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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2016

Oligodendrocytes in the mouse optic nerve originate in the preoptic area

The present study aims to examine the origin of oligodendrocyte progenitor cells (OPCs) in the mouse optic nerve (ON) by labeling OPCs in the fetal forebrain. The labeling of OPCs in the ON was performed by injection of a retrovirus vector carrying the lacZ gene into the lateral ventricle, or by inducible Cre/loxP of Olig2-positive cells. The retrovirus labeling revealed that ventricular zone-derived cells of the fetal forebrain relocated to the ON and differentiated into oligodendrocytes. In addition, lineage tracing of Olig2-positive cells and whole mount staining of PDGFR-positive cells demonstrated that OPCs appeared by E12.5 in the preoptic area, and spread caudally to enter the ON. Our results also suggest that OPCs generated during the early stage are depleted from the ON after maturation.

Neuroscience↗

bioRxiv2016

Brain activity and connectivity attributable to nociceptive signal block

Converging lines of evidence indicate that the pain experience emerges from distributed cortical nodes that share nociceptive information. While the theory of a single pain center is still not falsifiable by current neuroimaging technology, the validation of distinct brain mechanisms for acute pain and its relief is ongoing and strongly dependent on the employed experimental design. In the current study including a total of 28 subjects, a recently presented, innovative experimental approach was adopted that is able to clearly differentiate painful from non-pain perceptions without changing stimulus strength and while recording brain activity using functional magnetic resonance imaging (fMRI). Namely, we applied a repetitive and purely nociceptive stimulus to the tooth pulp with subsequent suppression of the nociceptive barrage via a regional nerve block. The study aims were 1) to replicate previous findings of acute pain demonstrating a fundamental role of the operculo-insular region and 2) to explore its functional connectivity during pain and subsequent relief. The brain activity reduction in the posterior insula (pINS) due to pain extinction was confirmed. In addition, the posterior S2 region (OP1) showed a similar activity pattern, thus confirming the relevance of the operculo-insular cortex in acute pain processing. Furthermore, the functional connectivity analysis yielded an enhanced positive coupling of the pINS with the cerebellar culmen during pain relief, whereas the OP1 demonstrated a positive coupling with the posterior midcingulate cortex during pain. The current results support the conceptual synthesis of localized specialization of pain processing with interactions across distributed neural targets.

Neuroscience↗

bioRxiv2016

Encoding of locomotion kinematics in the mouse cerebellum

The cerebellum has a well-established role in locomotion control, but how the cerebellar network regulates locomotion behaviour is still not well understood. We therefore characterized the activity of cerebellar neurons in awake mice engaged in a locomotion task, using high-density silicon electrode arrays. We characterized the activity of over 300 neurons in response to locomotion, finding tuning to speed of locomotion, turning, and phase of the step cycle. We found that the cerebellar neurons we recorded mainly encoded information about future locomotor activity. We were able to decode the speed of locomotion with a simple linear algorithm, needing relatively few well-chosen cells to provide an accurate estimate of locomotion speed. Our observation that cerebellar neuronal activity predicts locomotion in the near future, and encodes the required kinematic variables, points to this activity underlying the efference copy signal for vertebrate locomotion.

Neuroscience↗

bioRxiv2016

The Healthy Brain Network Serial Scanning Initiative: A resource for evaluating inter-individual differences and their reliabilities across scan conditions and sessions.

