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Interneuronal mechanisms of hippocampal theta oscillation in a full-scale model of the rodent CA1 circuit

The hippocampal theta rhythm plays important roles in information processing; however, the mechanisms of its generation are not well understood. We developed a data-driven, supercomputer-based, full-scale (1:1) model of the CA1 area and studied its interneurons during theta oscillations. Theta rhythm with phase-locked gamma oscillations and phase-preferential discharges of distinct in terneuronal types spontaneously emerged from the isolated CA1 circuit without rhythmic inputs. Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation. These simulations reveal new insights into the spatiotemporal organization of the CA1 circuit during theta oscillations.

neuroscience

Striatal Action-Value Neurons Reconsidered

It is generally believed that during economic decisions, striatal neurons represent the values associated with different actions. This hypothesis is based on a large number of studies, in which the neural activity of striatal neurons was measured while the subject was learning to prefer the more rewarding action. Here we show that these publications are subject to at least one of two critical confounds and that most are subject to both. First, we show that even weak temporal correlations in the neuronal data may result in an erroneous identification of action-value representations. We demonstrate this by erroneously identifying action-value representations, both in simulations and in the neural activity recorded in unrelated experiments. Second, we show that the experiments and analyses designed to dissociate action-value representation from the representation of other decision variables cannot do so. Specifically, we show that neurons representing policy may be erroneous identified as representing action-values. We suggest different solutions to identifying action-value representation that are not subject to these confounds. Applying one of these solutions to previously identified action-value neurons in the basal ganglia we fail to detect action-value representations there. Thus, we conclude that the claim that striatal neurons encode action-values must await new experiments and analyses.

neuroscience

Metrics for comparing Neuronal Tree Shapes based on Persistent Homology

The geometrical tree structures of axonal and dendritic processes play important roles in determining the architecture and capabilities of neuronal circuitry. Morphological features based on this tree structure have played a central role in classifying neurons for over a century. Yet geometrical trees are not automatically adapted to the basic mathematical tool used widely in data analysis, namely vector spaces and linear algebra, since tree geometries cannot be naturally added and subtracted. Current methods for analysis reduce trees to feature vectors in more or less ad hoc ways. A more natural mathematical object suited to characterizing neuronal tree geometries, is a metric space, where only distances between objects need be defined. In recent years, there have been significant developments in the fields of computational topology and geometry that promise to be useful for the analysis of neuronal geometries. In this paper, we adapt these tools to the problem of characterizing and analyzing neuronal morphology.\n\nAs more and more neuroanatomical data are made available through efforts such as NeuroMorpho.org and FlyCircuit.org, the need to develop computational tools to facilitate automatic knowledge discovery from such large datasets becomes more urgent. One fundamental question is how best to compare neuron structures, for instance to organize and classify large collection of neurons. We aim to develop a flexible yet powerful framework to support comparison and classification of large collection of neuron structures efficiently. Specifically we propose to use a topological persistence-based feature vectorization framework. Existing methods to vectorize a neuron (i.e, convert a neuron to a feature vector so as to support efficient comparison and/or searching) typically rely on statistics or summaries of morphometric information, such as the average or maximum local torque angle or partition asymmetry. These simple summaries have limited power in encoding global tree structures. Leveraging recent development in topological data analysis, we vectorize each neuron structure into a simple yet informative summary via the use of topological persistence. In particular, each type of information of interest can be represented as a descriptor function defined on the neuron tree, which is then mapped to a simple persistence-signature. Our framework can encode both local and global tree structure, as well as other information of interest (electrophysiological or dynamical measures), by considering multiple descriptor functions on the neuron. The resulting persistence-based signature is potentially more informative than simple statistical summaries (such as average/mean/max) of morphometric quantities - Indeed, we show that using a certain descriptor function will give a persistence-based signature containing strictly more information than the classical Sholl analysis. At the same time, our framework retains the efficiency associated with treating neurons as points in a simple Euclidean feature space, which would be important for constructing efficient searching or indexing structures over them. We present preliminary experimental results to demonstrate the effectiveness of our persistence-based neuronal feature vectorization framework.

