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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 847 records · Page 47Linked to original sources

bioRxiv2016

Magnetic Resonance Imaging Tracking of Distal Inflammatory Changes following Mild Traumatic Brain Injury (mTBI) in rats.

Sensorimotor disturbances continue to represent one of the most debilitating and widely reported complications in patients suffering mild traumatic brain injuries (mTBI). Loss of peripheral neuronal function at sites distal and disconnected to the central nervous control central centers is well documented. Distal muscular atrophy, complex regional pain symptoms, and poor wound healing are just a few of the many complications with often more severe secondary complications such decubitus ulcers and osteomyelitis seen at sites in the body distal to the center of injury. MRI has been widely established as a diagnostic and therapeutic planning tool in patients and animal models with neuronal disease. However, studies investigating the neural correlates of spinal cord changes after TBI are lacking. Here, we used T2 MR imaging to determine the effects of mTBI on the morphology and inflammatory changes of the spinal cord. We hypothesize that rats receiving mTBI utilizing a controlled cortical impact (CCI) contusion will demonstrate T2 signal changes at distal locomotor centers in the spine. Experimental mTBI and sham groups of Sprague-Dawley rats were used (n = 2 sham and 4 experimental). A mild CCI was applied to the right brain cortex. Rats were sacrificed at 60 days post injury and spinal cords harvested for ex vivo MRI T2 analysis. Focal areas/lesions of increased T2 hyperintensity were noted in mTBI injured rats (n = 4). Experimental group of rats also demonstrated secondary spinal cord locomotor and sensation adverse effects clinically. MR imaging showed volumetric reductions and T2 signal changes in the cervical, thoracic, and lumbar segments of the spinal cord at 8 weeks post-injury. T2 intensity values were elevated in all experimental groups in comparison to the sham group within the distal cord, suggesting that remote CCI causes secondary spinal cord inflammation and neurodegeneration at distant sites. These findings also further support the idea that the most peripheral nerves and spinal cord will be most negatively affected by a TBI. While our research is in its preliminary stages, our results further confirm that mTBI has more far reaching effects than previously understood. T2 MRI is an effective tool to assess the extent of spinal cord injury related to antecedent TBI.

Neuroscience↗

bioRxiv2016

Global and local connectivity differences converge with gene expression in a neurodevelopmental disorder of known genetic origin

Knowledge of genetic cause in neurodevelopmental disorders can highlight molecular and cellular processes critical for typical development. Furthermore, the relative homogeneity of neurodevelopmental disorders of known genetic origin allows the researcher to establish the subsequent neurobiological processes that mediate cognitive and behavioural outcomes. The current study investigated white matter structural connectivity in a group of individuals with intellectual disability due to mutations in ZDHHC9. In addition to shared cause of cognitive impairment, these individuals have a shared cognitive profile, involving oro-motor control difficulties and expressive language impairment. Analysis of structural network properties using graph theory measures showed global reductions in mean clustering coefficient and efficiency in the ZDHHC9 group, with maximal differences in frontal and parietal areas. Regional variation in clustering coefficient and local efficiency across cortical regions in cases and controls were significantly associated with known pattern of expression of ZDHHC9 in the normal adult human brain. The results demonstrate that a mutation in a single gene impacts upon white matter organisation across the whole-brain, but also shows regionally specific effects, according to variation in gene expression. Furthermore, these regionally specific patterns may link to specific developmental mechanisms, and correspond to specific cognitive deficits.

Neuroscience↗

bioRxiv2016

Biologically plausible learning in recurrent neural networks for flexible cognitive tasks

Neural activity during cognitive tasks exhibits complex dynamics that flexibly encode task-relevant variables. Chaotic recurrent networks, which spontaneously generate rich dynamics, have been proposed as a model of cortical computation during cognitive tasks. However, existing methods for training these networks are either biologically implausible, and/or require a continuous, real-time error signal to guide learning. Here we show that a biologically plausible learning rule can train such recurrent networks, guided solely by delayed, phasic rewards at the end of each trial. Networks endowed with this learning rule can successfully learn nontrivial tasks requiring flexible (context-dependent) associations, memory maintenance, nonlinear mixed selectivities, and coordination among multiple outputs. The resulting networks replicate complex dynamics previously observed in animal cortex, such as dynamic encoding of task features and selective integration of sensory inputs. We conclude that recurrent neural networks offer a plausible model of cortical dynamics during both learning and performance of flexible behavior.

