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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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

Periodic Non-Sinusoidal Activity Can Produce Cross-Frequency Coupling in Cortical Signals in the Absence of Functional Interaction Between Neural Sources

The analysis of cross-frequency coupling (CFC) has become popular in studies involving intracranial and scalp EEG recordings in humans. It has been argued that some cases where CFC is mathematically present may not reflect an interaction of two distinct yet functionally coupled neural sources with different frequencies. Here we provide two empirical examples from intracranial recordings where CFC can be shown to be driven by the shape of a periodic waveform rather than by a functional interaction between distinct sources. Using simulations, we also present a generalized and realistic scenario where such coupling may arise. This scenario, which we term waveform-dependent CFC, arises when sharp waveforms (e.g., cortical potentials) occur in a periodic manner throughout parts of the data. Since the waveforms are repeated periodically, they constitute a slow wave that is inherently phase-aligned with the high-frequency component carried by the same waveforms. We submit that such behavior of the data, which seems to be present in various cortical signals, cannot be interpreted as reflecting functional modulation between distinct neural sources without additional evidence. In addition, we show that even low amplitude periodic potentials that cannot be readily observed or controlled for, are sufficient for significant CFC to occur.

Neuroscience↗

bioRxiv2016

Lognormal firing rate distribution reveals prominent fluctuation-driven regime in spinal motor networks

When spinal circuits generate rhythmic movements it is important that the neuronal activity remains within stable bounds to avoid saturation and to preserve responsiveness. In what dynamical regime does the neuronal population operate in order to achieve this? Here, we simultaneously record from hundreds of neurons in lumbar spinal circuits and establish the neuronal fraction that operates within either a mean-driven or a fluctuation-driven regime during generation of multiple motor behaviors. We find a rich diversity of firing rates across the neuronal population as reflected in a lognormal distribution and demonstrate that half of the neurons spend at least 50% of the time in the fluctuation-driven regime regardless of behavior. Since neurons in this regime have a supralinear input-output curve, which enhances sensitivity, whereas the mean-driven regime reduces sensitivity, this fraction may reflect a fine trade-off between stability and sensitivity in order to maintain flexibility across motor behaviors.

Neuroscience↗

bioRxiv2016

Primate ventromedial prefrontal cortex neurons continuously encode the willingness to engage in reward directed behavior.

To survive in their complex environment, primates must integrate information over time and adjust their actions beyond immediate events. The underlying neurobiological processes, however, remain unclear. Here, we assessed the contribution of the ventromedial prefrontal cortex (VMPFC), a brain region important for value-based decision making. We recorded single VMPFC neurons in monkeys performing a task where obtaining fluid rewards required squeezing a grip. The willingness to perform the action was modulated not only by visual information about Effort and Reward levels, but also by contextual factors such as Trial Number (i.e fatigue and/or satiety) or behavior in recent trials. A greater fraction of VMPFC neurons encoded contextual information, compared to visual stimuli. Moreover, the dynamics of VMPFC firing was more closely related to slow changes in motivational states driven by these contextual factors rather than rapid responses to individual task events. Thus, the firing of VMPFC neurons continuously integrated contextual information and reliably predicted the monkeys willingness to perform the task. This function might be critical when animals forage in a complex environment and need to integrate information over time. Its relation with motivational states also resonates with the VMPFC implication in the default mode or in mood disorders.

