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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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

From affect to control: Functional specialization of the insula in motivation and regulation

The insula plays a key role in a wide range of brain processes, from viscerosensation and pain to motivation, emotion, and cognitive control. While human neuroimaging studies in all these domains report activations in the insula, little systematic attention is paid to anatomical subdivisions that may provide the basis for functional sub-regions. We conducted a meta-analysis of insular tasks across studies in four domains: emotion, pain, attention switching, and working memory. Using a priori subdivision of the insula based on anatomical studies, we provide evidence that different sub-regions are preferentially activated in different tasks. We suggest that the ventral anterior insula is most important for core affect, a term that describes broadly-tuned motivational states (e.g., excitement) with associated subjective feelings. The dorsal anterior insula, by contrast, may be critical for developing and updating motivational states with specific associated actions (i.e., goals). This region is activated by cognitive control tasks, pain, and some tasks that elicit affective processing. The posterior insula, including SII and portions of parietal operculum, is distinctly activated by pain, providing a double dissociation between pain and tasks that elicit emotions.

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bioRxiv2017

Learning place cells, grid cells and invariances: A unifying model

Neurons in the hippocampus and adjacent brain areas show a large diversity in their tuning to location and head direction. The underlying circuit mechanisms are not fully resolved. In particular, it is unclear why certain cell types are selective to one spatial variable, but invariant to another. For example, a place cell is highly selective to location, but typically invariant to head direction. Here, we propose that all observed spatial tuning patterns - in both their selectivity and their invariance - are a consequence of the same mechanism: Excitatory and inhibitory synaptic plasticity that is driven by the spatial tuning statistics of synaptic inputs. Using simulations and a mathematical analysis, we show that combined excitatory and inhibitory plasticity can lead to localized, grid-like or invariant activity. Combinations of different input statistics along different spatial dimensions reproduce all major spatial tuning patterns observed in rodents. The model is robust to changes in parameters, develops patterns on behavioral time scales and makes distinctive experimental predictions. Our results suggest that the interaction of excitatory and inhibitory plasticity is a general principle for the formation of neural representations.

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bioRxiv2017

Basal forebrain gating by somatostatin neurons drives cortical activity

The basal forebrain provides modulatory input to the cortex regulating brain states and cognitive processing. Somatostatin-expressing cells constitute a local GABAergic source known to functionally inhibit the major cortically-projecting cell types. However, it remains unclear if somatostatin cells can regulate the basal forebrains synaptic output and thus control cortical dynamics. Here, we demonstrate in mice that somatostatin neurons regulate the corticopetal synaptic output of the basal forebrain impinging on cortical activity and behavior. Optogenetic inactivation of somatostatin neurons in vivo increased spiking of some basal forebrain cells, rapidly enhancing and desynchronizing neural activity in the prefrontal cortex, inhibiting slow rhythms and increasing gamma oscillations. Locomotor activity was specifically increased in quiescent animals, but not in active mice. Altogether, we provide physiological and behavioral evidence indicating that somatostatin cells are pivotal in gating the synaptic output of the basal forebrain, thus indirectly controlling cortical operations via both cholinergic and non-cholinergic mechanisms.

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bioRxiv2017

The butterfly effect: amplification of local changes along the temporal processing hierarchy

Changing just a few words in a story can induce a substantial change in the overall narrative. How does the brain accumulate and process local and sparse changes, creating a unique situation model of the story, over the course of a real-life narrative? Recently, we mapped a hierarchy of processing timescales in the brain: from early sensory areas that integrate information over 10s-100s ms, to high-order areas that integrate information over many seconds to minutes. Based on this hierarchy, we hypothesize that early sensory areas would be sensitive to local changes in word use, but that there will be increasingly divergent neural responses along the processing hierarchy as higher-order areas accumulate and amplify these local changes. To test this hypothesis, we created two structurally related but interpretively distinct narratives by changing some individual words. We found that the neural response distance between the stories was amplified as story information is transferred from low-level regions (e.g. early auditory cortex) to high-level regions (e.g precuneus and prefrontal cortex) and that the neural difference between stories is highly correlated with an areas ability to integrate information over time. Our results suggest a neural mechanism by which two similar situations become easy to distinguish.