Neuroscience↗

bioRxiv2016

Initiation of Retina Regeneration By a Conserved Mechanism of Adult Neurogenesis

Retina damage or disease in humans often leads to reactive gliosis, preventing the formation of new cells and resulting in visual impairment or blindness. Current efforts to repair damaged retinas are inefficient and not capable of fully restoring vision. Conversely, the zebrafish retina is capable of spontaneous regeneration upon damage, using Muller glia (MG) derived progenitors. Understanding how zebrafish MG initiate regeneration may help develop new treatments that prompt mammalian retinas to regenerate. Here we show that inhibition of GABA signaling facilitates initiation of MG proliferation. GABA levels decrease following damage, and MG are positioned to detect the decrease. Using pharmacological and genetic approaches we demonstrate that GABAA receptor inhibition stimulates regeneration in undamaged retinas while activation inhibits regeneration in damaged retinas. GABA induced proliferation causes upregulation of regeneration associated genes. This is the first evidence that neurotransmitters control retina regeneration in zebrafish through an evolutionarily conserved mechanism of neurogenesis.

Neuroscience↗

bioRxiv2016

Binding of synGAP to PDZ Domains of PSD-95 is Regulated by Phosphorylation and Shapes the Composition of the Postsynaptic Density

SynGAP is a Ras/Rap GTPase-activating protein (GAP) present in high concentration in postsynaptic densities (PSDs) from mammalian forebrain where it binds to all three PDZ (PSD-95, Discs-large, ZO-1) domains of PSD-95. We show that phosphorylation of synGAP by Ca2+/calmodulin-dependent protein kinase II (CaMKII) decreases its affinity for the PDZ domains as much as 10-fold, measured by surface plasmon resonance. SynGAP is abundant enough in postsynaptic densities (PSDs) to occupy about one third of the PDZ domains of PSD-95. Therefore, we hypothesize that phosphorylation by CaMKII reduces synGAP's ability to restrict binding of other proteins to the PDZ domains of PSD-95. We support this hypothesis by showing that three critical postsynaptic signaling proteins that bind to the PDZ domains of PSD-95 are present at a higher ratio to PSD-95 in PSDs isolated from synGAP heterozygous mice.

Neuroscience↗

bioRxiv2016

Theta-burst transcranial magnetic stimulation to the prefrontal or parietal cortex does not impair metacognitive visual awareness

Neuroimaging studies commonly associate dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex with conscious perception. However, such studies only investigate correlation, rather than causation. In addition, many studies conflate objective performance with subjective awareness. In an influential recent paper, Rounis and colleagues addressed these issues by showing that theta burst transcranial magnetic stimulation (tbs-TMS) applied to the DLPFC impaired metacognitive (subjective) awareness for a perceptual task, while objective performance was kept constant. We attempted to replicate this finding, with minor modifications, including an active tbs-TMS control site. Using a between-subjects design for both DLPFC and posterior parietal cortices, we found no evidence of a tbs-TMS-induced metacognitive impairment. In a second experiment, we devised a highly rigorous within-subjects tbs-TMS design for DLPFC, but again failed to find any evidence of metacognitive impairment. One crucial difference between our results and the Rounis study is our strict exclusion of data deemed unsuitable for a signal detection theory analysis. Indeed, when we included this unstable data, a significant, though invalid, metacognitive impairment was found. These results cast doubt on previous findings relating metacognitive awareness to DLPFC, and inform the current debate concerning whether or not prefrontal regions are preferentially implicated in conscious perception.

