ABSTRACT
Perceptual sensitivity varies from moment to moment. One potential source of this variability is spontaneous fluctuations in cortical activity that can travel as waves1. Spontaneous travelling waves have been reported during anaesthesia2-7, but it is not known whether they have a role during waking perception. Here, using newly developed analytic techniques to characterize the moment-to-moment dynamics of noisy multielectrode data, we identify spontaneous waves of activity in the extrastriate visual cortex of awake, behaving marmosets (Callithrix jacchus). In monkeys trained to detect faint visual targets, the timing and position of spontaneous travelling waves before target onset predicted the magnitude of target-evoked activity and the likelihood of target detection. By contrast, spatially disorganized fluctuations of neural activity were much less predictive. These results reveal an important role for spontaneous travelling waves in sensory processing through the modulation of neural and perceptual sensitivity.
Subject(s)
Brain Waves , Visual Cortex/physiology , Visual Perception/physiology , Wakefulness/physiology , Action Potentials , Animals , Behavior, Animal , Callithrix/physiology , Electrodes , Evoked Potentials, Visual , Female , Male , Photic Stimulation , Probability , Retina/physiologyABSTRACT
Populations of cortical neurons generate rhythmic fluctuations in their ongoing spontaneous activity. These fluctuations can be seen in the local field potential (LFP), which reflects summed return currents from synaptic activity in the local population near a recording electrode. The LFP is spectrally broad, and many researchers view this breadth as containing many narrowband oscillatory components that may have distinct functional roles. This view is supported by the observation that the phase of narrowband oscillations is often correlated with cortical excitability and can relate to the timing of spiking activity and the fidelity of sensory evoked responses. Accordingly, researchers commonly tune in to these channels by narrowband filtering the LFP. Alternatively, neural activity may be fundamentally broadband and composed of transient, nonstationary rhythms that are difficult to approximate as oscillations. In this view, the instantaneous state of the broad ensemble relates directly to the excitability of the local population with no particular allegiance to any frequency band. To test between these alternatives, we asked whether the spiking activity of neocortical neurons in marmoset of either sex is better aligned with the phase of the LFP within narrow frequency bands or with a broadband measure. We find that the phase of broadband LFP fluctuations provides a better predictor of spike timing than the phase after filtering in narrow bands. These results challenge the view of the neocortex as a system composed of narrowband oscillators and supports a view in which neural activity fluctuations are intrinsically broadband.SIGNIFICANCE STATEMENT Research into the dynamical state of neural populations often attributes unique significance to the state of narrowband oscillatory components. However, rhythmic fluctuations in cortical activity are nonstationary and broad spectrum. We find that the timing of spontaneous spiking activity is better captured by the state of broadband fluctuations over any latent oscillatory component. These results suggest narrowband interpretations of rhythmic population activity may be limited, and broader representations may provide higher fidelity in describing moment-to-moment fluctuations in cortical activity.
Subject(s)
Neocortex , Neurons , Action Potentials/physiology , Neocortex/physiology , Neurons/physiologyABSTRACT
Multichannel recording technologies have revealed travelling waves of neural activity in multiple sensory, motor and cognitive systems. These waves can be spontaneously generated by recurrent circuits or evoked by external stimuli. They travel along brain networks at multiple scales, transiently modulating spiking and excitability as they pass. Here, we review recent experimental findings that have found evidence for travelling waves at single-area (mesoscopic) and whole-brain (macroscopic) scales. We place these findings in the context of the current theoretical understanding of wave generation and propagation in recurrent networks. During the large low-frequency rhythms of sleep or the relatively desynchronized state of the awake cortex, travelling waves may serve a variety of functions, from long-term memory consolidation to processing of dynamic visual stimuli. We explore new avenues for experimental and computational understanding of the role of spatiotemporal activity patterns in the cortex.
