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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

Pebbles as Dry Ice Replacement for Snap Freezing of Rodents Brains

Dry ice is commonly used as a cooling agent in the preclinical research environment. It permits rapid freezing of tissues and organs through liquid media. Laboratories depend on a constant supply of dry ice because it disintegrates in a matter of days. Here we tested whether commercially available pebble gravel could be used as dry ice replacement for snap freezing mouse brains in 2-methylbutane. We monitored 2-methylbutane temperature for one hour and tested different setups with the focus on creating a practical solution that can be used in every research laboratory. While gravel pebbles cannot replace dry ice in the laboratory entirely, they present a useful addition as readily available and reusable cooling agent.

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bioRxiv2017

Excessive ERK-dependent synaptic clustering with enhanced motor learning in the MECP2 duplication syndrome mouse model of autism

Autism-associated genetic mutations may produce altered learning abilities by perturbing the balance between stability and plasticity of synaptic connections in the brain. Here we report an increase in the stabilization of dendritic spines formed during repetitive motor learning in the mouse model of MECP2-duplication syndrome, a high-penetrance form of syndromic autism. This increased stabilization is mediated entirely by spines that form cooperatively in clusters. The number of clusters formed and stabilized predicts the mutants enhanced motor learning and memory phenotype, reminiscent of savant-like behaviors occasionally associated with autism.\n\nThe ERK signaling pathway, which promotes cooperative plasticity between spines, was found to be hyperactive in MECP2-duplication motor cortex specifically after training. Inhibition of ERK signaling normalizes clustered spine stabilization and rescues motor learning behavior in mutants. We conclude that learning-associated dendritic spine clustering stabilized by hyperactive ERK signaling drives abnormal motor learning and memory consolidation in this model of syndromic autism.

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bioRxiv2017

Real-time spike sorting platform for high-density extracellular probes with ground-truth validation and drift correction

Electrical recordings from a large array of electrodes give us access to neural population activity with single-cell, single-spike resolution. These recordings contain extracellular spikes which must be correctly detected and assigned to individual neurons. Despite numerous spike-sorting techniques developed in the past, a lack of high-quality ground-truth datasets hinders the validation of spike-sorting approaches. Furthermore, existing approaches requiring manual corrections are not scalable for hours of recordings exceeding 100 channels. To address these issues, we built a comprehensive spike-sorting pipeline that performs reliably under noise and probe drift by incorporating covariance-based features and unsupervised clustering based on fast density-peak finding. We validated performance of our workflow using multiple ground-truth datasets that recently became available. Our software scales linearly and processes up to 1000-channel recording in real-time using a single workstation. Accurate, real-time spike sorting from large recording arrays will enable more precise control of closed-loop feedback experiments and brain-computer interfaces.

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bioRxiv2017

Demonstration of short-term plasticity in the dorsolateral prefrontal cortexwith theta burst stimulation: A TMS-EEG study

ObjectivesTo examine the effects of intermittent TBS (iTBS) and continuous TBS (cTBS) on cortical reactivity in the dorsolateral prefrontal cortex.\n\nMethods10 healthy participants were stimulated with either iTBS, cTBS or sham at F3 electrode. Single- and paired-pulse TMS and concurrent electroencephalography (EEG) were used to assess change in cortical reactivity and long-interval intracortical inhibition (LICI) via TMS-evoked potentials (TEPs) and TMS-evoked oscillations.\n\nResultsSignificant increases in N120 amplitudes (p < 0.01) were observed following iTBS over prefrontal cortex. Changes in TMS-evoked theta oscillations and LICI of theta oscillations were also observed following iTBS (increase) and cTBS (decrease). Change in LICI of theta oscillations correlated with change in N120 amplitude following TBS (r = -0.670, p = 0.001).\n\nConclusionsThis study provides preliminary evidence that TBS produces direct changes in cortical reactivity in the prefrontal cortex. Combining TBS with TMS-EEG may be a useful approach to optimise stimulation paradigms prior to the conduct of clinical trials.\n\nSignificanceTBS is able to modulate cortical reactivity and cortical inhibition in the prefrontal cortex.\n\nHighlightsO_LIEffects of iTBS and cTBS were studied in the DLPFC using TMS-EEG\nC_LIO_LIiTBS increased N120 amplitude, theta power and LICI of theta\nC_LIO_LIcTBS decreased theta power alone\nC_LI

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bioRxiv2017

Brain reorganization in anticipation of predictable words

How is speech understood despite the lack of a deterministic relationship between the sounds reaching auditory cortex and what we perceive? One possibility is that unheard words that are unconsciously activated in association with listening context are used to constrain interpretation. We hypothesized that a mechanism for doing so involves reusing the ability of the brain to predict the sensory effects of speaking associated words. Predictions are then compared to signals arriving in auditory cortex, resulting in reduced processing demands when accurate. Indeed, we show that sensorimotor brain regions are more active prior to words predictable from listening context. This activity resembles lexical and speech production related processes and, specifically, subsequent but still unpresented words. When those words occur, auditory cortex activity is reduced, through feedback connectivity. In less predictive contexts, activity patterns and connectivity for the same words are markedly different. Results suggest that the brain reorganizes to actively use knowledge about context to construct the speech we hear, enabling rapid and accurate comprehension despite acoustic variability.