Neuroscience↗

bioRxiv2016

Estimating the efficacy of transcranial magnetic stimulation in small animals

The efficacy of transcranial magnetic stimulation (TMS) is determined by the magnitude and direction of the induced electric field in the cortex. The electric field distribution is influenced by the conductivity structure, in particular, the size of the head and the shapes of conductivity boundaries. We show that neglecting the head size can result in overestimating the stimulus intensity by a factor of 5-8 in the case of the rat brain. In the current modelling literature, the TMS-induced electric field is estimated with detailed computational simulations; however, in many experimental studies, less attention is paid on modelling. We attempt to bridge this gap by suggesting the use of simple simulations, for example with the spherical head model, when studying bioelectromagnetic phenomena.

Neuroscience↗

bioRxiv2016

Vision and locomotion shape the interactions between neuron types in mouse visual cortex

In the mouse primary visual cortex (V1), sensory responses are shaped by behavioral factors such as locomotion. These factors are thought to control a disinhibitory circuit, whereby interneurons expressing vasoactive intestinal peptide (Vip) inhibit those expressing somatostatin (Sst), disinhibiting pyramidal cells (Pyr). We measured the effect of locomotion on these neurons and on interneurons expressing parvalbumin (Pvalb) in layer 2/3 of mouse V1, and found in-consistencies with the disinhibitory model. In the presence of large stimuli, locomotion increased Sst cell responses without suppressing Vip cells. In the presence of small stimuli, locomotion increased Vip cell responses without suppressing Sst cells. A circuit model could reproduce each cell types activity from the measured activity of other cell types, but only if we allowed locomotion to increase feedforward synaptic weights while modulating recurrent weights. These results suggest that locomotion alters cortical function by changing effective synaptic connectivity, rather than only through disinhibition.

Neuroscience↗

bioRxiv2016

Video-rate volumetric functional imaging of the brain at synaptic resolution

Neurons and neural networks often extend hundreds to thousands of micrometers in three dimensions. To capture all the calcium transients associated with their activity, we need volume imaging methods with sub-second temporal resolution. Such speed is challenging for conventional two-photon laser scanning microscopy (2PLSM) to achieve, because of its dependence on serial focal scanning in 3D and the limited brightness of indicators. Here we present an optical module that can be easily integrated into standard 2PLSMs to generate an axially elongated Bessel focus. Scanning the Bessel focus in 2D turned frame rate into volume rate and enabled video-rate volumetric imaging. Using Bessel foci designed to maintain synaptic-level lateral resolution in vivo, we demonstrated the power of this approach in enabling discoveries for neurobiology by imaging the calcium dynamics of volumes of neurons and synapses in fruit flies, zebrafish larvae, mice, and ferrets in vivo.

Neuroscience↗

bioRxiv2016

Familiarity Facilitates Feature-based Face Processing

Recognition of personally familiar faces is remarkably efficient, effortless and robust. We asked if feature-based face processing facilitates detection of familiar faces by testing the effect of face inversion on a visual search task for familiar and unfamiliar faces. Because face inversion disrupts configural and holistic face processing, we hypothesized that inversion would diminish the familiarity advantage to the extent that it is mediated by such processing. Subjects detected personally familiar and stranger target faces in arrays of two, four, or six face images. Subjects showed significant facilitation of personally familiar face detection for both upright and inverted faces. The effect of familiarity on target absent trials, which involved only rejection of unfamiliar face distractors, suggests that familiarity facilitates rejection of unfamiliar distractors as well as detection of familiar targets. The preserved familiarity effect for inverted faces suggests that facilitation of face detection afforded by familiarity reflects mostly feature-based processes.

Neuroscience↗

bioRxiv2016

ICGenealogy: Mapping the function of neuronal ion channels in model and experiment

Ion channel models are the building blocks of computational neuron models. Their biological fidelity is therefore crucial for the interpretability of simulations. However, the number of published models, and the lack of standardization, make the comparison of models with one another and with experimental data difficult. Here, we present a framework for the automated large-scale classification of ion channel models. Using annotated metadata and model responses to a set of voltage-clamp protocols, we assigned 2378 models of voltage- and calcium-gated ion channels coded in NEURON to 211 clusters. The IonChannelGenealogy web interface provides an interactive resource for the categorization of new and existing models and experimental recordings. It enables quantitative comparisons of simulated and/or measured ion channel kinetics, and facilitates field-wide standardization of experimentally-constrained modeling.