Subject(s)
Brain Waves/physiology , Cerebral Cortex/physiology , Computer Simulation , Neural Pathways/physiology , Animals , Electroencephalography , Humans , Models, NeurologicalABSTRACT
Networks with different levels of interactions, including multilayer and multiplex networks, can display a rich diversity of dynamical behaviors and can be used to model and study a wide range of systems. Despite numerous efforts to investigate these networks, obtaining mathematical descriptions for the dynamics of multilayer and multiplex systems is still an open problem. Here, we combine ideas and concepts from linear algebra and graph theory with nonlinear dynamics to offer a novel approach to study multiplex networks of Kuramoto oscillators. Our approach allows us to study the dynamics of a large, multiplex network by decomposing it into two smaller systems: one representing the connection scheme within layers (intra-layer), and the other representing the connections between layers (inter-layer). Particularly, we use this approach to compose solutions for multiplex networks of Kuramoto oscillators. These solutions are given by a combination of solutions for the smaller systems given by the intra- and inter-layer systems, and in addition, our approach allows us to study the linear stability of these solutions.
ABSTRACT
One of the simplest mathematical models in the study of nonlinear systems is the Kuramoto model, which describes synchronization in systems from swarms of insects to superconductors. We have recently found a connection between the original, real-valued nonlinear Kuramoto model and a corresponding complex-valued system that permits describing the system in terms of a linear operator and iterative update rule. We now use this description to investigate three major synchronization phenomena in Kuramoto networks (phase synchronization, chimera states, and traveling waves), not only in terms of steady state solutions but also in terms of transient dynamics and individual simulations. These results provide new mathematical insight into how sophisticated behaviors arise from connection patterns in nonlinear networked systems.
Subject(s)
Chimera , Nonlinear Dynamics , Models, TheoreticalABSTRACT
Sleep spindles are brief oscillatory events during non-rapid eye movement (NREM) sleep. Spindle density and synchronization properties are different in MEG versus EEG recordings in humans and also vary with learning performance, suggesting spindle involvement in memory consolidation. Here, using computational models, we identified network mechanisms that may explain differences in spindle properties across cortical structures. First, we report that differences in spindle occurrence between MEG and EEG data may arise from the contrasting properties of the core and matrix thalamocortical systems. The matrix system, projecting superficially, has wider thalamocortical fanout compared to the core system, which projects to middle layers, and requires the recruitment of a larger population of neurons to initiate a spindle. This property was sufficient to explain lower spindle density and higher spatial synchrony of spindles in the superficial cortical layers, as observed in the EEG signal. In contrast, spindles in the core system occurred more frequently but less synchronously, as observed in the MEG recordings. Furthermore, consistent with human recordings, in the model, spindles occurred independently in the core system but the matrix system spindles commonly co-occurred with core spindles. We also found that the intracortical excitatory connections from layer III/IV to layer V promote spindle propagation from the core to the matrix system, leading to widespread spindle activity. Our study predicts that plasticity of intra- and inter-cortical connectivity can potentially be a mechanism for increased spindle density as has been observed during learning.
Subject(s)
Cerebral Cortex/physiology , Sleep/physiology , Thalamus/physiology , Adult , Computer Simulation , Connectome , Electroencephalography/methods , Female , Healthy Volunteers , Humans , Magnetoencephalography/methods , Male , Memory Consolidation/physiology , Neurons/physiology , Sleep Stages/physiologyABSTRACT
Beta (ß)- and gamma (γ)-oscillations are present in different cortical areas and are thought to be inhibition-driven, but it is not known if these properties also apply to γ-oscillations in humans. Here, we analyze such oscillations in high-density microelectrode array recordings in human and monkey during the wake-sleep cycle. In these recordings, units were classified as excitatory and inhibitory cells. We find that γ-oscillations in human and ß-oscillations in monkey are characterized by a strong implication of inhibitory neurons, both in terms of their firing rate and their phasic firing with the oscillation cycle. The ß- and γ-waves systematically propagate across the array, with similar velocities, during both wake and sleep. However, only in slow-wave sleep (SWS) ß- and γ-oscillations are associated with highly coherent and functional interactions across several millimeters of the neocortex. This interaction is specifically pronounced between inhibitory cells. These results suggest that inhibitory cells are dominantly involved in the genesis of ß- and γ-oscillations, as well as in the organization of their large-scale coherence in the awake and sleeping brain. The highest oscillation coherence found during SWS suggests that fast oscillations implement a highly coherent reactivation of wake patterns that may support memory consolidation during SWS.