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bioRxiv2017

Experience-induced forgetting by WT1 enables learning of sequential tasks.

Under physiological conditions, strength and persistence of memory must be regulated in order to produce behavioral flexibility. In fact, impairments in memory flexibility are associated with pathologies such as post-traumatic stress disorder or autism; however the underlying mechanisms that enable memory flexibility are still poorly understood. Here we identified the transcriptional repressor Wilms Tumor 1 (WT1) as a critical synaptic plasticity regulator that decreases memory strength, promoting memory flexibility. WT1 was activated in the hippocampus following induction of long-term potentiation (LTP) or learning. WT1 knockdown enhanced CA1 neuronal excitability, LTP and long-term memory whereas its over-expression weakened memory retention. Moreover, forebrain WT1-deficient mice showed deficits in both reversal, sequential learning tasks and contextual fear extinction, exhibiting impaired memory flexibility. We conclude that WT1 limits memory strength or promotes memory weakening, thus enabling memory flexibility, a process that is critical for learning from new experience.

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bioRxiv2017

Predicted sensory consequences of voluntary actions modulate amplitude and temporal dynamics of preceding readiness potentials

Self-generated, voluntary actions, are preceded by a slow negativity in the scalp electroencephalography (EEG) signal recorded from frontal regions (termed readiness potential; RP). This signal, and its lateralized subcomponent (LRP), is mainly regarded as preparatory motor activity associated with the forthcoming motor act. However, it is not clear whether this neural signature is associated with preparatory motor activity, expectation of its associated sensory consequences, or both. Here we recorded EEG data from 12 healthy subjects while they performed self-paced button presses with their right index and middle fingers. In one condition (motor+sound) these button-presses triggered a sound while in another (motor-only) they did not. Additionally, subjects passively listened to sounds delivered in expected timings (sound-only). We found that the RP amplitude (locked to time of button press) was significantly more negative in the motor+sound compared with motor-only conditions starting ~1.4 seconds prior to button press. Importantly, no signal negativity was observed prior to expected sound delivery in the sound-only condition. Thus, the differences in RP amplitude between motor+sound and motor-only conditions are beyond differences in mere expectation of a forthcoming auditory sound. No significant differences between the two conditions were obtained in the LRP component. Our results suggest that expected auditory consequences are encoded in the early phase of the RP preceding the voluntary actions that generate them.

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bioRxiv2017

Differential hemispheric and visual stream involvement in ensemble coding of emotion in facial crowds

The visual system takes advantage of redundancies in the scene by extracting summary statistics from a set of items. Similarly, in many social situations where scrutinizing each individuals expression is inefficient, human observers make snap judgments of crowds of people by reading \"crowd emotion\" to avoid danger (e.g., mass panic or violent mobs) or to seek help. However, how the brain accomplishes this feat remains unaddressed. Here we report a set of behavioral and fMRI studies in which participants made avoidance or approach decisions by choosing between two facial crowds presented in the left and right visual fields (LVF/RVF). Participants were most accurate for crowds containing task-relevant cues: avoiding angry crowds and approaching happy crowds. This effect was amplified by sex-linked facial cues (angry male/happy female crowds) and highly lateralized, with better recognition of the task-congruent facial crowd when presented in LVF. fMRI results showed that the dorsal visual stream was preferentially activated in crowd emotion processing, with intraparietal sulcus and superior frontal gyrus predicting behavioral crowd emotion efficiency, whereas the ventral visual stream showed greater involvement in individual face emotion processing, with fusiform cortex activity predicting the accuracy of decisions about individual face emotion. Our results shed new light on the distinction between global vs. local processing of face stimuli, revealing differential involvement of the left and right hemispheres and the dorsal and ventral pathways in reading crowd vs. individual emotion.