neuroscience

Optical-flow analysis toolbox for characterization of spatiotemporal dynamics in mesoscale optical imaging of brain activity

Wide-field optical imaging techniques constitute powerful tools to sample and study mesoscale neuronal activity. The sampled data constitutes a sequence of image frames in which one can perceive the flow of brain activity starting and terminating at source and sink locations respectively. The most common data analyses include qualitative assessment to identify sources and sinks of activity as well as their trajectories. The quantitative analyses is mostly based on computing the temporal variation of the intensity of pixels while a few studies have also reported estimates of wave motion using optical-flow techniques from computer vision. A comprehensive toolbox for the quantitative analyses of mesoscale brain activity data however is still missing. We present a graphical-user-interface based Matlab(R) toolbox for investigating the spatiotemporal dynamics of mesoscale brain activity using optical-flow analyses. The toolbox includes the implementation of three optical-flow methods namely Horn-Schunck, Combined Local-Global, and Temporospatial algorithms for estimating velocity vector fields of perceived flow in mesoscale brain activity. From the velocity vector fields we determine the locations of sources and sinks as well as the trajectories and temporal velocities of activity flow. Using our toolbox, we compare the efficacy of the three optical-flow methods for determining spatiotemporal dynamics by using simulated data. We also demonstrate the application of optical-flow methods onto sensory-evoked calcium and voltage imaging data. Our results indicate that the combined local-global method we employ, yields results that correlate with the manual assessment. The automated approach permits rapid and effective quantification of mesoscale brain dynamics and may facilitate the study of brain function in response to new experiences or pathology.\n\nConflicts of Interestnone\n\nAuthor contribution statementMHM, MM, NV, and SI designed the study. NA and SI wrote Matlab(R) code for the toolbox and designed the simulated data. MHM, and NA performed the experiments. NA and SI analyzed the data. SI, NA, and MHM wrote the manuscript.

neuroscience

Modulation of Body Mass Composition using Vestibular Nerve Stimulation.

There is increasing evidence of a \"set-point\" for body weight in the brain, that is regulated by the hypothalamus. This system modifies feeding behavior and metabolic rate, to keep body fat within predetermined parameters. It is also known that animals subjected to chronic centrifugation show a reduction in body fat. Experiments with mutant mice found that this loss of fat appears to be mediated by a vestibulo-hypothalamic pathway. Vestibular nerve stimulation (VeNS), also known as galvanic vestibular stimulation, involves non-invasively stimulating the vestibular system by applying a small electrical current between two electrodes placed over the mastoid processes. We suggest that any means of repeatedly stimulating the otolith organs in humans would cause a reduction in total body fat, and that VeNS would be a useful technique to use in this regard. Below we provide pilot data to support this idea.

neuroscience

Antenatal maternal anxiety modulates the BOLD response in 20-year old adolescents during an endogenous cognitive control task

Evidence is building for an association between the level of anxiety experienced by a mother during pregnancy and the cognitive development of her offspring. The current study uses fMRI to examine whether there is an association between prenatal exposure to maternal anxiety and brain activity in 20 year old adolescents. In line with previous results of this follow-up study, it was found that adolescents of mothers reporting high levels of anxiety during weeks 12-22 of their pregnancy had a different pattern of decision making in a Gambling paradigm requiring endogenous cognitive control compared to adolescents of mothers reporting low to average levels of anxiety during pregnancy. Moreover, the blood oxygenation level dependent (BOLD) response in a number of prefrontal cortical areas was modulated by the level of antenatal maternal anxiety. In particular a number of right lateralized clusters including inferior frontal junction, that were modulated in the adolescents of mothers reporting low to average levels of anxiety during pregnancy by a task manipulation of cognitive control, were not modulated by this manipulation in the adolescents of mothers reporting high levels of anxiety during pregnancy. These results provide a neurobiological underpinning for our previous hypothesis of an association between a deficit in endogenous cognitive control in adolescence and exposure to maternal anxiety in the prenatal life period.