Neuroscience↗

bioRxiv2016

Extrinsic repair of injured dendrites as a paradigm for regeneration by fusion

Injury triggers regeneration of axons and dendrites. Research identified factors required for axonal regeneration outside the CNS, but little is known about regeneration triggered by dendrotomy. Here we study neuronal plasticity triggered by dendrotomy and determine the fate of complex PVD arbors following laser surgery of dendrites. We find that severed primary dendrites grow towards each other and reconnect via branch fusion. Simultaneously, terminal branches lose self-avoidance and grow towards each other, meeting and fusing at the tips via an AFF-1-mediated process. Ectopic branch growth is identified as a step in the regeneration process required for bypassing the lesion site. Failure of reconnection to the severed dendrites results in degeneration of the distal end of the neuron. We discover pruning of excess branches via EFF-1 that acts to recover the original wild-type arborization pattern in a cell-autonomous process. In contrast, AFF-1 activity during dendritic auto-fusion is derived from the lateral seam cells and not autonomously from the PVD neuron. We propose a model in which AFF-1-vesicles derived from the epidermal seam cells fuse neuronal dendrites from without. Thus, EFF-1 and AFF-1 fusion proteins emerge as new players in neuronal arborization and maintenance of arbor connectivity following injury in C. elegans. Our results demonstrate that there is a genetically determined multi-step pathway to repair broken dendrites in which EFF-1 and AFF-1 act on different steps of the pathway. Intrinsic EFF-1 is essential for dendritic pruning after injury and extrinsic AFF-1 mediates dendrite fusion to bypass injuries.\n\nAuthor summaryNeurons in the central nervous system have very limited regenerative ability, they fail to remodel following amputation and only in some invertebrates, axons can repair themselves by fusion. Some genetic pathways have been identified for axonal regeneration but few studies exist on dendrite regeneration following injury. To determine how neurons regenerate dendrites following injury we study the C. elegans PVD polymodal neurons that display an arborized pattern of repetitive menorah-like structures. We injure dendrites by laser microsurgery, follow their fate and show that broken primary dendrites often regenerate via fusion. We describe how PVD dendrites regenerate and present roles for EFF-1 and AFF-1 proteins in fusion and remodeling of menorahs. Menorahs lose self-avoidance and AFF-1 fuses them, bypassing the injury site. Branch sprouting, EFF-1-mediated pruning, and arbor simplification completes regeneration. When auto-fusion fails the distal arbor degenerates. Surprisingly, AFF-1 acts non-cell autonomously to mediate dendrite fusion. We propose that extracellular vesicles derived from the lateral epidermis fuse severed dendrites in a process reminiscent of enveloped virus-mediated cell fusion without infection.

Neuroscience↗

bioRxiv2016

Humans do not evidence choice biases in simple discrimination tasks

The contribution of sensory and decisional processes to perceptual decision making is still unclear, even in simple perceptual tasks. When a decision maker needs to select an action from a set of balanced alternatives, any tendency to choose one alternative more often- choice bias-is consistent with a bias in the sensory evidence, but also with a preference to select that alternative independently of the sensory evidence. To decouple sensory from decisional biases, here we asked humans to perform a simple perceptual discrimination task with two symmetric alternatives under two different task instructions. The instructions varied the response mapping between perception and the category of the alternatives. In two experiments, we found that 30 out of 32 participants exhibited sensory biases and 15 decisional biases. The decisional biases were consistent with a criterion change in a simple signal detection theory model. Perceptual decision making, thus, even in simple scenarios, is affected by sensory and decisional choice biases.

Neuroscience↗

bioRxiv2016

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products.

The increasing incidence of autism suggests a major environmental influence. Epidemiology has implicated many candidates and genetics many susceptibility genes. Gene/environment interactions in autism were analysed using 206 autism genes (ASGs) to interrogate ~1 million chemical/gene interactions in the comparative toxicogenomics database. Bias towards ASGs was statistically determined for each chemical. Many suspect compounds identified in epidemiology, including tetrachlorodibenzodioxin, pesticides, particulate matter, benzo(a)pyrene, heavy metals, valproate, acetaminophen, SSRIs, cocaine, bisphenol A, phthalates, polyhalogenated biphenyls, flame retardants, diesel constituents, terbutaline and oxytocin, inter alia showed a significant degree of bias towards ASGs, as did relevant endogenous agents (retinoids, sex steroids, thyroxine, melatonin, folate, dopamine, serotonin). Numerous other endocrine disruptors selectively targeted ASGs including paraquat, atrazine and other pesticides not yet studied in autism and many compounds used in food, cosmetics or household products, including tretinoin, soy phytoestrogens, aspartame, titanium dioxide and sodium fluoride. Autism polymorphisms are known to influence sensitivity to some of these chemicals and these same genes play an important role in barrier function and control of respiratory cilia sweeping particulate matter from the airways. The close gene/environment relationships, for multiple suspect pollutants, suggest that the rising incidence of autism might be chemically driven by numerous environmental contaminants in a gene dependent manner. The protective dappled camouflage of the peppered moth was rendered invalid by industrial soot covering the trees, a situation reversed by clean air acts. The rising tide of neurodevelopmental and other childhood disorders linked to multiple pollutants may need a similar solution.

