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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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

Age differences in brain white matter microstructure in UK Biobank (N = 3,513)

Quantifying the microstructural properties of the human brains connections is necessary for understanding normal ageing and disease states. We examined brain white matter MRI data in 3,513 generally healthy people aged 45-75 years from the UK Biobank sample. Using conventional water diffusion measures and newer, as-yet rarely-studied indices from neurite orientation dispersion and density imaging (NODDI), we document large age differences in white matter microstructure. Mean diffusivity was the most age-sensitive diffusion measure, with negative age associations strongest in the thalamic radiation and association fibres. Inter-individual differences in white matter microstructure across brain tracts become increasingly correlated in older age. This connectivity de-differentiation may reflect an age-related aggregation of systemic detrimental effects on the brain. We report several other novel results, including comparative age associations with volumetric indices and associations with hemisphere and sex. Results from this unusually large, single-scanner sample provide one of the most definitive characterisations to date of age differences in major white matter tracts in the human brain.\n\nAbbreviations

Neuroscience↗

bioRxiv2016

Data-Driven Phenotypic Categorization for Neurobiological Analyses: Beyond DSM-5 Labels

BackgroundData-driven approaches can capture behavioral and biological variation currently unaccounted for by contemporary diagnostic categories, thereby enhancing the ability of neurobiological studies to characterize brain-behavior relationships.\n\nMethodsA community-ascertained sample of individuals (N=347, ages 18-59) completed a battery of behavioral measures, psychiatric assessment, and resting state functional magnetic resonance imaging (R-fMRI) in a cross-sectional design. Bootstrap-based exploratory factor analysis was applied to 49 phenotypic subscales from 10 measures. Hybrid Hierarchical Clustering was applied to resultant factor scores to identify nested groups. Adjacent groups were compared via independent samples t-tests and chi-square tests of factor scores, syndrome scores, and psychiatric prevalence. Multivariate Distance Matrix Regression examined functional connectome differences between adjacent groups.\n\nResultsReduction yielded six factors, which explained 77.8% and 65.4% of the variance in exploratory and constrained exploratory models, respectively. Hybrid Hierarchical Clustering of these 6 factors identified 2, 4, and 8 nested groups (i.e., phenotypic communities). At the highest clustering level, the algorithm differentiated functionally adaptive and maladaptive groups. At the middle clustering level, groups were separated by problem type (maladaptive groups; internalizing vs. externalizing problems) and behavioral type (adaptive groups; sensation-seeking vs. extraverted/emotionally stable). Unique phenotypic profiles were also evident at the lowest clustering level. Group comparisons exhibited significant differences in intrinsic functional connectivity at the highest clustering level in somatomotor, thalamic, basal ganglia, and limbic networks.\n\nConclusionsData-driven approaches for identifying homogenous subgroups, spanning typical function to dysfunction not only yielded clinically meaningful groups, but captured behavioral and neurobiological variation among healthy individuals as well.

Neuroscience↗

bioRxiv2016

Complementary learning systems within the hippocampus: A neural network modeling approach to reconciling episodic memory with statistical learning

A growing literature suggests that the hippocampus is critical for the rapid extraction of regularities from the environment. Although this fits with the known role of the hippocampus in rapid learning, it seems at odds with the idea that the hippocampus specializes in memorizing individual episodes. In particular, the Complementary Learning Systems theory argues that there is a computational trade-off between learning the specifics of individual experiences and regularities that hold across those experiences. We asked whether it is possible for the hippocampus to handle both statistical learning and memorization of individual episodes. We exposed a neural network model that instantiates known properties of hippocampal projections and subfields to sequences of items with temporal regularities. We found that the monosynaptic pathway -- the pathway connecting entorhinal cortex directly to region CA1 -- was able to support statistical learning, while the trisynaptic pathway -- connecting entorhinal cortex to CA1 through dentate gyrus and CA3 -- learned only individual episodes, with apparent representations of regularities resulting from associative reactivation through recurrence. Thus, in paradigms involving rapid learning, the computational trade-off between learning episodes and regularities may be handled by separate anatomical pathways within the hippocampus itself.