BackgroundAlthough typically measured during the resting state, a growing literature is illustrating the ability to map intrinsic connectivity in task and naturalistic viewing fMRI paradigms. These paradigms are drawing excitement due to their greater tolerability in clinical and developing populations and because they enable a wider range of analyses (e.g. inter-subject correlations). To be clinically useful, the test-retest reliability of connectivity measured during these paradigms needs to be established. This resource provides data for evaluating testretest reliability for full-brain connectivity patterns detected during each of four scan conditions that differ with respect to level of engagement (rest, abstract animations, movie clips, flanker task). Data is provided for thirteen participants, each scanned in twelve sessions with 10 minutes for each scan of the four conditions. Diffusion kurtosis imaging data was also obtained at each session.\n\nFindingsTechnical validation and demonstrative reliability analyses found that variation in intrinsic functional connectivity across sessions was greater than that attributable to scan condition. Between-condition reliability was generally high, particularly for the frontoparietal and default networks. Between-session reliabilities obtained separately for the different scan conditions were comparable, though notably lower than between-condition reliabilities.\n\nConclusionsThe described resource provides a test-bed for quantifying the reliability of connectivity indices across conditions and time. The resource can be used to compare and optimize different frameworks for measuring connectivity and data collection parameters such as scan length. Additionally, investigators can explore the unique perspectives of the brains functional architecture offered by each of the scan conditions.

Neuroscience↗

bioRxiv2016

A network of topographic numerosity maps in human association cortex

Sensory and motor cortices each contain multiple topographic maps with the structure of sensory organs (such as the retina or cochlea) mapped onto the cortical surface. These sensory maps are hierarchically organized. For example, visual field maps contain neurons that represent increasing large parts of visual space with increasingly complex responses. Some visual neurons respond to stimuli with a particular numerosity, the number of objects in a set. We recently discovered a parietal topographic numerosity map where neural numerosity preferences progress gradually across the cortical surface, analogous to sensory maps. Following this analogy, we hypothesised that there may be multiple numerosity maps. Numerosity perception is implicated in many cognitive functions including foraging, multiple object tracking, dividing attention, decision making and mathematics. Here we use ultra-high-field (7T) fMRI and neural model-based analyses to reveal numerosity-selective neural populations organized into six widely separated topographic maps in each hemisphere. Although we describe subtle differences between these maps, their properties are very similar, unlike in sensory map hierarchies. These maps are found in areas implicated in object recognition, motion perception, attention control, decision-making and mathematics. Multiple numerosity maps may allow interactions with these many cognitive systems, suggesting a broad role for quantity processing in supporting many perceptual and cognitive functions.

Neuroscience↗

bioRxiv2016

On the Effectiveness of Event-related Beta tACS on Episodic Memory Formation and Motor Cortex Excitability

BackgroundTranscranial alternating current stimulation (tACS) is widely used to entrain or modulate brain oscillations in order to investigate causal relationships between oscillations and cognition.\n\nObjectiveIn a series of experiments we here addressed the question of whether event-related, transient tACS in the beta frequency range can be used to entrain beta oscillations in two different domains: episodic memory formation and motor cortex excitability.\n\nMethodsIn experiments 1 and 2, 72 healthy human participants engaged in an incidental encoding task of verbal and non-verbal material while receiving tACS to the left and right inferior frontal gyrus (IFG) at 6.8Hz, 10.7Hz, 18.5Hz, 30Hz, 48Hz and sham stimulation for 2s during stimulus presentation.\n\nIn experiment 3, tACS was administered to M1 at the individual motor beta frequency of eight subjects. We investigated the relationship between the size of TMS induced MEPs and tACS phase.\n\nResultsBeta tACS did not affect memory performance compared to sham stimulation in experiments 1 and 2. Likewise, in experiment 3, MEP size was not modulated by the tACS phase.\n\nConclusionsOur findings suggest that event-related, transient tACS in the beta frequency range cannot be used to modulate the formation of episodic memories or motor cortex excitability. These null-results question the effectiveness of event-related tACS to entrain beta oscillations and modulate cognition.