neuroscience

Persistent neural activity encoding real-time presence of visual stimuli decays along the ventral stream

Neural populations that encode sensory experience should be persistently active for as long as the experience persists. However, research into visual neural activity has focused almost exclusively on onset-driven responses that cannot account for sustained perception. We used intracranial recordings in humans to determine the degree to which the presence of a visual stimulus is persistently encoded by neural activity. The correspondence between stimulus duration and response duration was strongest in early visual cortex and gradually diminished along the visual hierarchy, such that is was weakest in inferior-temporal category-selective regions. A similar posterior-anterior gradient was found within inferior temporal face-selective regions, with posterior but not anterior sites showing persistent face-selective activity. The results suggest that regions that appear uniform in terms of their category selectivity are dissociated by how they temporally represent a stimulus in support of real-time experience, and delineate a large-scale organizing principle of the ventral visual stream.

neuroscience

Structural and functional brain changes following four weeks of unimanual motor training: evidence from behaviour, neural stimulation, cortical thickness and functional MRI

Although different aspects of neuroplasticity can be quantified with behavioural probes, brain stimulation, and brain imaging assessments, no study to date has combined all these approaches into one comprehensive assessment of brain plasticity. Here, 24 healthy right-handed participants practised a sequence of finger-thumb opposition movements for 10 minutes each day with their left hand. After four weeks, performance for the practised sequence improved significantly (p < 0.05 FWE) relative to a matched control sequence, with both the left (mean increase: 53.0% practised, 6.5% control) and right (21.0%; 15.8%) hands. Training also induced significant (cluster p-FWE < 0.001) reductions in functional MRI activation for execution of the learned sequence, relative to the control sequence. These changes were observed as clusters in the premotor and supplementary motor cortices (right hemisphere, 301 voxel cluster; left hemisphere 700 voxel cluster), as well as sensorimotor cortices and superior parietal lobules (right hemisphere 864 voxel cluster; left hemisphere, 1947 voxel cluster). Transcranial magnetic stimulation over the right ( trained) primary motor cortex yielded a 58.6% mean increase in a measure of motor evoked potential amplitude, as recorded at the left abductor pollicis brevis muscle. Cortical thickness analyses based on structural MRI suggested changes in the right precentral gyrus, right post central gyrus, right dorsolateral prefrontal cortex and potentially the right supplementary motor area. Such findings are consistent with LTP-like neuroplastic changes in areas that were already responsible for finger sequence execution, rather than improved recruitment of previously non-utilised tissue.

neuroscience

Multivariate association between single-nucleotide polymorphisms in Alzgene linkage regions and structural changes in the brain: discovery, refinement and validation

Both genetic variants and brain region abnormalities are recognized to play a role in cognitive decline. We explore the association between singlenucleotide polymorphisms (SNPs) in linkage regions for Alzheimers disease and rates of decline in brain structure using data from the Alzheimers Disease Neuroimaging Initiative (ADNI).\n\nIn an initial discovery stage, we assessed the presence of linear association between the minor allele counts of 75,845 SNPs in the Alzgene linkage regions and predicted rates of change in structural MRI measurements for 56 brain regions using an RV test. In a second, refinement stage, we reduced the number of SNPs using a bootstrap-enhanced sparse canonical correlation analysis (SCCA) with a fixed tuning parameter. Each SNP was assigned an importance measure proportional to the number of times it was estimated to have a nonzero coefficient in repeated re-sampling from the ADNI-1 sample. We created refined lists of SNPs based on importance probabilities greater than 50% and 90%, respectively. In a third, validation stage, we assessed the multivariate association between these refined lists of SNPs and the rates of structural change in the independent ADNI-2 study dataset.\n\nThere was strong statistical evidence for linear association between the SNPs in the Alzgene linkage regions and the 56 imaging phenotypes in both the ADNI-1 and ADNI-2 samples (p < 0.0001). The bootstrap-enhanced SCCA identified 1,694 priority SNPs with importance probabilities > 50% and 22 SNPs with importance probabilities > 90%. The 1,694 prioritized SNPs in the ADNI-1 data were associated with imaging phenotypes in the ADNI-2 data (p = 0.0021).\n\nThis manuscript presents an analysis that addresses challenges in current imaging genetics studies such as biased sampling designs and highdimensional data with low-signal. Genes corresponding to priority SNPs having the highest contribution in the validation data have previously been implicated or hypothesized to be implicated in AD, including GCLC, IDE, and STAMBP1andFAS. We hypothesize that the effect sizes of the 1,694 SNPs in the priority set are likely small, but further investigation within this set may advance understanding of the missing heritability in late-onset Alzheimers disease. Multivariate analysis; Linkage regions; Imaging genetics; Endophenotypes; Inverse probability weighting; Variable importance probabilities