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bioRxiv2017

A Bayesian Perspective on Accumulation in the Magnitude System

Theoretical and empirical work posits the existence of a common magnitude system in the brain. Such a proposal implies that manipulating stimuli in one magnitude dimension (e.g. time) should interfere with the subjective estimation of another magnitude dimension (e.g. space). Here, we asked whether a generalized Bayesian magnitude estimation system would sample sensory evidence using a common, amodal prior. Two psychophysical experiments separately tested participants on their perception of duration, surface, and numerosity when non-target magnitude dimensions and the rate of sensory evidence accumulation were manipulated. First, we found that duration estimation was resilient to changes in surface or numerosity, whereas lengthening (shortening) duration yielded under- (over-) estimations of surface and numerosity. Second, the perception of numerosity and surface were affected by changes in the rate of sensory evidence accumulation, whereas duration was not. Our results suggest that a generalized magnitude system based on Bayesian computations would minimally necessitate multiple priors.

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bioRxiv2017

Myosin II activity is required for structural plasticity at the axon initial segment

In neurons, axons possess a molecularly defined and highly organised proximal region - the axon initial segment (AIS) - that is a key regulator of both electrical excitability and cellular polarity. Despite existing as a large, dense structure with specialised cytoskeletal architecture, the AIS is surprisingly plastic, with sustained alterations in neuronal activity bringing about significant alterations to its position, length or molecular composition. However, although the upstream activity-dependent signalling pathways that lead to such plasticity have begun to be elucidated, the downstream mechanisms that produce structural changes at the AIS are completely unknown. Here, we use dissociated cultures of rat hippocampus to show that two forms of AIS plasticity in dentate granule cells - long-term relocation, and more rapid shortening - are completely blocked by treatment with blebbistatin, a potent and selective myosin II ATPase inhibitor. These data establish a link between myosin II and AIS function, and suggest that myosin IIs primary role at the structure may be to effect activity-dependent morphological alterations.

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bioRxiv2017

Symptoms of Depression in a Large Healthy Population Cohort are related to Subjective Memory Complaints and Memory Performance in Negative Contexts

Decades of research have investigated the impact of clinical depression on memory, which has revealed biases and in some cases impairments. However, little is understood about the effects of sub-clinical symptoms of depression on memory performance in the general population. Here we report the effects of symptoms of depression on memory problems in a large population-derived cohort (N = 2544), 87% of whom reported at least one symptom of depression. Specifically, we investigate the impact of depressive symptoms on subjective memory complaints, objective memory performance on a standard neuropsychological task and, in a subsample (n = 288), objective memory in affective contexts. There was a dissociation between subjective and objective memory performance, with depressive symptoms showing a robust relationship with self-reports of memory complaints, even after adjusting for age, gender, general cognitive ability and symptoms of anxiety, but not with performance on the standardised measure of verbal memory. Contrary to our expectations, hippocampal volume (assessed in a subsample, n = 592) did not account for significant variance in subjective memory, objective memory or depressive symptoms. Nonetheless, depressive symptoms were related to poorer memory for pictures presented in negative contexts, even after adjusting for memory for pictures in neutral contexts. Thus the symptoms of depression, associated with subjective memory complaints, appear better assessed by memory performance in affective contexts, rather than standardised memory measures. We discuss the implications of these findings for understanding the impact of depressive symptoms on memory functioning in the general population.

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bioRxiv2017

Cognitive task information is transferred between brain regions via resting-state network topology

Resting-state network connectivity has been associated with a variety of cognitive abilities, yet it remains unclear how these connectivity properties might contribute to the neurocognitive computations underlying these abilities. We developed a new approach - information transfer mapping - to test the hypothesis that resting-state functional network topology describes the computational mappings between brain regions that carry cognitive task information. Here we report that the transfer of diverse, task-rule information in distributed brain regions can be predicted based on estimated activity flow through resting-state network connections. Further, we find that these task-rule information transfers are coordinated by global hub regions within cognitive control networks. Activity flow over resting-state connections thus provides a large-scale network mechanism for cognitive task information transfer and global information coordination in the human brain, demonstrating the cognitive relevance of resting-state network topology.

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bioRxiv2017

Grid cells show field-to-field variability and this explains the aperiodic response of inhibitory interneurons

Research on network mechanisms and coding properties of grid cells assume that the firing rate of a grid cell in each of its fields is the same. Furthermore, proposed network models predict spatial regularities in the firing of inhibitory interneurons that are inconsistent with experimental data. In this paper, by analyzing the response of grid cells recorded from rats during free navigation, we first show that there are strong variations in the mean firing rate of the fields of individual grid cells and thus show that the data is inconsistent with the theoretical models that predict similar peak magnitudes. We then build a two population excitatory-inhibitory network model in which sparse spatially selective input to the excitatory cells, presumed to arise from e.g. salient external stimuli, hippocampus or a combination of both, leads to the variability in the firing field amplitudes of grid cells. We show that, when combined with appropriate connectivity between the excitatory and inhibitory neurons, the variability in the firing field amplitudes of grid cells results in inhibitory neurons that do not exhibit regular spatial firing, consistent with experimental data. Finally, we show that even if the spatial positions of the fields are maintained, variations in the firing rates of the fields of grid cells are enough to cause remapping of hippocampal cells.