Subject(s)
Neocortex/physiology , Sleep/physiology , Wakefulness/physiology , Animals , Electroencephalography , Female , Haplorhini , Humans , Middle AgedABSTRACT
In estimating the frequency spectrum of real-world time series data, we must violate the assumption of infinite-length, orthogonal components in the Fourier basis. While it is widely known that care must be taken with discretely sampled data to avoid aliasing of high frequencies, less attention is given to the influence of low frequencies with period below the sampling time window. Here, we derive an analytic expression for the side-lobe attenuation of signal components in the frequency domain representation. This expression allows us to detail the influence of individual frequency components throughout the spectrum. The first consequence is that the presence of low-frequency components introduces a 1/f[Formula: see text] component across the power spectrum, with a scaling exponent of [Formula: see text]. This scaling artifact could be composed of diffuse low-frequency components, which can render it difficult to detect a priori. Further, treatment of the signal with standard digital signal processing techniques cannot easily remove this scaling component. While several theoretical models have been introduced to explain the ubiquitous 1/f[Formula: see text] scaling component in neuroscientific data, we conjecture here that some experimental observations could be the result of such data analysis procedures.
Subject(s)
Artifacts , Fourier Analysis , Nonlinear Dynamics , Signal Processing, Computer-Assisted , Animals , HumansABSTRACT
The correlation method from brain imaging has been used to estimate functional connectivity in the human brain. However, brain regions might show very high correlation even when the two regions are not directly connected due to the strong interaction of the two regions with common input from a third region. One previously proposed solution to this problem is to use a sparse regularized inverse covariance matrix or precision matrix (SRPM) assuming that the connectivity structure is sparse. This method yields partial correlations to measure strong direct interactions between pairs of regions while simultaneously removing the influence of the rest of the regions, thus identifying regions that are conditionally independent. To test our methods, we first demonstrated conditions under which the SRPM method could indeed find the true physical connection between a pair of nodes for a spring-mass example and an RC circuit example. The recovery of the connectivity structure using the SRPM method can be explained by energy models using the Boltzmann distribution. We then demonstrated the application of the SRPM method for estimating brain connectivity during stage 2 sleep spindles from human electrocorticography (ECoG) recordings using an [Formula: see text] electrode array. The ECoG recordings that we analyzed were from a 32-year-old male patient with long-standing pharmaco-resistant left temporal lobe complex partial epilepsy. Sleep spindles were automatically detected using delay differential analysis and then analyzed with SRPM and the Louvain method for community detection. We found spatially localized brain networks within and between neighboring cortical areas during spindles, in contrast to the case when sleep spindles were not present.
Subject(s)
Brain Mapping , Brain/physiology , Electrocorticography/methods , Models, Neurological , Neural Pathways/physiology , Sleep/physiology , Computer Simulation , Humans , Nonlinear Dynamics , Time FactorsABSTRACT
In the past two decades, significant advances have been made in understanding the structural and functional properties of biological networks, via graph-theoretic analysis. In general, most graph-theoretic studies are conducted in the presence of serious uncertainties, such as major undersampling of the experimental data. In the specific case of neural systems, however, a few moderately robust experimental reconstructions have been reported, and these have long served as fundamental prototypes for studying connectivity patterns in the nervous system. In this paper, we provide a comparative analysis of these "historical" graphs, both in their directed (original) and symmetrized (a common preprocessing step) forms, and provide a set of measures that can be consistently applied across graphs (directed or undirected, with or without self-loops). We focus on simple structural characterizations of network connectivity and find that in many measures, the networks studied are captured by simple random graph models. In a few key measures, however, we observe a marked departure from the random graph prediction. Our results suggest that the mechanism of graph formation in the networks studied is not well captured by existing abstract graph models in their first- and second-order connectivity.