neuroscience

Structural and functional brain changes following four weeks of unimanual motor training: evidence from fMRI-guided diffusion MRI tractography

We have reported reliable changes in behaviour, brain structure and function in 24 healthy right-handed adults who practiced a finger-thumb opposition sequence task with their left hand for 10 mins daily, over four weeks. Here we extend these findings by employing diffusion MRI to investigate white-matter changes in the corticospinal tract, basal-ganglia, and connections of the dorsolateral prefrontal cortex. Twenty-three participant datasets were available with pre-training and post-training scans. Task performance improved in all participants (mean: 52.8%, SD: 20.0%; group p<0.01 FWE) and widespread microstructural changes were detected across the motor system of the trained hemisphere. Specifically, region-of-interest based analyses of diffusion MRI (n=21) revealed significantly increased fractional anisotropy in the right caudate nucleus (4.9%; p<0.05 FWE), and decreased mean diffusivity in the left nucleus accumbens (-1.3%; p<0.05 FWE). Diffusion MRI tractography (n=22), seeded by sensorimotor cortex fMRI activation, also revealed increased fractional anisotropy in the right corticomotor tract (mean 3.28%; p<0.05 FWE) predominantly reflecting decreased radial diffusivity. These changes were consistent throughout the entire length of the tract. The left corticomotor tract did not show any changes. FA also increased in white matter connections between the right middle frontal gyrus and both right caudate nucleus (17/22 participants; p<0.05 FWE) and right supplementary motor area (18/22 participants; p<0.05 FWE). Equivalent changes in FA were not seen in the left ( non-trained) hemisphere. In combination with our functional and structural findings, this study provides detailed, multifocal evidence for widespread neuroplastic changes in the human brain resulting from motor training.

neuroscience

Role of somatostatin-positive cortical interneurons in the generation of sleep slow waves

Cortical slow waves - the hallmark of NREM sleep - reflect near-synchronous OFF periods in cortical neurons. However, the mechanisms triggering such OFF periods are unclear, as there is little evidence for somatic inhibition. We studied cortical inhibitory interneurons that express somatostatin (SOM), because [~]70% of them are Martinotti cells that target diffusely layer 1 and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation triggers neuronal OFF periods during sleep. Next, we show that chemogenetic activation of SOM+ cells increases slow wave activity (SWA), the slope of individual slow waves, and the duration of NREM sleep; whereas their chemogenetic inhibition decreases SWA and slow wave incidence without changing time spent asleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing. These results indicate that SOM+ cells, but not PV+ cells, are involved in the generation of sleep slow waves. Whether Martinotti cells are solely responsible for this effect, or are complemented by other classes of inhibitory neurons, remains to be investigated.

neuroscience

Sexually satiated male Drosophila melanogaster uses gustatory-to-neuropeptide integrative circuits to reduce time investment for mating