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bioRxiv2017

Untangling cortical maps in mouse primary visual cortex

Local populations of neurons in mouse visual cortex exhibit diverse tuning preferences. We show this seeming disorder can be untangled -- the similarity of tuning between pairs of neurons is correlated better with the overlap between their receptive fields in visual space rather than with their distance in the cortex. These findings are consistent with the hypothesis that salt-and-pepper maps arise from the lateral dispersion of clonally related neurons.

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bioRxiv2017

Adaptive motivational signalling from the Anterior Cingulate Cortex to the Ventral Tegmental Area

Information gained during goal pursuit motivates adaptive behaviour. The anterior cingulate cortex (ACC) supports adaptive behaviour, but how ACC signals are translated into motivational signals remains unclear. Rats implanted in the ACC and ventral tegmental area (VTA), a dopaminergic brain area implicated in motivation, were trained to run laps around a rectangular track for a fixed reward, where each lap varied in physical effort (a 30cm climbable barrier). Partial directed coherence analysis of local field potentials revealed that ACC theta (4-12 Hz) activity increased as rats entered the barrier-containing region of the maze on trials when the barrier was absent, and predicted similar changes in VTA theta. This did not occur on effortful, barrier-present trials. These data suggest that ACC provides a top-down modulating signal which can influence the motivation with which to pursue a reward, and which may be, in our task, a neural correlate of relief.

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bioRxiv2017

The idiosyncratic nature of confidence

Confidence is the feeling of knowing that accompanies decision making and guides processes such as learning, error detection, and inter-personal communication. Bayesian theory proposes that confidence is a function of the probability that a decision is correct given the evidence. Empirical research has shown, however, that humans tend to report confidence in very different ways. This idiosyncratic behaviour suggests that different individuals may perform different computations to estimate confidence from uncertain evidence. We tested this hypothesis by collecting confidence reports from healthy adults making decisions under either visual or numerical uncertainty. We found that for most individuals, confidence did indeed reflect the perceived probability of being correct. However, in approximately half of them, confidence also reflected a different probabilistic quantity: the observed Fisher information. We isolated the influence of each of these two quantities on confidence, and found that this decomposition is stable across weeks, and consistent across tasks involving uncertainty in both perceptual and cognitive domains. Our findings provide, for the first time, a mechanistic interpretation of individual differences in the human sense of confidence.

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bioRxiv2017

Challenges for Bayesian Model Selection of Dynamic Causal Models

Achieving a mechanistic explanation of brain function requires understanding causal relationships among regions. A relatively new technique to assess effective connectivity in fMRI data is Dynamic Causal Modeling (DCM). As DCM is more frequently used, it becomes increasingly important to further validate the technique and understand its limitations. With DCM, Bayesian Model Selection (BMS) is used to select the most likely causal model. We conducted simulations to test the degree to which BMS is robust to two types of challenges when applied to DCMs, those inherent to data (Category 1) and those inherent to model space (Category 2). Category 1 challenges tested properties of the data (low signal-to-noise, different response magnitudes and shapes across regions) that could either blur the distinction between models or potentially bias model selection. These challenges are impossible or difficult to measure and control in real data, so investigating their effect upon BMS through simulation is critical. Category 2 challenges tested properties of model space that create subsets of confusable models. Our results suggest that given data that conform to the prior assumptions of DCM, BMS is robust to challenges from Category 1. However, in the face of Category 2 challenges (when a more homogenous model space was tested) the false positive rate rose above an acceptable level. We show that such errors are neither trivial nor easily avoided with existing approaches. However, we argue that it is possible to detect Category 2 challenges, and avoid inappropriate interpretations by conducting simulations prior to applying DCM.\n\nAcronyms

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bioRxiv2017

A genetic basis for molecular asymmetry at vertebrate electrical synapses

Neural network function is based upon the patterns and types of connections made between neurons. Neuronal synapses are adhesions specialized for communication and they come in two types, chemical and electrical. Communication at chemical synapses occurs via neurotransmitter release whereas electrical synapses utilize gap junctions for direct ionic and metabolic coupling. Electrical synapses are often viewed as symmetrical structures, with the same components making both sides of the gap junction. By contrast, we show that a broad set of electrical synapses in zebrafish, Danio rerio, require two gap-junction-forming Connexins for formation and function. We find that one Connexin functions presynaptically while the other functions postsynaptically in forming the channels. We also show that these synapses are required for the speed and coordination of escape responses. Our data identify a genetic basis for molecular asymmetry at vertebrate electrical synapses and show they are required for appropriate behavioral performance.

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