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bioRxiv2017

Locomotion enhances neural encoding of visual stimuli in mouse V1

Neurons in mouse primary visual cortex (V1) are selective for particular properties of visual stimuli. Locomotion causes a change in cortical state that leaves their selectivity unchanged but strengthens their responses. Both locomotion and the change in cortical state are initiated by projections from the mesencephalic locomotor region (MLR), the latter through a disinhibitory circuit in V1. The function served by this change in cortical state is unknown. By recording simultaneously from a large number of single neurons in alert mice viewing moving gratings, we investigated the relationship between locomotion and the information contained within the neural population. We found that locomotion improved encoding of visual stimuli in V1 by two mechanisms. First, locomotion-induced increases in firing rates enhanced the mutual information between visual stimuli and single neuron responses over a fixed window of time. Second, stimulus discriminability was improved, even for fixed population firing rates, because of a decrease in noise correlations across the population during locomotion. These two mechanisms contributed differently to improvements in discriminability across cortical layers, with changes in firing rates most important in the upper layers and changes in noise correlations most important in layer V. Together, these changes resulted in a three- to five-fold reduction in the time needed to precisely encode grating direction and orientation. These results support the hypothesis that cortical state shifts during locomotion to accommodate an increased load on the visual system when mice are moving.\n\nSignificance StatementThis paper contains three novel findings about the representation of information in neurons within the primary visual cortex of the mouse. First, we show that locomotion reduces by at least a factor of three the time needed for information to accumulate in the visual cortex that allows the distinction of different visual stimuli. Second, we show that the effect of locomotion is to increase information in cells of all layers of the visual cortex. Third we show that the means by which information is enhanced by locomotion differs between the upper layers, where the major effect is the increasing of firing rates, and in layer V, where the major effect is the reduction in noise correlations.

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bioRxiv2017

Family history and APOE4 risk for Alzheimer’s Disease impact the neural correlates of episodic memory by early midlife

Episodic memory impairment is a consistent, pronounced deficit in pre-clinical stages of late-onset Alzheimers disease (AD). Individuals with risk factors for AD exhibit altered brain function several decades prior to the onset of AD-related symptoms. In the current event-related fMRI study of spatial context memory we tested the hypothesis that middle-aged adults (MA; 40-58yrs) with a family history of late onset AD (MA+FH), or a combined +FH and apolipoprotein E {varepsilon}4 allele risk factors for AD (MA+FH+APOE4), will exhibit differences in encoding and retrieval-related brain activity, compared to - FH-APOE4 MA controls. We also hypothesized that the two at-risk MA groups will exhibit distinct patterns of correlation between brain activity and memory performance, compared to controls. To test these hypotheses we conducted multivariate task, and behavior, partial least squares analysis of fMRI data obtained during successful context encoding and retrieval. Our results indicate that even though there were no significant group differences in context memory performance, there were significant differences in brain activity and brain-behavior correlations involving hippocampus, left angular gyrus, cingulate, and precuneus in MA with AD risk factors, compared to controls. In addition, we observed that brain activity and brain-behavior correlations in anterior-medial PFC and in ventral visual cortex differentiated the two MA risk groups from each other, and from MAcontrols. This is the first study to show that there are differences in the brain areas engaged during context memory encoding and retrieval in middle-aged adults with +FH and +APOE-4 risk factors for late onset AD, compared to controls.

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bioRxiv2017

Spatial Attention Enhances the Neural Representation of Invisible Signals Embedded in Noise

Recent evidence suggests that voluntary spatial attention can affect neural processing of visual stimuli that do not enter conscious awareness (i.e. invisible stimuli), supporting the notion that attention and awareness are dissociable processes (Watanabe et al., 2011; Wyart, Dehaene, & Tallon-Baudry, 2012). To date, however, no study has demonstrated that these effects reflect enhancement of the neural representation of invisible stimuli per se, as opposed to other neural processes not specifically tied to the stimulus in question. In addition, it remains unclear whether spatial attention can modulate neural representations of invisible stimuli in direct competition with highly salient and visible stimuli. Here we developed a novel electroencephalography (EEG) frequency-tagging paradigm to obtain a continuous readout of human brain activity associated with visible and invisible signals embedded in dynamic noise. Participants (N = 23) detected occasional contrast changes in one of two flickering image streams on either side of fixation. Each image stream contained a visible or invisible signal embedded in every second noise image, the visibility of which was titrated and checked using a two-interval forced-choice detection task. Steady-state visual-evoked potentials (SSVEPs) were computed from EEG data at the signal and noise frequencies of interest. Cluster-based permutation analyses revealed significant neural responses to both visible and invisible signals across posterior scalp electrodes. Control analyses revealed that these responses did not reflect a subharmonic response to noise stimuli. In line with previous findings, spatial attention increased the neural representation of visible signals. Crucially, spatial attention also increased the neural representation of invisible signals. As such, the present results replicate and extend previous studies by demonstrating that attention can modulate the neural representation of invisible signals that are in direct competition with highly salient masking stimuli.