Neuroscience↗

bioRxiv2016

How Transcranial Magnetic Stimulation over Early Visual Cortex impacts short-term memory precision and guess rate

Neuroimaging studies have demonstrated that activity patterns in early visual areas predict stimulus properties actively maintained in visual short-term memory. Yet, the mechanisms by which such information is represented remain largely unknown. In this study, observers remembered the orientations of 4 briefly presented gratings, one in each quadrant of the visual field. A 10Hz Transcranial Magnetic Stimulation (TMS) triplet was applied directly at stimulus offset, or midway through a 2-second delay, targeting early visual cortex corresponding retinotopically to a sample item in the lower hemifield. Memory for one of the four gratings was probed at random, and participants reported this orientation via method of adjustment. Replication errors were smaller when the visual field location targeted by TMS overlapped with that of the cued memory item, compared to errors for stimuli probed diagonally to TMS. This implied topographic storage of orientation information, and a memory-enhancing effect at the targeted location. Furthermore, early pulses impaired performance at all four locations, compared to late pulses. Next, response errors were fit empirically using a mixture model analysis to characterize memory precision and guess rates. Memory was more precise for items proximal to the pulse location, irrespective of pulse timing. Guesses were more probable with early TMS pulses, regardless of stimulus location. Thus, whereas TMS administered at the offset of the stimulus array might disrupt early-phase consolidation in a topographically unspecific manner, TMS also boosts the precise representation of an item at its targeted retinotopic location, perhaps by increasing attentional resources or by injecting a beneficial amount of noise.

Neuroscience↗

bioRxiv2016

Commentary: BRAIN NETWORKS. Correlated gene expression supports synchronous activity in brain networks. Science 348, 1241-4.

A recent report claims that functional brain networks defined with resting-state functional magnetic resonance imaging (fMRI) can be recapitulated with correlated gene expression (i.e. high within-network tissue-tissue \"strength fraction\", SF) (Richiardi et al., 2015). However, the authors do not adequately control for spatial proximity. We replicated their main analysis, performed a more effective adjustment for spatial proximity, and tested whether \"null networks\" (i.e. clusters with center coordinates randomly placed throughout cortex) also exhibit high SF. Removing proximal tissue-tissue correlations by Euclidean distance, as opposed to removing correlations within arbitrary tissue labels as in (Richiardi et al., 2015), reduces within-network SF to no greater than null. Moreover, randomly placed clusters also have significantly high SF, indicating that high within-network SF is entirely attributable to proximity and is unrelated to functional brain networks defined by resting-state fMRI. We discuss why additional validations in the original article are invalid and/or misleading and suggest future directions.

Neuroscience↗

bioRxiv2016

A transcallosal fiber network between left and right homotopic inferior frontal regions for supporting complex linguistic processing

Inferior frontal regions in the left and right hemisphere support different aspects of language processing. In the canonical model, left inferior frontal regions are mostly involved in processing based on phonological, syntactic and semantic features of language, whereas the right inferior frontal regions process paralinguistic aspects like affective prosody.\n\nUsing diffusion tensor imaging (DTI) based probabilistic fiber tracking in 20 healthy volunteers, we identify a callosal fiber system connecting left and right inferior frontal regions that are involved in linguistic processing of varying complexity. Anatomically, we show that the interhemispheric fibers are highly aligned and distributed along a rostral to caudal gradient in the body and genu of the corpus callosum to connect homotopic inferior frontal regions.\n\nIn light of converging data, taking previous DTI-based tracking studies and clinical case studies into account, our findings suggest that the right inferior frontal cortex not only processes paralinguistic aspects of language (such as affective prosody), as purported by the canonical model, but also supports the computation of linguistic aspects of varying complexity in the human brain. Our model may explain patterns of right hemispheric contribution to stroke recovery as well as disorders of prosodic processing. Beyond language-related brain function, we discuss how interspecies differences in interhemispheric connectivity and fiber density, including the system we described here, may also explain differences in transcallosal information transfer and cognitive abilities across different mammalian species.