Neuroscience↗

bioRxiv2016

Towards an emotional stress test: a reliable, non-subjective cognitive measure of anxious responding.

Response to stress is a key factor in mood and anxiety disorder aetiology. Current measures of stress-response are limited because they largely rely on retrospective self-report. Objectively quantifying individual differences in stress response would be a valuable step towards improving our understanding of disorder vulnerability. Our goal is to develop a reliable, objective, within-subject probe of stress response. To this end, we examined stress-potentiated performance on an inhibitory control task from baseline to 2-4 weeks (n=50) and again after 5-9 months (n=22) as well as examining population measures for a larger sample (n=165). Replicating previous findings, threat of shock improved distractor accuracy and slowed target reaction time on this task. Critically, both within-subject self-report measures of stress (ICC=0.74) and stress-potentiated task performance (ICC=0.58) showed clinically useful test-retest reliability. Threat-potentiated task performance may therefore hold promise as a non-subjective measure of individual stress-reactivity.

Neuroscience↗

bioRxiv2016

Cell fusion proteins can rejuvenate adult dendritic trees

The aging brain undergoes structural changes, affecting brain homeostasis, neuronal function and consequently cognition. The complex architecture of dendritic arbors poses a challenge to understanding age-dependent morphological alterations, behavioral plasticity and remodeling following brain injury. Here, we use the PVD polymodal neurons of C. elegans as a model to study how aging affects neuronal plasticity. Using confocal live imaging of C. elegans PVD neurons, we demonstrate age-related progressive morphological alterations of intricate dendritic arbors. We show that insulin/IGF-1 receptor mutations (daf-2) fail to inhibit the progressive morphological aging of dendrites and do not prevent the minor decline in response to harsh touch during aging. We uncovered that PVD aging is characterized by a major decline in regenerative potential of dendrites following experimental laser dendrotomy. Furthermore, the remodeling of transected dendritic trees via AFF-1-mediated self-fusion can be restored in old animals by DAF-2 insulin/IGF-1 receptor mutations, and can be differentially reestablished by ectopic expression of AFF-1 fusion protein (fusogen). Thus, AFF-1 fusogen ectopically expressed in the PVD and mutations in DAF-2/IGF-1R, differentially rejuvenate some aspects of dendritic regeneration following injury.\n\nSummary statementEctopic expression of AFF-1 fusogen or low activity of IGF-1R/DAF-2 rejuvenate the regeneration potential of dendrites following injury in aging C. elegans

Neuroscience↗

bioRxiv2016

A conceptual view at microtubule plus end dynamics in neuronal axons

Axons are the cable-like protrusions of neurons which wire up the nervous system. Polar bundles of microtubules (MTs) constitute their structural backbones and are highways for life-sustaining transport between proximal cell bodies and distal synapses. Any morphogenetic changes of axons during development, plastic rearrangement, regeneration or degeneration depend on dynamic changes of these MT bundles. A key mechanism for implementing such changes is the coordinated polymerisation and depolymerisation at the plus ends of MTs within these bundles. To gain an understanding of how such regulation can be achieved at the cellular level, we provide here an integrated overview of the extensive knowledge we have about the molecular mechanisms regulating MT de/polymerisation. We first summarise insights gained from work in vitro, then describe the machinery which supplies the essential tubulin building blocks, the protein complexes associating with MT plus ends, and MT shaft-based mechanisms that influence plus end dynamics. We briefly summarise the contribution of MT plus end dynamics to important cellular functions in axons, and conclude by discussing the challenges and potential strategies of integrating the existing molecular knowledge into conceptual understanding at the level of axons.

