parkinson's disease (PD) patients' leukocytes pre- and post- Deep Brain Stimulation (DBS) treatment and compared to healthy controls. Disease-mediated changes included decreased usage of alternative promoters and N-termini, 5'-end variations and mutually-exclusive exons. The PD regulated FUS and HNRNP A/B included prion-like domains regulated regions. We also present here a workflow to identify and analyze long non-coding RNAs (lncRNAs) via RNA-Seq data. We identified reduced lncRNA expression and selective PD-induced changes in 13 of over 6,000 detected leukocyte lncRNAs, four of which were inversely altered post-DBS. These included the U1 spliceosomal lncRNA and RP11-462G22.1, each entailing sequence complementarity to numerous microRNAs. Analysis of RNA-Seq from PD and unaffected controls brains revealed over 7,000 brain-expressed lncRNAs, of which 3,495 were co-expressed in the leukocytes including U1, which showed both leukocyte and brain increases. Furthermore, qRT-PCR validations confirmed these co-increases in PD leukocytes and two brain regions, the amygdala and substantia-nigra, compared to controls. This novel workflow allows deep multi-level inspection of RNA-Seq datasets and provides a comprehensive new resource for understanding disease transcriptome modifications in PD and other neurodegenerative diseases.
Soreq, L, Guffanti A, Salomonis N, Simchovitz A, Israel Z, Bergman H, Soreq H.  2014.  Long non-coding RNA and alternative splicing modulations in Parkinson's leukocytes identified by RNA sequencing.. PLoS computational biology. 10(3) Abstract
The continuously prolonged human lifespan is accompanied by increase in neurodegenerative diseases incidence, calling for the development of inexpensive blood-based diagnostics. Analyzing blood cell transcripts by RNA-Seq is a robust means to identify novel biomarkers that rapidly becomes a commonplace. However, there is lack of tools to discover novel exons, junctions and splicing events and to precisely and sensitively assess differential splicing through RNA-Seq data analysis and across RNA-Seq platforms. Here, we present a new and comprehensive computational workflow for whole-transcriptome RNA-Seq analysis, using an updated version of the software AltAnalyze, to identify both known and novel high-confidence alternative splicing events, and to integrate them with both protein-domains and microRNA binding annotations. We applied the novel workflow on RNA-Seq data from Parkinson's disease (PD) patients' leukocytes pre- and post- Deep Brain Stimulation (DBS) treatment and compared to healthy controls. Disease-mediated changes included decreased usage of alternative promoters and N-termini, 5'-end variations and mutually-exclusive exons. The PD regulated FUS and HNRNP A/B included prion-like domains regulated regions. We also present here a workflow to identify and analyze long non-coding RNAs (lncRNAs) via RNA-Seq data. We identified reduced lncRNA expression and selective PD-induced changes in 13 of over 6,000 detected leukocyte lncRNAs, four of which were inversely altered post-DBS. These included the U1 spliceosomal lncRNA and RP11-462G22.1, each entailing sequence complementarity to numerous microRNAs. Analysis of RNA-Seq from PD and unaffected controls brains revealed over 7,000 brain-expressed lncRNAs, of which 3,495 were co-expressed in the leukocytes including U1, which showed both leukocyte and brain increases. Furthermore, qRT-PCR validations confirmed these co-increases in PD leukocytes and two brain regions, the amygdala and substantia-nigra, compared to controls. This novel workflow allows deep multi-level inspection of RNA-Seq datasets and provides a comprehensive new resource for understanding disease transcriptome modifications in PD and other neurodegenerative diseases.
Benitah, S A, Bracken A, Dou Y, Huangfu D, Ivanova N, Koseki H, Laurent L, Lim DA, Meshorer E, Pombo A et al..  2014.  Stem cell epigenetics: looking forward.. Cell stem cell. 14(6):706-9.