Neuroscience↗

bioRxiv2016

Task-specific shaping of feature-based attention in area MT

Non-spatial selective attention is based on the notion that specific features or objects in the visual environment are effectively prioritized in cortical visual processing. Feature-based attention (FBA) in particular, is a well-studied process that dynamically and selectively enhances neurons preferentially processing the attended feature attribute (e.g. leftward motion). In everyday life, however, behavior may require high sensitivity for an entire feature dimension (e.g. motion). Yet, evidence for feature dimension-specific attentional modulation on a cellular level is lacking. We here investigate neuronal activity in macaque motion-selective medio-temporal area (MT) in an experimental setting requiring the monkeys to detect either a motion change or a color change. We hypothesized that neural activity in MT is enhanced if the task requires perceptual sensitivity to motion. Despite identical visual stimulation, we found that mean firing rates were higher in the motion task, and response variability and latency were lower as compared to the color task. This task-specific response modulation in the processing of visual motion was independent from the relation between attended and stimulating motion direction. It emerged already in the absence of visual input, and consisted of a spatially global and tuning-independent shift of the MT baseline activity. The results provide single cell support for the hypothesis of a feature dimension-specific top-down signal emphasizing the processing of an entire feature class.

Neuroscience↗

bioRxiv2016

Local and thalamic origins of ongoing and sensory evoked cortical correlations

Thalamic inputs of layer 4 (L4) cells in sensory cortices are outnumbered by local connections. Thus, it was suggested that robust sensory response in L4 emerges due to synchronized thalamic activity. In order to investigate the role of both inputs in generation of cortical synchronization, we isolated the thalamic excitatory inputs of cortical cells by optogenetically silencing cortical firing. In anesthetized mice, we measured the correlation between isolated thalamic synaptic inputs of simultaneously patched nearby L4 cells of the barrel cortex. In contrast to correlated activity of excitatory synaptic inputs in the intact cortex, isolated thalamic inputs exhibit lower variability and asynchronous spontaneous and sensory evoked inputs. These results were further supported in awake mice when we recorded the excitatory inputs of individual cortical cells simultaneously with the local field potential (LFP) in a nearby site. Our results therefore indicate that cortical synchronization emerges by intracortical coupling.

Neuroscience↗

bioRxiv2016

Intrinsic functional architecture of the macaque dorsal and ventral lateral frontal cortex

Investigations of the cellular and connectional organization of the lateral frontal cortex (LFC) of the macaque monkey provide indispensable knowledge for generating hypotheses about the human LFC. However, despite numerous investigations, there are still debates on the organization of this brain region. In vivo neuroimaging techniques such as resting-state fMRI can be used to define the functional circuitry of brain areas producing results largely consistent with gold-standard invasive tract-tracing techniques and offering the opportunity for cross-species comparison within the same modality. Our results using resting-state fMRI from macaque monkeys to uncover the intrinsic functional architecture of the LFC corroborate previous findings and inform current debates. Specifically, we show that i) the region in the midline and anterior to the superior arcuate sulcus is divided in two areas separated by the posterior supraprincipal dimple; ii) the cytoarchitectonically defined area 6DC/F2 contains two connectional divisions; and, iii) a distinct area occupies the cortex around the spur of the arcuate, updating what was previously proposed to be the border between dorsal and ventral motor/premotor areas. Within the ventral LFC specifically, the derived parcellation clearly suggests the presence of distinct areas i) with a somatomotor/orofacial connectional signature (putative area 44), ii) with an occulomotor connectional signature (putative frontal eye fields), and iii) premotor areas possibly hosting laryngeal and arm representations. Our results illustrate in detail the intrinsic functional architecture of the macaque LFC, thus providing valuable evidence for debates on its organization.