Neuroscience↗

bioRxiv2016

BK Channel Function Bidirectionally Influences Behavioral Deficits Following Withdrawal from Chronic Ethanol in Caenorhabditis elegans

The severity of withdrawal from chronic ethanol is a driving force for relapse in alcohol dependence. Thus, uncovering molecular changes that can be targeted to lessen withdrawal symptoms is key to breaking the cycle of dependence. Using the model nematode Caenorhabditis elegans, we tested whether one highly conserved ethanol target, the BK potassium channel, may play a major role in alcohol withdrawal. Consistent with a previous report, we found that C. elegans displays behavioral impairment during withdrawal from chronic ethanol that can be reduced by low-dose ethanol. We discovered that the degree of impairment is exacerbated in worms lacking the BK channel, SLO-1, and is alleviated by selective rescue of the BK channel in the nervous system. Conversely, behavioral impairment during withdrawal was dramatically lower in worms with BK channel function enhanced via gain-of-function mutation or overexpression. Consistent with these results, we found that chronic ethanol exposure decreased BK channel expression in a subset of neurons. In addition, we found that a distinct, conserved large-conductance potassium channel, SLO-2, showed the inverse functional relationship, influencing withdrawal behavior via a SLO-1 channel-dependent mechanism. Our findings demonstrate that withdrawal symptoms in C. elegans are mechanistically explained in part by a functional imbalance in the nervous system associated with a reduction in SLO-1 channel expression. Therefore, selective modulation of Slo family ion channel activity may represent a novel therapeutic approach to explore for normalizing behaviors during alcohol withdrawal.\n\nARTICLE SUMMARYPeople addicted to alcohol maintain maladaptive drinking patterns in part to avoid the terrible symptoms of withdrawal. It is unclear whether any single molecule may be genetically modified to alleviate withdrawal symptoms. Here, we discover that for the nematode C. elegans, upregulating function of the conserved BK potassium channel SLO-1 prevents alcohol withdrawal symptoms. Conversely, downregulating SLO-1 channel function makes withdrawal worse. Moreover, we identify an inverse relation between SLO-1 and a second type of BK channel named SLO-2 in the severity of withdrawal. The BK channel thus represents an attractive molecular target to consider for alleviating alcohol withdrawal symptoms.\n\nStatement on data and reagent availabilityStrains are available upon request or through the Caenorhabditis Genetics Center.

Neuroscience↗

bioRxiv2016

Rett syndrome - biological pathways leading from MECP2 to disorder phenotypes

Rett syndrome (RTT) is a rare disease but still one of the most abundant causes for intellectual disability in females. Typical symptoms are onset at month 6-18 after normal pre-and postnatal development, loss of acquired skills and severe intellectual disability. The type and severity of symptoms are individually highly different. A single mutation in one gene, coding for methyl-CpG-binding protein 2 (MECP2), is responsible for the disease. The most important action of MECP2 is regulating epigenetic imprinting and chromatin condensation, but MECP2 influences many different biological pathways on multiple levels. In this review the known changes in metabolite levels, gene expression and biological pathways in RTT are summarized. It is discussed how they are leading to some characteristic RTT phenotypes and identifies the gaps of knowledge, namely which phenotypes have currently no mechanistic explanation leading back to MECP2 related pathways. As a result of this review the visualization of the biologic pathways showing MECP2 up-and downstream regulation was developed and published on WikiPathways.

Neuroscience↗

bioRxiv2016

Schizophrenia hiPSC neurons display expression changes that are enriched for disease risk variants and a blunted activity-dependent response

IMPORTANCESchizophrenia (SCZ) is a common illness with complex genetic architecture where both common genetic variation and rare mutations have been implicated. SCZ candidate genes participate in common molecular pathways that are regulated by activity-dependent changes in neurons, including the signaling network that modulates synaptic strength and the network of genes that are targets of fragile X mental retardation protein. One important next step is to further our understanding on the role of activity-dependent changes of genes expression in the etiopathogenesis of SCZ.\n\nOBJECTIVETo examine whether neuronal activity-dependent changes of gene expression is dysregulated in SCZ.\n\nDESIGN, SETTING, AND PARTICIPANTSNeurons differentiated from human induced pluripotent stem cells (hiPSCs) derived from 4 cases with SCZ and 4 unaffected controls were depolarized using potassium chloride. RNA was extracted followed by genome-wide profiling of the transcriptome.\n\nMAIN OUTCOMES AND MEASURESWe performed differential expression analysis and gene co-expression analysis to identify activity-dependent or disease-specific changes of the transcriptome. Further, we used gene set analyses to identify co-expressed modules that are enriched for SCZ risk genes.\n\nRESULTSWe identified 1,669 genes that are significantly different in SCZ-associated vs. control hiPSC-derived neurons and 1,199 genes that are altered in these cells in response to depolarization. We show that the effect of activity-dependent changes of gene expression in SCZ-associated neurons is attenuated compared to controls. Furthermore, these differentially expressed genes are co-expressed in modules that are highly enriched for genes affected by genetic risk variants in SCZ and other neurodevelopmental disorders.\n\nCONCLUSIONS AND RELEVANCEOur results show that SCZ candidate genes converge to gene networks that are associated with a blunted effect of activity-dependent changes of gene expression in SCZ-associated neurons. Overall, these findings show that hiPSC neurons demonstrate activity-dependent transcriptional changes that can be utilized to examine underlying mechanisms and therapeutic interventions related to SCZ.