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bioRxiv2017

Neural correlates of perceptual constancy in Auditory Cortex

Perceptual constancy requires neural representations that are selective for object identity, but also tolerant for identity-preserving transformations. How such representations arise in the brain and contribute to perception remains unclear. Here we studied tolerant representations of sound identity in the auditory system by recording multi-unit activity in tonotopic auditory cortex of ferrets discriminating the identity of vowels which co-varied across orthogonal stimulus dimensions (fundamental frequency, sound level, location and voicing). We found that neural decoding of vowel identity was most successful across the same orthogonal dimensions over which animals generalized their behavior. We also decoded orthogonal sound features and behavioral variables including choice and accuracy to show a behaviorally-relevant, multivariate and multiplexed representation of sound, with each variable represented over a distinct time-course. Finally, information content and timing of sound feature encoding was modulated by task-engagement and training, suggesting that tolerant representations during perceptual constancy are attentionally and experience-dependent.

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bioRxiv2017

Disambiguating brain functional connectivity

Functional connectivity (FC) analyses of correlations of neural activity are used extensively in neuroimaging and electrophysiology to gain insights into neural interactions. However, correlation fails to distinguish sources as different as changes in neural signal amplitudes or noise levels. This ambiguity substantially diminishes the value of FC for inferring system properties and clinical states. Network modelling approaches may avoid ambiguities, but require specific assumptions. We present an enhancement to FC analysis with improved specificity of inferences, minimal assumptions and no reduction in flexibility. The Additive Signal Change (ASC) approach characterises FC changes into certain prevalent classes involving additions of signal. With FMRI data, the approach reveals a rich diversity of signal changes underlying measured changes in FC, bringing into question standard interpretations. The ASC method can also be used to disambiguate other measures of dependency, such as regression and coherence, providing a flexible tool for the analysis of neural data.

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bioRxiv2017

Pure Correlates of Exploration and Exploitation in the Human Brain

Balancing exploration and exploitation is a fundamental problem in reinforcement learning. Previous neuroimaging studies of the exploration-exploitation dilemma could not completely disentangle these two processes, making it difficult to unambiguously identify their neural signatures. We overcome this problem using a task in which subjects can either observe (pure exploration) or bet (pure exploitation). Insula and dorsal anterior cingulate cortex showed significantly greater activity on observe trials compared to bet trials, suggesting that these regions play a role in driving exploration. A model-based analysis of task performance suggested that subjects chose to observe until a critical evidence threshold was reached. We observed a neural signature of this evidence accumulation process in ventromedial prefrontal cortex. These findings support theories positing an important role for anterior cingulate cortex in exploration, while also providing a new perspective on the roles of insula and ventromedial prefrontal cortex.\n\nSignificance StatementSitting down at a familiar restaurant, you may choose to order an old favorite or sample a new dish. In reinforcement learning theory, this is known as the exploration-exploitation dilemma. The optimal solution is known to be intractable; therefore, humans must use heuristic strategies. Behavioral studies have revealed several candidate strategies, but identifying the neural mechanisms underlying these strategies is complicated due to the fact that exploration and exploitation are not perfectly dissociable in standard tasks. Using an \"observe or bet\" task, we identify for the first time pure neural correlates of exploration and exploitation in the human brain.

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bioRxiv2017

Spontaneous development of cerebrovascular pathology and microinfarcts in a mouse model of sickle cell disease.