Neuroscience↗

bioRxiv2016

Refined biomimetic model of chronic pain healed with erythropoietin

Humans suffering with chronic pain may have no evidence of a lesion or disease. They are managed with a morass of drugs and invasive procedures. In many, their persistent pain occurs after the healing of a soft tissue injury, with a neural source hypothesized. Opiates, commonly used to mitigate their symptoms, can cause an increase in neuropathic pain over time. Current animal models of neuropathic pain commonly create direct neural damage with open surgeries using ligatures, neurectomies, chemicals or other forms of intentional trauma. However, we have observed clinically that after an injury in humans, the naturally occurring process of tissue repair can cause chronic neural pain. We show here how the refined biomimetic NeuroDigm GELTM Model, in the mature male rat, gradually induces neuropathic pain behavior with a nonsurgical percutaneous injection of tissue-derived hydrogel in the tunnel of the distal tibial nerve. This perineural model creates a mononeuritis with the biogenic matrix induction of tissue remodeling, the last stage of tissue repair. Repeated behavioral analgesic testing over 5 months in the model implied a unique predictive validity for all analgesics tested. Morphine, initially effective, had an increase in pain behavior over time, suggesting an opioid-induced hyperalgesia, as seen in humans. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses had profound analgesia. Histology reveals focal neural remodeling, with neural regeneration, as in human biopsies. For the first time, targeted erythropoietin appears to heal neural pain, by extinguishing bilateral pain behavior present for over 4 months.\n\ntranslational model, neuropathic pain, erythropoietin, neural regeneration, soft tissue injuries, neuritis, tissue repair, hydrogel, animal model of disease, neural remodeling, age, opioid-induced hyperalgesia, morphine resistance, analgesics, refined pain model, matrix remodeling, neuroinflammation, predictive validity, habituation, estrogen

Neuroscience↗

bioRxiv2016

GEFs and Rac GTPases control directional specificity of neurite extension along the anterior-posterior axis

Although previous studies have identified many extracellular guidance molecules and intracellular signaling proteins that regulate axonal outgrowth and extension, most were conducted in the context of unidirectional neurite growth, in which the guidance cues either attract or repel growth cones. Very few studies addressed how intracellular signaling molecules differentially specify bidirectional outgrowth. Here, using the bipolar PLM neurons in C. elegans, we show that the guanine nucleotide exchange factors (GEFs) UNC-73/Trio and TIAM-1 promote anterior and posterior neurite extension, respectively. The Rac subfamily GTPases act downstream of the GEFs; CED-10/Rac1 is activated by TIAM-1, whereas CED-10 and MIG-2/RhoG act redundantly downstream of UNC-73. Moreover, these two pathways antagonize each other and, thus, regulate the directional bias of neuritogenesis. Our study suggests that directional specificity of neurite extension is conferred through the intracellular activation of distinct GEFs and Rac GTPases.\n\nSignificance StatementMost previous studies on intracellular signaling during neurite guidance were performed in the context of unidirectional neurite growth. They could not address the molecular basis of directional outgrowth of multiple neurites mainly because of the lack of a good model system. Using a pair of bipolar neurons in the nematode Caenorhabditis elegans, we found that distinct sets of intracellular molecules are required for neurite extension towards the anterior and the posterior. Moreover, signaling pathways that promote neurite extension in different directions antagonize each other to achieve balanced growth. Therefore, our study offers an in vivo example for a long-standing concept that spatially selective activation of intracellular signaling molecules could enable a diverse range of neuronal growth patterns.

Neuroscience↗

bioRxiv2016

Local field potentials primarily reflect inhibitory neuron activity in human and monkey cortex

The local field potential (LFP) is generated by large populations of neurons, but unitary contribution of spiking neurons to LFP is not well characterised. We investigated this contribution in multi-electrode array recordings from human and monkey neocortex by examining the spike-triggered LFP average (st-LFP). The resulting st-LFPs were dominated by broad spatio-temporal components due to ongoing activity, synaptic inputs and recurrent connectivity. To reduce the spatial reach of the st-LFP and observe the local field related to a single spike we applied a spatial filter, whose weights were adapted to the covariance of ongoing LFP. The filtered st-LFPs were limited to the perimeter of 800 m around the neuron, and propagated at axonal speed, which is consistent with their unitary nature. In addition, we discriminated between putative inhibitory and excitatory neurons and found that the inhibitory st-LFP peaked at shorter latencies, consistently with previous findings in hippocampal slices. Thus, in human and monkey neocortex, the LFP reflects primarily inhibitory neuron activity.