Neuroscience↗

bioRxiv2016

Functional connectivity patterns underlying the experience of auditory verbal hallucinations in patients with schizophrenia

AbstractSchizophrenia is characterized by functional connectivity aberrations between brain regions that mediate different cognitive processes. The characteristic symptoms of schizophrenia such as delusions, hallucinations, passivity experiences etc. are suggested to reflect a disordered self-awareness. In the present study, we used a novel fMRI paradigm, the Hallucination Attentional Modulation Task (HAMT)\", to examine the functional connectivity patterns underlying the experience of auditory verbal hallucinations in contrast to the patterns associated with processing of visual stimuli. We found that there was substantial overlap amongst healthy (n=8) and schizophrenia (n=6) subjects with respect to the functional connectivity patterns during the free attention and visual attention conditions of the paradigm. In patients with schizophrenia having continuous auditory verbal hallucinations, the connectivity between the bilateral superior parietal lobules and bilateral thalami were stronger during the hallucination attention condition. These results provide preliminary leads that link auditory verbal hallucinations to an underlying disorder of self-agency.

Neuroscience↗

bioRxiv2016

Visual guidance of bimanual coordination relies on movement direction

Visual spatial information is paramount in guiding bimanual coordination, but anatomical factors, too, modulate performance in bimanual tasks. Vision conveys not only abstract spatial information, but also informs about body-related aspects such as posture. Here, we asked whether, accordingly, visual information induces body-related, or merely abstract, perceptual-spatial constraints in bimanual movement guidance. Human participants made rhythmic, symmetrical and parallel, bimanual index finger movements with the hands held in the same or different orientations. Performance was more accurate for symmetrical than parallel movements in all postures, but additionally when homologous muscles were concurrently active, such as when parallel movements were performed with differently rather than identically oriented hands. Thus, both perceptual and anatomical constraints were evident. We manipulated visual feedback with a mirror between the hands, replacing the image of the left with that of the right hand and creating the visual impression of bimanual symmetry independent of the right hands true movement. Symmetrical mirror feedback impaired parallel, but improved symmetrical bimanual performance compared with regular hand view. Critically, these modulations were independent of hand posture and muscle homology. Thus, vision appears to contribute exclusively to spatial, but not to body-related, anatomical movement coding in the guidance of bimanual coordination.

Neuroscience↗

bioRxiv2016

Beyond spike-timing-dependent plasticity: a computational study of plasticity gradients across basal dendrites.

Synaptic plasticity is thought to be the principal mechanism underlying learning in the brain. Models of plastic networks typically combine point neurons with spike-timing-dependent plasticity (STDP) as the learning rule. However, a point neuron does not capture the complexity of dendrites, which allow non-linear local processing of the synaptic inputs. Furthermore, experimental evidence suggests that STDP is not the only learning rule available to neurons. Implementing biophysically realistic neuron models, we studied how dendrites allow for multiple synaptic plasticity mechanisms to coexist in a single cell. In these models, we compared the conditions for STDP and for the synaptic strengthening by local dendritic spikes. We further explored how the connectivity between two cells is affected by these plasticity rules and the synaptic distributions. Finally, we show how memory retention in associative learning can be prolonged in networks of neurons with dendrites.