Stroke is a dramatic complication of sickle cell disease (SCD) and is associated with aneurysms, moya moya, intravascular thrombi, cerebral hyperemia and increased vessel tortuosity. We show that aged SCD mice spontaneously develop the characteristics features of cerebral vasculopathy seen in human SCD. Thirteen month old Townes SCD mice and age-matched controls had a cranial windows implanted over the somatosensory cortex. Cortical capillaries were imaged using in vivo two-photon microscopy after the blood plasma was labeled with a fluorescent dye. Results showed that SCD mice compared to controls, had significantly higher red blood cell (RBC) velocity and capillary vessel diameter. SCD mice also had a significantly higher number of occlusive events in the capillary bed, resulting in more stalling of RBC flow. Microvascular topology was also altered, as SCD mice had significantly higher vessel tortuosity and shorter capillary branch lengths. Finally, post-mortem analyses revealed a greater number of cortical microinfarcts, likely caused by vascular occlusion since local tissue hypoxia and blood-brain barrier leakage was prominent. We concluded that aged Townes sickle cell mice spontaneously develop SCD-associated cerebral vasculopathy, and that in vivo two-photon imaging is a powerful approach to investigate the mechanisms of vascular complications in SCD.

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bioRxiv2017

Heterogeneity of hypothalamic Pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing

Arcuate proopiomelanocortin (POMC) neurons are critical nodes in the control of body weight. Often characterised simply as direct targets for leptin, recent data suggest a more complex architecture. Using single cell RNA sequencing, we have generated an atlas of gene expression in murine POMC neurons. Of 163 neurons, 118 expressed high levels of Pomc with little/no Agrp expression and were considered \"canonical\" POMC neurons (P+). The other 45/163 expressed low levels of Pomc and high levels of Agrp (A+P+). Unbiased clustering analysis of P+ neurons revealed four different classes, each with distinct cell surface receptor gene expression profiles. Further, only 12% (14/118) of P+ neurons expressed the leptin receptor (Lepr) compared with 58% (26/45) of A+P+ neurons. In contrast, the insulin receptor (Insr) was expressed at similar frequency on P+ and A+P+ neurons (64% and 55%, respectively). These data reveal arcuate POMC neurons to be a highly heterogeneous population.

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bioRxiv2017

Neural noise in the age-varying human brain predicts perceptual decisions

Sensory representations of the physical world and thus human percepts are susceptible to fluctuations in brain state or \"neural irregularity\". Furthermore, aging brains display altered levels of irregularity. We here show that a single, within-trial information-theoretic measure (weighted permutation entropy) captures neural irregularity in the human electroencephalogram as a proxy for both, trait-like differences between individuals of varying age, and state-like fluctuations that bias perceptual decisions. First, the overall level of neural irregularity increased with participants age, paralleled by a decrease in variability over time, likely indexing age-related disintegration on structural and functional levels of brain activity. Second, states of higher neural irregularity were associated with optimized sensory encoding and a subsequently increased probability of choosing the first of two physically identical stimuli. In sum, neural irregularity not only characterizes behaviorally relevant brain states, but also can identify trait-like changes that come with age.

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bioRxiv2017

In vivo translatome profiling reveals early defects in ribosome biology underlying SMA pathogenesis

BackgroundGenetic alterations impacting on ubiquitously expressed proteins involved in mRNA metabolism often result in neurodegenerative conditions, with increasing evidence suggesting that translational defects can contribute to disease. Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, whose role in disease pathogenesis remains unclear.\n\nResultsBy determining in parallel the in vivo transcriptome and translatome in SMA mice we identified a robust decrease in translational efficiency, arising during early stages of disease. Translational defects affected translation-related transcripts, were cell autonomous, and were fully rescued after treatment with antisense oligonucleotides to restore SMN levels. Defects in translation were accompanied by a decrease in the number of ribosomes in motor neurons in vivo.\n\nConclusionOur findings suggest that neuronal tissues and cells are particularly sensitive to perturbations in translation during SMA, and identify ribosome biology as an important, yet largely neglected, factor in motor neuron degeneration.

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bioRxiv2017

No evidence of early head circumference enlargements in children later diagnosed with autism in Israel