Neuroscience↗

bioRxiv2016

A cellular and regulatory map of the GABAergic nervous system of C. elegans

Neurotransmitter maps are important complements to anatomical maps and represent an invaluable resource to understand how signals are transmitted throughout the nervous system and how a nervous system is developmentally patterned. We report here a comprehensive map of neurons in the C. elegans nervous system that contain the neurotransmitter GABA, revealing twice as many GABA-positive neuron classes as previously reported. We define previously unknown glia-like cells that reuptake GABA, as well as \"GABA reuptake neurons\" which do not synthesize GABA but take it up from the extracellular environment. We used the map of GABA-positive neurons for a comprehensive analysis of transcriptional regulators that define the GABA phenotype. We synthesize our findings of specification of GABAergic neurons with previous reports on the specification of glutamatergic and cholinergic neurons into a nervous system-wide regulatory map which defines neurotransmitter specification mechanisms for more than half of all neuron classes in C. elegans.

Neuroscience↗

bioRxiv2016

The effect of local inter-inhibitory connectivity on the dynamics of an activity-dependent neuronal network growth model

The balance between excitation and inhibition in a neuronal network is considered to be an important predictor of neural excitability. Various processes are thought to maintain this balance across a range of stimuli/conditions. However, the developmental formation of this balance remains an open question, especially regarding the interplay between network blue-print (the spatial arrangement of excitatory and inhibitory nodes) and homeostatic processes. In this paper, we use a published model of activity-dependent growth to show that the E/I ratio alone cannot accurately predict system behaviour but rather it is the combination of this ratio and the underlying spatial arrangement of neurones that predict both activity in, and structure of, the resulting network. In particular, we highlight the particular role of clustered inter-inhibitory connectivity. We develop a measure that allows us to determine the relationship between inter-inhibitory connectivity clustering and system behaviour in an exhaustive list of spatial arrangements with a given fixed number of excitatory and inhibitory neurones. Our results reveal that, for a given E/I ratio, networks with high levels of inter-inhibitory clustering are more likely to experience oscillatory behaviour than networks with low levels, and we investigate the network attributes which characterise each global behaviour type produced by the model. We identify possible approaches for extensions of the current work, and discuss the implications these results may have on future modelling studies in this field.

Neuroscience↗

bioRxiv2016

Spatial mnemonic encoding: Theta power decreases co-occur with medial temporal lobe BOLD increases during the usage of the Method of Loci

The Method of Loci is one, if not the most, efficient mnemonic encoding strategy. This strategy combines the core cognitive processes commonly linked to medial temporal lobe (MTL) activity: spatial processing and associative memory processes. During such tasks fMRI studies consistently demonstrate increases in medial temporal lobe (MTL) activity, while electrophysiological studies have emphasized the important role of theta oscillations (3-8 Hz) in the MTL. How MTL activity is linked to theta oscillatory EEG power, however, is unknown. Specifically, it is not known whether increases or decreases in MTL theta power are associated with increased BOLD signal. To investigate this question we recorded EEG and fMRI while participants used the spatial Method of Loci contrasted to the Pegword Method, a similarly associative but non spatial mnemonic. Surprisingly, the more effective spatial mnemonic induced a pronounced theta power decrease in the left MTL compared to the non-spatial associative mnemonic strategy. This effect was mirrored by BOLD signal increases in the MTL. This pattern of results suggests that theta oscillations in the MTL are negatively related to BOLD signal increases. These findings extend the well-known negative relation of alpha/beta oscillations and BOLD signals in the cortex to theta oscillations in the MTL. The results also demonstrate that decreases in theta power can index MTL involvement during encoding.\n\nSignificance StatementStudies investigating the oscillatory correlates of memory encoding largely focus on activity in the theta frequency and often implicitly assume that increases in theta activity reflect similar processes as typically reported increases MTL activity changes in fMRI studies. The presented study found decreases in theta power, not increases, closely mapping to MTL BOLD signal increases during the same paradigm. This finding is in line with studies showing a negative relationship between low frequency power and BOLD changes in the cortex, but challenges the assumption that theta power increases reflect MTL activity. The reported findings importantly contribute to answer the question of how and which oscillatory activity indexes MTL memory processes.