Males rely on a time investment strategy to maximize reproductive success. Here we report a novel behavioral plasticity whereby male fruit flies exhibit a shortened mating duration when sexually satiated, which we named Shorter-Mating-Duration (SMD). SMD requires the sexually dimorphic Gr5a-positive neurons for detecting female body pheromones. The memory circuitry within the ellipsoid body (EB) and mushroom body (MB) brain regions is crucial for SMD, which depends on the circadian clock genes Clock and cycle, but not timeless or period. SMD also relies on signaling via the neuropeptide sNPF, but not PDF or NPF. Sexual experience modifies the neuronal activity of a subset of sNPF-positive neurons involved in neuropeptide signaling, which modulates SMD. Thus, our study delineates the molecular and cellular basis for SMD - a plastic social behavior that serves as a model system to study how the brain switches the internal states between sexual drive and satiety.

neuroscience

Visual crowding is a combination of an increase of positional uncertainty, source confusion, and featural averaging

Although we perceive a richly detailed visual world, our ability to identify 1 individual objects is severely limited in clutter, particularly in peripheral vision. Models of such crowding have generally been driven by the phenomenological misidentifications of crowded targets: using stimuli that do not easily combine to form a unique symbol (e.g. letters or objects), observers typically confuse the source of objects and report either the target or a distractor, but when continuous features are used (e.g. orientated gratings or line positions) observers report a feature somewhere between the target and distractor. To reconcile these accounts, we develop a hybrid method of adjustment that allows detailed analysis of these multiple error categories. Observers reported the orientation of a target, under several distractor conditions, by adjusting an identical foveal target. We apply new modelling to quantify whether perceptual reports show evidence of positional uncertainty, source confusion, and featural averaging on a trial-by-trial basis. Our results show that observers make a large proportion of source-confusion errors. However, our study also reveals the distribution of perceptual reports that underlie performance in this crowding task more generally: aggregate errors cannot be neatly labelled because they are heterogeneous and their structure depends on target-distractor distance.

neuroscience

Distinct sources of deterministic and stochastic components of action timing decisions in rodent frontal cortex

The selection and timing of actions are subject to determinate influences such as sensory cues and internal state as well as to effectively stochastic variability. Although stochastic choice mechanisms are assumed by many theoretical models, their origin and mechanisms remain poorly understood. Here we investigated this issue by studying how neural circuits in the frontal cortex determine action timing in rats performing a waiting task. Electrophysiological recordings from two regions necessary for this behavior, medial prefrontal cortex (mPFC) and secondary motor cortex (M2), revealed an unexpected functional dissociation. Both areas encoded deterministic biases in action timing, but only M2 neurons reflected stochastic trial-by-trial fluctuations. This differential coding was reflected in distinct timescales of neural dynamics in the two frontal cortical areas. These results suggest a two-stage model in which stochastic components of action timing decisions are injected by circuits downstream of those carrying deterministic bias signals.

neuroscience

Age and sex affect intersubject correlation of EEGthroughout development

Neural development is generally marked by an increase in the efficiency and diversity of neural processes. In a large sample (N = 114) of children and adults with ages ranging from 5 -44 years, we investigated the neural responses to naturalistic video stimuli. Videos from both real-life classroom settings and Hollywood feature films were used to probe different aspects of attention and engagement. For all stimuli, older ages were marked by more variable neural responses. Variability was assessed by the inter-subject correlation of evoked electroencephalographic (EEG) responses. Young males also had more variable responses than young females. These results were replicated in an independent cohort (N = 303). When interpreted in the context of neural maturation, we conclude that neural function becomes more variable with maturity, at least in during the passive viewing of real-world stimuli.\n\nSignificance StatementNaturalistic videos were used to measure how a large sample of children and adults process environmentally meaningful stimuli. As age increased, neural responses were more variable, and females responded more variably than males - a difference that disappeared with age. These results are consistent with developmental theories positing that neural variability increases with maturation, and that neural maturation typically occurs earlier in females. This is the first study to investigate neural variability under naturalistic conditions in a developmental sample.