Neuroscience↗

bioRxiv2016

Recovery of hand function after stroke: separable systems for finger strength and control

Loss of hand function after stroke is a major cause of long-term disability. Hand function can be partitioned into strength and independent control of fingers (individuation). Here we developed a novel paradigm, which independently quantifies these two aspects of hand function, to track hand recovery in 54 patients with hemiparesis over the first year after their stroke. Most recovery of both strength and individuation occurred in the first three months after stroke. Improvement in strength and individuation were tightly correlated up to a strength level of approximately 60% of the unaffected side. Beyond this threshold, further gains in strength were not accompanied by improvements in individuation. Any observed improvements in individuation beyond the 60% threshold were attributable instead to a second independent stable factor. Lesion analysis revealed that damage to the hand area in motor cortex and the corticospinal tract (CST) correlated more with individuation than with strength. CST involvement correlated with individuation even after factoring out the strength-individuation correlation. The most parsimonious explanation for these behavioral and lesion-based findings is that most strength recovery, along with some individuation, can be attributed to descending systems other than the CST, whereas further recovery of individuation is CST dependent.

Neuroscience↗

bioRxiv2016

A dual-strategy expression screen for candidate connectivity labels in the developing thalamus

The thalamus or \"inner chamber\" of the brain is divided into ~30 discrete nuclei, with highly specific patterns of afferent and efferent connectivity. To identify genes that may direct these patterns of connectivity, we used two strategies. First, we used a bioinformatics pipeline to survey the predicted proteomes of nematode, fruitfly, mouse and human for extracellular proteins containing any of a list of motifs found in known guidance or connectivity molecules. Second, we performed clustering analyses on the Allen Developing Mouse Brain Atlas data to identify genes encoding surface proteins expressed with temporal profiles similar to known guidance or connectivity molecules. In both cases, we then screened the resultant genes for selective expression patterns in the developing thalamus. These approaches identified 82 candidate connectivity labels in the developing thalamus. These molecules include many members of the Ephrin, Eph-receptor, cadherin, protocadherin, semaphorin, plexin, Odz/teneurin, Neto, cerebellin, calsyntenin and Netrin-G families, as well as diverse members of the immunoglobulin (Ig) and leucine-rich receptor (LRR) superfamilies, receptor tyrosine kinases and phosphatases, a variety of growth factors and receptors, and a large number of miscellaneous membrane-associated or secreted proteins not previously implicated in axonal guidance or neuronal connectivity. The diversity of their expression patterns indicates that thalamic nuclei are highly differentiated from each other, with each one displaying a unique repertoire of these molecules, consistent with a combinatorial logic to the specification of thalamic connectivity.

Neuroscience↗

bioRxiv2016

A Neural Locus for Perceptually-Relevant Saccadic Suppression in Visual-Motor Neurons of the Primate Superior Colliculus

Saccadic eye movements cause rapid retinal-image shifts that go perceptually unnoticed several times per second. The mechanisms for perceptual saccadic suppression have been controversial, in part due to sparse understanding of neural substrates. Here we uncovered an unexpectedly specific neural locus for saccadic suppression in the primate superior colliculus (SC). We first developed a sensitive behavioral measure of perceptual suppression in two male macaque monkeys (Macaca mulatta), demonstrating known selectivity to low spatial frequencies. We then investigated visual responses in either purely visual SC neurons or anatomically-deeper visual-motor neurons, which are also involved in saccade generation commands. Surprisingly, visual-motor neurons showed the strongest visual suppression, and the suppression was dependent on spatial frequency like in perception. Most importantly, visual-motor neuron suppression selectivity was highly predictive of behavioral suppression effects in each individual animal, with our recorded population explaining up to ~74% of behavioral variance even on completely different experimental sessions. In contrast, purely visual SC neurons only had mild and unselective suppression (only explaining up to ~48% of behavioral variance). These results run contrary to a hypothesized SC mechanism for saccadic suppression, in which a motor command in the visual-motor and motor neurons is relayed to the more superficial purely visual neurons to suppress them, and to then potentially be fed back to cortex. Instead, our results indicate that an extra-retinal modulatory signal mediating perceptual suppression is already established in visual-motor neurons.\n\nNew & NoteworthySaccades, which repeatedly re-align the line of sight, introduce spurious signals in retinal images that normally go unnoticed. In part, this happens because of peri-saccadic suppression of visual sensitivity. Here we discovered that a specific sub-type of superior colliculus (SC) neurons may play a critical role in saccadic suppression. Curiously, it is the neurons that help mediate the saccadic command itself that exhibit perceptually-relevant changes in visual sensitivity, not the previously hypothesized purely visual neurons.