Neuroscience↗

bioRxiv2016

Goggatomy: a Method for Opening Small Cuticular Compartments in Arthropods for Physiological Experiments

Most sense organs of arthropods are ensconced in small exoskeletal compartments that hinder direct access to plasma membranes. We have developed a method for exposing live sensory and supporting cells in such structures. The technique uses a viscous light cured resin to embed and support the structure, which is then sliced with a sharp blade. We term the procedure a goggatomy, from the Khoisan word for a bug, gogga. To demonstrate the utility of the method we show that it can be used to expose the auditory chordotonal organs in the second antennal segment and the olfactory receptor neurons in the third antennal segment of Drosophila melanogaster, preserving the transduction machinery. The procedure can also be used on other small arthropods, like mites, Daphnia, mosquitoes, wasps and ants to expose a variety of cells.

Neuroscience↗

bioRxiv2016

Nociceptor-enriched genes required for normal thermal nociception.

Here, we describe a targeted reverse genetic screen for thermal nociception genes of Drosophila larvae. Using laser capture microdissection and microarray analyses of nociceptive and non-nociceptive neurons we identified 275 nociceptor-enriched genes. We then tested the function of the enriched genes with nociceptor-specific RNAi and thermal nociception assays. Tissue specific RNAi targeted against 14 genes caused insensitive thermal nociception while targeting of 22 genes caused hypersensitive thermal nociception. Previously uncategorized genes were named for heat resistance (ie. boilerman, fire dancer, oven mitt, trivet, thawb and bunker gear) or heat sensitivity (firelighter, black match, eucalyptus, primacord, jet fuel, detonator, gasoline, smoke alarm, and jetboil). Insensitive nociception phenotypes were often associated with severely reduced branching of nociceptor neurites and hyperbranched dendrites were seen in two of the hypersensitive cases. Many genes that we identified were not isolated in a prior genome-wide screen, and are evolutionarily conserved in mammals.

Neuroscience↗

bioRxiv2016

Figure-ground organization in visual cortex for natural scenes

Figure-ground organization and border-ownership assignment are essential for understanding natural scenes. It has been shown that many neurons in the macaque visual cortex signal border-ownership in displays of simple geometric shapes such as squares, but how well these neurons resolve border-ownership in natural scenes is not known. We studied area V2 neurons in behaving macaques with static images of complex natural scenes. We found that about half of the neurons were border-ownership selective for contours in natural scenes and this selectivity originated from the image context. The border-ownership signals emerged within 70 ms after stimulus onset, only ~30 ms after response onset. A substantial fraction of neurons were highly consistent across scenes. Thus, the cortical mechanisms of figure-ground organization are fast and efficient even in images of complex natural scenes. Understanding how the brain performs this task so fast remains a challenge.\n\nSignificance StatementHere we show, for the first time, that neurons in primate visual area V2 signal border-ownership for objects in complex natural scenes. Surprisingly, these signals appear as early as the border-ownership signals for simple figure displays. In fact, they emerge well before object selective activity appears in infero-temporal cortex, which rules out feedback from that region as an explanation. Thus, \"objectness\" is detected by extremely fast mechanisms that do not depend on feedback from the known object-recognition centers.

Neuroscience↗

bioRxiv2016

Bottom-up and top-down computations in high-level visual cortex

The ability to read a page of text or recognize a persons face depends on category-selective visual regions in ventral temporal cortex (VTC). To understand how these regions mediate word and face recognition, it is necessary to characterize how stimuli are represented and how this representation is used in the execution of a cognitive task. Here, we show that the response of a category-selective region in VTC can be computed as the degree to which the low-level properties of the stimulus match a category template. Moreover, we show that during execution of a task, the bottom-up representation is scaled by the intraparietal sulcus (IPS), and that the level of IPS engagement reflects the cognitive demands of the task. These results provide a unifying account of neural processing in VTC in the form of a model that addresses both bottom-up and top-down effects and quantitatively predicts VTC responses.