BackgroundLarge controversy exists regarding the potential existence and clinical significance of larger brain volumes in toddlers who later develop autism. Assessing this relationship is important for determining the clinical utility of early head circumference (HC) measures and for assessing the validity of the early overgrowth hypothesis of autism, which suggests that early accelerated brain development may be a hallmark of the disorder\n\nMethodWe performed a retrospective comparison of HC, height, and weight measurements between 66 toddlers who were later diagnosed with autism and 66 matched controls. These toddlers represent an unbiased regional sample from a single health service provider in the southern district of Israel. Using 4-12 measurements between birth and the age of two, we were able to characterize individual HC, height, and weight development with high precision and fit a negative exponential growth model to the data of each toddler with exceptional accuracy\n\nResultsThe analyses revealed that HC sizes and growth rates were not significantly larger in toddlers with autism even when stratifying the autism group based on verbal capabilities at the time of diagnosis. In addition, there were no significant correlations between ADOS scores at the time of diagnosis and HC at any time-point during the first two years of life\n\nConclusionsThese negative results add to accumulating evidence, which suggest that brain volume is not necessarily larger in toddlers who develop autism. While early brain overgrowth may characterize specific individuals with autism, it is not likely to represent a common etiology of the entire autism population

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bioRxiv2017

A computational toolbox and step-by-step tutorial for the analysis of neuronal population dynamics in calcium imaging data

The development of new imaging and optogenetics techniques to study the dynamics of large neuronal circuits is generating datasets of unprecedented volume and complexity, demanding the development of appropriate analysis tools. We present a tutorial for the use of a comprehensive computational toolbox for the analysis of neuronal population activity imaging. It consists of tools for image pre-processing and segmentation, estimation of significant single-neuron single-trial signals, mapping event-related neuronal responses, detection of activity-correlated neuronal clusters, exploration of population dynamics, and analysis of clusters features against surrogate control datasets. They are integrated in a modular and versatile processing pipeline, adaptable to different needs. The clustering module is capable of detecting flexible, dynamically activated neuronal assemblies, consistent with the distributed population coding of the brain. We demonstrate the suitability of the toolbox for a variety of calcium imaging datasets, and provide a case study to explain its implementation.

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bioRxiv2017

Sensitivity of Neurons in the Middle Temporal Area of Marmoset Monkeys to Random Dot Motion

Neurons in the Middle Temporal area (MT) of the primate cerebral cortex respond to moving visual stimuli. The sensitivity of MT neurons to motion signals can be characterized by using random-dot stimuli, in which the strength of the motion signal is manipulated by adding different levels of noise (elements that move in random directions). In macaques, this has allowed the calculation of \"neurometric\" thresholds. We characterized the responses of MT neurons in sufentanil/nitrous oxide anesthetized marmoset monkeys, a species which has attracted considerable recent interest as an animal model for vision research. We found that MT neurons show a wide range of neurometric thresholds, and that the responses of the most sensitive neurons could account for the behavioral performance of macaques and humans. We also investigated factors that contributed to the wide range of observed thresholds. The difference in firing rate between responses to motion in the preferred and null directions was the most effective predictor of neurometric threshold, whereas the direction tuning bandwidth had no correlation with the threshold. We also showed that it is possible to obtain reliable estimates of neurometric thresholds using stimuli that were not highly optimized for each neuron, as is often necessary when recording from large populations of neurons with different receptive field concurrently, as was the case in this study. These results demonstrate that marmoset MT shows an essential physiological similarity to macaque MT, and suggest that its neurons are capable of representing motion signals that allow for comparable motion-in-noise judgments.\n\nNew and NoteworthyWe report the activity of neurons in marmoset MT in response to random-dot motion stimuli of varying coherence. The information carried by individual MT neurons was comparable to that of the macaque, and that the maximum firing rates were a strong predictor of sensitivity. Our study provides key information regarding the neural basis of motion perception in the marmoset, a small primate species that is becoming increasingly popular as an experimental model.

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bioRxiv2017

Gender-specific brain activation during visual art perception

The human body is the most common object of pictorial representation in western art. The goal of this study was to probe its evolutionary basis of visual art perception by investigating neural markers of gender-specific brain activity triggered by paintings of male and female images. Our results show significant activity in brain areas other than those recently associated with visual arts perception. Novel findings concern participant-general as well as gender specific brain activity. Although our participants were fully aware that they were viewing artworks, the inferior parietal lobule - known for its role in the perception of emotional body images - and the somatosensory cortex - which is related to touch - were selectively active for female body paintings in all participants. The most interesting finding as regards gender was that the sight of female bodies activates the subgenual anterior cingulate cortex in males, an area known to subserve autonomic arousal. In contrast, in females the sight of the male body activated reward and control related parts of the dorsal anterior cingulate cortex. This supports the notion that basic evolutionary processes operate when we view body images, also when they are paintings far removed from daily experience.

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