neuroscience

NeuroExpresso: A cross-laboratory database of brain cell-type expression profiles with applications to marker gene identification and bulk brain tissue transcriptome interpretation

The identification of cell type marker genes, genes highly enriched in specific cell types, plays an important role in the study of the nervous system. In particular, marker genes can be used to identify cell types to enable studies of their properties. Marker genes can also aid the interpretation of bulk tissue expression profiles by revealing cell type specific changes.\n\nWe assembled a database, NeuroExpresso, of publicly available mouse brain cell type-specific gene expression datasets. We then used stringent criteria to select marker genes highly expressed in individual cell types. We found a substantial number of novel markers previously unknown in the literature and validated a subset of them using in silico analyses and in situ hybridization. We next demonstrate the use of marker genes in analysis of whole tissue data by summarizing their expression into \"cell type profiles\" that can be thought of as surrogates for the relative abundance of the cell types across the samples studied.\n\nFurther analysis of our cell type-specific expression database confirms some recent findings about brain cell types along with revealing novel properties, such as Ddc expression in oligodendrocytes. To facilitate further use of this expanding database, we provide a user-friendly web interface for the visualization of expression data.\n\nSignificance StatementCell type markers are powerful tools in the study of the nervous system that help reveal properties of cell types and acquire additional information from large scale expression experiments. Despite their usefulness in the field, known marker genes for brain cell types are few in number. We present NeuroExpresso, a database of brain cell type specific gene expression profiles, and demonstrate the use of marker genes for acquiring cell type specific information from whole tissue expression. The database will prove itself as a useful resource for researchers aiming to reveal novel properties of the cell types and aid both laboratory and computational scientists to unravel the cell type specific components of brain disorders.

neuroscience

The dynamics of human cognition: increasing global integration coupled with decreasing segregation found using intracortical EEG

Cognitive processing requires the ability to flexibly integrate and process information across large brain networks. More information is needed on how brain networks dynamically reorganize to allow such broad communication across many different brain regions in order to integrate the necessary information. Here, we use intracranial EEG to record neural activity from 12 epileptic patients while they perform three cognitive tasks in order to study how the functional connectivity changes to facilitate communication across the underlying network spanning many different brain regions. At the topological level, this facilitation is characterized by measures of integration and segregation. Across all patients, we found significant increases in integration and decreases in segregation during cognitive processing, especially in the gamma band (50-90 Hz). Accordingly, we also found significantly higher level of global synchronization and functional connectivity during the execution of the cognitive task, again particularly in the gamma band. More importantly, we demonstrate here for the first time that the modulations at the level of functional connectivity facilitating communication across the network were not caused by changes in the level of the underlying oscillations but caused by a rearrangement of the mutual synchronisation between the different nodes as proposed by the \"Communication Through Coherence\" Theory.

neuroscience

Prestimulus alpha-band power biases visual discrimination confidence, but not accuracy

Oscillations in the alpha-band (8-13 Hz) of human electroencephalographic (EEG) recordings are thought to reflect cortical excitability. As such, the magnitude of alpha power prior to the onset of a near threshold visual stimulus has been shown to predict stimulus detectability. Mechanistically, however, non-specific increases in visual-cortical excitability should result in amplified signal as well as amplified noise, leaving actual discriminability unchanged. Using a two-choice orientation discrimination task with equally probable stimuli, we found that discrimination accuracy was unaffected by fluctuations in prestimulus alpha-band power. Decision confidence, on the other hand, was strongly negatively correlated with prestimulus alpha power. This finding constitutes a clear dissociation between objective and subjective measures of visual perception as a function of prestimulus cortical excitability. This dissociation is predicted by models of perceptual confidence under which the balance of evidence in favor of each choice drives objective performance but only the magnitude of evidence in favor of the chosen stimulus drives subjective reports, suggesting that human perceptual confidence can be suboptimal.

neuroscience