Neuroscience↗

bioRxiv2016

Dopamine neurons change the type of excitability in response to stimuli

The dynamics of neural excitability determine the neuronal response to stimuli, its synchronization and resonance properties and, ultimately, the computations it performs in the brain. We investigated the dynamical mechanisms underlying the excitability type of dopamine (DA) neurons, using a conductance based biophysical model, and its regulation by intrinsic and synaptic currents. By calibrating the model to reproduce low frequency tonic firing, NMDA excitation is balanced by GABA-mediated inhibition and leads to type I excitable behavior characterized by a continuous decrease in firing frequency in response to hyperpolarizing currents. Furthermore, we analyzed how excitability type of the DA neuron model is influenced by changes in the intrinsic current composition. A subthreshold sodium current is necessary for a continuous frequency decrease during application of a negative current, and the low-frequency balanced state during simultaneous activation of NMDA and GABA receptors. Blocking this current switches the neuron to type II. Enhancing the anomalous rectifier Ih current also switches the excitability to type II. Key characteristics of synaptic conductances that may be observed in vivo also change the type of excitability: a depolarized GABAR reversal potential or co-activation of AMPARs leads to an abrupt frequency drop to zero, which is typical for type II excitability. Coactivation of NMDARs together with AMPARs and GABARs shifts the the type I/II boundary toward more hyperpolarized GABAR reversal potentials. To better understand how altering each of the aforementioned currents leads to changes in excitability profile of DA neuron, we provide a thorough dynamical analysis. Collectively, these results imply that type I excitability in dopamine neurons might be important for low firing rates and fine-tuning basal dopamine levels, while switching excitability to type II during NMDAR and AMPAR activation may facilitate a transient increase in dopamine concentration, as type II neurons are more amenable to synchronization.\n\nAuthor summaryDopamine neurons play a central role in guiding motivated behaviors. However, complete understanding of computations these neurons perform to encode rewarding and salient stimuli is still forthcoming. Network connectivity influences neural responses to stimuli but so do intrinsic excitability properties of individual neurons, as they define their synchronization properties and neural coding strategy. We investigated the excitability type of the DA neuron and found that, depending on the synaptic and intrinsic current composition, DA neurons can switch from type I to type II excitability. In short, without synaptic inputs or under balanced excitatory and inhibitory inputs DA neurons exhibits type I excitability, while excitatory AMPAR inputs can switch the neuron to type II. Type I neurons are best suited for coding the stimulus intensity due to their ability to smoothly decrease the firing rate. Type I excitability might be important for achieving low a basal DA concentration necessary for normal brain functioning. Switching to type II excitability further enables robust transient DA release of heterogeneous DA neuron population in response to correlated inputs, partially due to evoked population synchrony.

Neuroscience↗

bioRxiv2016

Cerebellar learning using perturbations

The cerebellum aids the learning and execution of fast coordinated movements, with acquired information being stored by plasticity of parallel fibre--Purkinje cell synapses. According to the current consensus, erroneously active parallel fibre synapses are depressed by complex spikes arising when climbing fibres signal movement errors. However, this theory cannot solve the credit assignment problem of using the limited information from a global movement evaluation to optimise behaviour by guiding the plasticity in numerous neurones. We identify the possible implementation of an algorithm solving this problem, whereby spontaneous complex spikes perturb ongoing movements, create an eligibility trace for plasticity and signal resulting error changes to guide plasticity. These error changes are extracted by adaptively cancelling the average error. This framework, stochastic gradient descent with estimated global errors, generates specific predictions for synaptic plasticity rules that contradict the current consensus. However, in vitro plasticity experiments under physiological conditions verified our predictions, highlighting the sensitivity of plasticity studies to unphysiological conditions. Using numerical and analytical approaches we demonstrate the convergence and estimate the capacity of learning in our implementation. Finally, a similar mechanism may operate during optimisation of action sequences by the basal ganglia, where dopamine could both initiate movements and signal rewards, analogously to the dual perturbation and correction role of the climbing fibre outlined here.