Neuroscience↗

bioRxiv2016

The Missing Link: Predicting Connectomes from Noisy and Partially Observed Tract Tracing Data

Our understanding of the wiring map of the brain, known as the connectome, has increased greatly in the last decade, mostly due to technological advancements in neuroimaging techniques and improvements in computational tools to interpret the vast amount of available data. Despite this, with the exception of the C. elegans roundworm, no definitive connectome has been established for any species. In order to obtain this, tracer studies are particularly appealing, as these have proven highly reliable. The downside of tract tracing is that it is costly to perform, and can only be applied ex vivo. In this paper, we suggest that instead of probing all possible connections, hitherto unknown connections may be predicted from the data that is already available. Our approach uses a latent space model that embeds the connectivity in an abstract physical space. Regions that are close in the latent space have a high chance of being connected, while regions far apart are most likely disconnected in the connectome. After learning the latent embedding from the connections that we did observe, the latent space allows us to predict connections that have not been probed previously. We apply the methodology to two connectivity data sets of the macaque and we demonstrate that the latent space model is successful in predicting unobserved connectivity, outperforming two alternative baselines in nearly all cases. Furthermore, we show how the latent spatial embedding may be used to integrate multimodal observations (i.e. anterograde and retrograde tracers) for the mouse neocortex. Finally, our probabilistic approach enables us to make explicit which connections are easy to predict and which prove difficult, allowing for informed follow-up studies.

Neuroscience↗

bioRxiv2016

Neural signatures of value comparison in human cingulate cortex during decisions requiring an effort-reward trade-off

Integrating costs and benefits is crucial for optimal decision-making. While much is known about decisions that involve outcome-related costs (e.g., delay, risk), many of our choices are attached to actions and require an evaluation of the associated motor costs. Yet how the brain incorporates motor costs into choices remains largely unclear. We used human functional magnetic resonance imaging during choices involving monetary reward and physical effort to identify brain regions that serve as a choice comparator for effort-reward trade-offs. By independently varying both options' effort and reward levels, we were able to identify the neural signature of a comparator mechanism. A network involving supplementary motor area (SMA) and the caudal portion of dorsal anterior cingulate cortex (dACC) encoded the difference in reward (positively) and effort levels (negatively) between chosen and unchosen choice options. We next modelled effort-discounted subjective values using a novel behavioural model. This revealed that the same network of regions involving dACC and SMA encoded the difference between the chosen and unchosen options' subjective values, and that activity was best described using a concave model of effort-discounting. In addition, this signal reflected how precisely value determined participants' choices. By contrast, separate signals in SMA and ventro-medial PFC (vmPFC) correlated with participants' tendency to avoid effort and seek reward, respectively. This suggests that the critical neural signature of decision-making for choices involving motor costs is found in human cingulate cortex and not vmPFC as typically reported for outcome-based choice. Furthermore, distinct frontal circuits drive behaviour towards reward-maximization and effort-minimization.\n\nSignificance StatementThe neural processes that govern the trade-off between expected benefits and motor costs remain largely unknown. This is striking because energetic requirements play an integral role in our day-to-day choices and instrumental behaviour, and a diminished willingness to exert effort is a characteristic feature of a range of neurological disorders. We use a new behavioural characterization of how humans trade-off reward-maximization with effort-minimization to examine the neural signatures that underpin such choices, using BOLD MRI neuroimaging data. We find the critical neural signature of decision-making, a signal that reflects the comparison of value between choice options, in human cingulate cortex, whereas two distinct brain circuits drive behaviour towards reward-maximization or effort-minimization.

Neuroscience↗

bioRxiv2016

Functional Cliques in Developmentally Correlated Neural Networks

We consider a sparse random network of excitatory leaky integrate-andfire neurons with short-term synaptic depression. Furthermore to mimic the dynamics of a brain circuit in its first stages of development we introduce for each neuron correlations among in-degree and out-degree as well as among excitability and the corresponding total degree, We analyze the influence of single neuron stimulation and deletion on the collective dynamics of the network. We show the existence of a small group of neurons capable of controlling and even silencing the bursting activity of the network. These neurons form a functional clique since only their activation in a precise order and within specific time windows is capable to ignite population bursts.

Neuroscience↗