Neuroscience↗

bioRxiv2016

A robust role for motor cortex

The role of motor cortex in non-primate mammals remains unclear. More than a century of stimulation, anatomical and electrophysiological studies has implicated neural activity in this region with all kinds of movement. However, following the removal of motor cortex, rats retain most of their adaptive behaviours, including previously learned skilled movements. Here we revisit these two conflicting views of motor cortex and present a new behaviour assay, challenging animals to respond to unexpected situations while navigating a dynamic obstacle course. Surprisingly, rats with motor cortical lesions show clear impairments facing an unexpected collapse of the obstacles, while showing no impairment with repeated trials in many motor and cognitive metrics of performance. We propose a new role for motor cortex: extending the robustness of sub-cortical movement systems, specifically to unexpected situations demanding rapid motor responses adapted to environmental context. The implications of this idea for current and future research are discussed.

Neuroscience↗

bioRxiv2016

Long-term, layer-specific modification of spontaneous activity in the mouse somatosensory cortex following sensory stimulation

Neocortical circuits exhibit spontaneous neuronal activity whose functional relevance remains enigmatic. Several proposed functions assume that sensory experience can influence subsequent spontaneous activity. However, long-term alterations in spontaneous firing rates following sensory stimulation have not been reported until now. Here we show that multi-whisker, spatiotemporally rich stimulation of mouse vibrissae induces a laminar-specific, long-term increase of spontaneous activity in the somatosensory cortex. Such stimulation additionally produces stereotypical neural ensemble firing patterns from simultaneously recorded single neurons, which are maintained during spontaneous activity following stimulus offset. The increased neural activity and concomitant ensemble firing patterns are sustained for at least 25 minutes after stimulation, and specific to layers IV and Vb. In contrast, the same stimulation protocol applied to a single whisker fails to elicit this effect. Since layer Vb has the largest receptive fields and, together with layer IV, receives direct thalamic and lateral drive, the increase in firing activity could be the result of mechanisms involving the integration of spatiotemporal patterns across multiple whiskers. Our results provide direct evidence of modification of spontaneous cortical activity by sensory stimulation and could offer insight into the role of spatiotemporal integration in memory storage mechanisms for complex stimuli.

Neuroscience↗

bioRxiv2016

Mechanical flexibility reduces the foreign body response to long- term implanted microelectrodes in rabbit cortex

Micromotion between the brain and implanted electrodes is a major contributor to the failure of invasive microelectrodes. Movements of the electrode tip cause recording instabilities while spike amplitudes decline over the weeks/months post-implantation due to glial cell activation caused by sustained mechanical trauma. We compared the glial response over a 26-96 week period following implantation in the rabbit cortex of microwires and a novel flexible electrode. Horizontal sections were used to obtain a depth profile of the radial distribution of microglia, astrocytes and neurofilament. We found that the flexible electrode was associated with decreased gliosis compared to the microwires over these long indwelling periods. This was in part due to a decrease in overall microgliosis and enhanced neuronal density around the flexible probe, especially at longer periods of implantation.

Neuroscience↗

bioRxiv2016

Auditory Nerve Stochasticity Impedes Category Learning: the Role of Cochlear Nucleus and Inferior Colliculus in Stabilising Auditory Nerve Firing

It is well known that auditory nerve (AN) fibers overcome bandwidth limitations through the \"volley principle\", a form of multiplexing. What is less well known is that the volley principle introduces a degree of unpredictability into AN neural firing patterns which makes even simple stimulus categorization tasks difficult. We use a physiologically grounded, unsupervised spiking neural network model of the auditory brain with STDP learning to demonstrate that plastic auditory cortex is unable to learn even simple auditory object categories when exposed to the raw AN firing input without subcortical preprocessing. We then demonstrate the importance of non-plastic subcortical preprocessing within the cochlear nucleus (CN) and the inferior colliculus (IC) for stabilising and denoising AN responses. Such preprocessing enables the plastic auditory cortex to learn efficient robust representations of the auditory object categories. The biological realism of our model makes it suitable for generating neurophysiologically testable hypotheses.

Neuroscience↗