Neuroscience↗

bioRxiv2016

Representations of Subjective Effort Cost

The perceived effort level of an action shapes everyday decisions. Despite the importance of these perceptions for decision-making, the behavioral and neural representations of the subjective cost of effort are not well understood. While a number of studies have implicated anterior cingulate cortex (ACC) in decisions about effort/reward trade-offs, none have experimentally isolated effort valuation from reward and choice difficulty, a function that is commonly ascribed to this region. We used functional magnetic resonance imaging (fMRI) to monitor brain activity while human participants engaged in uncertain choices for prospective physical effort. Our task was designed to examine effort-based decision making in the absence of reward and separated from choice difficulty - allowing us to investigate the brains role in effort valuation, independent of these other factors. Participants exhibited subjectivity in their decision-making, displaying increased sensitivity to changes in subjective effort as objective effort levels increased. Analysis of blood-oxygenation level dependent (BOLD) activity revealed that the ventromedial prefrontal cortex (vmPFC) encoded the subjective valuation of prospective effort and ACC encoded choice difficulty. These results provide insight into the processes responsible for decision-making regarding effort, dissociating the roles of vmPFC and ACC in prospective valuation of effort and choice difficulty.

Neuroscience↗

bioRxiv2016

A causal role of the right superior temporal sulcus in emotion recognition from biological motion

Understanding the emotions of others through nonverbal cues is critical for successful social interactions. The right posterior superior temporal sulcus (rpSTS) is one brain region thought to be key in the recognition of the mental states of others based on body language and facial expression. In the present study, we temporarily disrupted functional activity of the rpSTS by using continuous, theta-burst transcranial magnetic stimulation (cTBS) to test the hypothesis that the rpSTS plays a causal role in emotion recognition from body movements. Participants (N=23) received cTBS of the rpSTS, which was individually localized using fMRI, and a vertex control site. Before and after cTBS, we tested the ability of participants to identify emotions from point-light biological motion stimuli and a non-biological global motion identification task. Results revealed that the ability of participants to accurately identify emotional states from biological motion was reduced following cTBS stimulation to the rpSTS, but was unimpaired following vertex stimulation. Accuracy on the global motion tasks was unaffected by cTBS to either site. These results support the causal role of the rpSTS in decoding information about others emotional state from their body movements and gestures.

Neuroscience↗

bioRxiv2016

Alzheimer’s disease pathogenesis is dependent on neuronal receptor PTPσ

Due to limited understanding of disease mechanisms and the lack of molecular targets, translational research for Alzheimer disease has not been fruitful hitherto. Here we report findings that indicate neuronal receptor phosphatase PTP{sigma} as a potential therapeutic target for this dementia. In two TgAPP mouse models, a spectrum of Alzheimer-related pathologies, including aged-induced progression of {beta}-amyloidosis, Tau aggregation, neuroinflammation, synaptic loss, as well as behavioral deficits, all show unambiguous dependency on PTP{sigma}. APP amyloidogenic metabolites diminish upon PTP{sigma} genetic depletion or pharmacological inhibition. Binding to APP in the brain, PTP{sigma} regulates APP proteolytic metabolism via its phosphatase activity, likely through downstream signaling that modulates APP membrane localization and affinity to the {beta}-secretase, in a specific manner that does not broadly affect {beta}- and {gamma}-secretase processing of other major substrates. Together, these findings unveil a gatekeeping role of PTP{sigma} upstream in Alzheimer-like pathogenic pathway.