Neuroscience↗

bioRxiv2016

A brush fire feedback loop for the ramp-like rise in hominin brain size that began 2.4 million years ago

The rapid three-fold enlargement of the hominin brain1,2 began about 2.3 million years ago (myr) as Africa dried and grass replaced brush, creating great savannas3. Seeking an amplifying feedback loop, I analyzed the lightning-brush-fire ecology for grazing animals in a grassy burn scar4. Discovering the new grass by exploring brush byways could promote a population boom-but only after grass-specialized herbivores evolved from mixed feeders5 at 2.4 myr. When the brush returned several decades later, the grazer boom would turn to bust, squeezing numerous descendants back into the core grasslands. Meat-eating Homo species would boom and bust when grazers did, enriching the core in whatever alleles were earlier concentrated in the brush fringe catchment zone for that boom. This return migration for Homo is what creates the amplifying feedback loop that speeds brain enlargement rate, likely up to the mutation rate limit. It also promotes trait hitchhiking: any brush-relevant allele, not just those for hunting, can experience amplifying feedback merely by hanging out in the catchment zone4. The shade offered by brush would have been the default location for cooperative nurseries, time-consuming food preparation, and toolmaking. Increased behavioral versatility correlates with larger brain size and the more versatile brains of a current generation need only spend more-than-average time in the booms catchment zone for this recursive evolutionary process to keep average brain size increasing via assortative mating. This helps account for the time when enlargement began, why it was linear, when it ended, and why it slowed in Neanderthals and in Asian Homo erectus. Without utilizing Darwins selective survival, the feedback loop makes advance room for \"free\" future functionality in the cerebral cortex, likely relevant to the evolutionary emergence of our structured intellectual functions6 such as syntax, contingent planning, games, and logic.

Neuroscience↗

bioRxiv2016

Spatiotemporal structure of intracranial electric fields induced by transcranial electric stimulation in human and nonhuman primates

Transcranial electric stimulation (TES) is an emerging technique, developed to non-invasively modulate brain function. However, the spatiotemporal distribution of the intracranial electric fields induced by TES remains poorly understood. In particular, it is unclear how much current actually reaches the brain, and how it distributes across the brain. Lack of this basic information precludes a firm mechanistic understanding of TES effects. In this study we directly measure the spatial and temporal characteristics of the electric field generated by TES using stereotactic EEG (s-EEG) electrode arrays implanted in cebus monkeys and surgical epilepsy patients. We found a small frequency dependent decrease (10%) in magnitudes of TES induced potentials and negligible phase shifts over space. Electric field strengths were strongest in superficial brain regions with maximum values of about 0.5 mV/mm. Our results provide crucial information for the interpretation of human TES studies and the optimization and design of TES stimulation protocols. In addition, our findings have broad implications concerning electric field propagation in non-invasive recording techniques such as EEG/MEG.

Neuroscience↗

bioRxiv2016

C. elegans PVD Neurons: A Platform for Functionally Validating and Characterizing Neuropsychiatric Risk Genes

One of the primary challenges in the field of psychiatric genetics is the lack of an in vivo model system in which to functionally validate candidate neuropsychiatric risk genes (NRGs) in a rapid and cost-effective manner1-3. To overcome this obstacle, we performed a candidate-based RNAi screen in which C. elegans orthologs of human NRGs were assayed for dendritic arborization and cell specification defects using C. elegans PVD neurons. Of 66 NRGs, identified via exome sequencing of autism (ASD)4 or schizophrenia (SCZ)5-9 probands and whose mutations are de novo and predicted to result in a complete or partial loss of protein function, the C. elegans orthologs of 7 NRGs were found to be required for proper neuronal development and represent a variety of functional classes, including transcriptional regulators and chromatin remodelers, molecular chaperones, and cytoskeleton-related proteins. Notably, the positive hit rate, when selectively assaying C. elegans orthologs of ASD and SCZ NRGs, is enriched >14-fold as compared to unbiased RNAi screening10. Furthermore, we find that RNAi phenotypes associated with the depletion of NRG orthologs is recapitulated in genetic mutant animals, and, via genetic interaction studies, we show that the NRG ortholog of ANK2, unc-44, is required for SAX-7/MNR-1/DMA-1 signaling. Collectively, our studies demonstrate that C. elegans PVD neurons are a tractable model in which to discover and dissect the fundamental molecular mechanisms underlying neuropsychiatric disease pathogenesis.

Neuroscience↗