Neuroscience↗

bioRxiv2016

Temporal and spatial localization of prediction-error signals in the visual brain

It has been suggested that the brain pre-empts changes in the visual environment through generating predictions, although real-time eletrophysiological evidence of prediction violations remains elusive. In a series of experiments we showed participants sequences of images that followed a predictable implied sequence or whose final image violated the implied sequence. Through careful design we were able to use the same final image transitions across predictable and unpredictable conditions, ensuring that any differences in neural responses were due only to preceding context and not to the images themselves. EEG and MEG recordings showed that early/mid-latency visual evoked potentials were robustly modulated by images that violated the implied sequence across a range of types of image change (expression deformations, rigid-rotations and visual field location). This modulation occurred irrespective of stimulus object category. Although the stimuli were static images, MEG source reconstruction of the early latency signal (N/M170) localised expectancy violation signals to brain areas associated with motion perception. Our findings suggest that the N/M170 can index mismatches between predicted and actual visual inputs in a system that predicts trajectories based on ongoing context. This has important implications for understanding the N/M170 and investigating how the brain represents context to generate perceptual predictions.

Neuroscience↗

bioRxiv2016

Long-range suppressive influences from the visual surround can be explained by anatomically plausible recruitment of local competition in a model of columnar cortex

Although neurons in columns of visual cortex of adult carnivores and primates share similar orientation tuning preferences, responses of nearby neurons are surprisingly sparse and temporally uncorrelated, especially in response to complex visual scenes. The mechanisms underlying this counter-intuitive combination of response properties are still unknown. Here we present a computational model of columnar visual cortex which explains experimentally observed integration of complex features across the visual field, and which is consistent with anatomical and physiological profiles of cortical excitation and inhibition. In this model, sparse local excitatory connections within columns, coupled with strong unspecific local inhibition and functionally-specific long-range excitatory connections across columns, give rise to competitive dynamics that reproduce experimental observations. Our results explain surround modulation of responses to simple and complex visual stimuli, including reduced correlation of nearby excitatory neurons, increased excitatory response selectivity, increased inhibitory selectivity, and complex orientation-tuning of surround modulation.

neuroscience↗

bioRxiv2016

Connecting myelin-related and synaptic dysfunction in schizophrenia with SNP-rich gene expression hubs

The recent availability of several genome-wide data sets such as genome-wide mapping of SNP-rich regions and differentially methylated genes in schizophrenic individuals and gene expression data in all brain compartments across the span of human life prompted us to integrate these datasets to gain a better insight into the underlying gene networks driving this enigmatic disease.\n\nWe summed up the differentially methylated \"expression neighbors\" (i.e. genes with positively or negatively correlating expression values) of genes that fall into one of 108 distinct schizophrenia-associated genetic loci with high number of SNPs in schizophrenic patients derived from a large cohort of pooled sequencing experiments. Surprisingly, the number of expression neighbors (with a Pearson correlation of R>=0.8 or R<=-0.7) of the genes falling into the 108 genomic regions were about 35 times higher for the positively correlating genes and 32 times higher for the negatively correlating ones than for the rest of the ~16000 genes outside these loci. While the genes in the 108 loci have relatively little known impact in schizophrenia, using this approach we identified many more known schizophrenia-related important genes with a high degree of connectedness to other genes and high scores of differentially methylated probes for their expression neighbors (such as MBP, MOBP, GRIA1, COMT, SYNGR1, MAP2 and DGCR6), validating our approach.\n\nThe analysis revealed that the most positively correlating as well as the most negatively correlating genes affect synapse-related genes the most, offering an explanation and a unified view into the root cause of schizophrenia.

Neuroscience↗