Subject(s)
Brain/physiology , Models, Neurological , Nerve Net/physiology , Neural Networks, Computer , Neural Pathways/physiology , Nonlinear Dynamics , Algorithms , Animals , Brain/anatomy & histology , Humans , Neural Pathways/anatomy & histologyABSTRACT
Intrinsic, ongoing fluctuations of cortical activity form traveling waves that modulate the gain of sensory-evoked responses and perceptual sensitivity. Several lines of evidence suggest that intrinsic traveling waves (iTWs) may arise, in part, from the coordination of synaptic activity through the recurrent horizontal connectivity within cortical areas, which include long range patchy connections that link neurons with shared feature preferences. In a spiking network model with anatomical topology that incorporates feature-selective patchy connections, which we call the Balanced Patchy Network (BPN), we observe repeated iTWs, which we refer to as motifs. In the model, motifs stem from fluctuations in the excitability of like-tuned neurons that result from shifts in E/I balance as action potentials traverse these patchy connections. To test if feature-selective motifs occur in vivo, we examined data previously recorded using multielectrode arrays in Area MT of marmosets trained to perform a threshold visual detection task. Using a newly developed method for comparing the similarity of wave patterns we found that some iTWs can be grouped into motifs. As predicted by the BPN, many of these motifs are feature selective, exhibiting direction-selective modulations in ongoing spiking activity. Further, motifs modulate the gain of the response evoked by a target and perceptual sensitivity to the target if the target matches the preference of the motif. These results provide evidence that iTWs are shaped by the patterns of horizontal fiber projections in the cortex and that patchy connections enable iTWs to regulate neural and perceptual sensitivity in a feature selective manner.
ABSTRACT
The role of the hippocampus in spatial navigation has been primarily studied in nocturnal mammals, such as rats, that lack many adaptations for daylight vision. Here we demonstrate that during 3D navigation, the common marmoset, a new world primate adapted to daylight, predominantly uses rapid head-gaze shifts for visual exploration while remaining stationary. During active locomotion marmosets stabilize the head, in contrast to rats that use low-velocity head movements to scan the environment as they locomote. Pyramidal neurons in the marmoset hippocampus CA3/CA1 regions predominantly show mixed selectivity for 3D spatial view, head direction, and place. Exclusive place selectivity is scarce. Inhibitory interneurons are predominantly mixed selective for angular head velocity and translation speed. Finally, we found theta phase resetting of local field potential oscillations triggered by head-gaze shifts. Our findings indicate that marmosets adapted to their daylight ecological niche by modifying exploration/navigation strategies and their corresponding hippocampal specializations.
Subject(s)
Callithrix , Hippocampus , Spatial Navigation , Animals , Callithrix/physiology , Spatial Navigation/physiology , Hippocampus/physiology , Male , Locomotion/physiology , Vision, Ocular/physiology , Pyramidal Cells/physiology , Head Movements/physiology , Interneurons/physiology , Female , Behavior, Animal/physiology , CA1 Region, Hippocampal/physiology , CA1 Region, Hippocampal/cytologyABSTRACT
Linking sensory-evoked traveling waves to underlying circuit patterns is critical to understanding the neural basis of sensory perception. To form this link, we performed simultaneous electrophysiology and two-photon calcium imaging through transparent NeuroGrids and mapped touch-evoked cortical traveling waves and their underlying microcircuit dynamics. In awake mice, both passive and active whisker touch elicited traveling waves within and across barrels, with a fast early component followed by a variable late wave that lasted hundreds of milliseconds post-stimulus. Strikingly, late-wave dynamics were modulated by stimulus value and correlated with task performance. Mechanistically, the late wave component was i) modulated by motor feedback, ii) complemented by a sparse ensemble pattern across layer 2/3, which a balanced-state network model reconciled via inhibitory stabilization, and iii) aligned to regenerative Layer-5 apical dendritic Ca 2+ events. Our results reveal a translaminar spacetime pattern organized by cortical feedback in the sensory cortex that supports touch-evoked traveling waves. GRAPHICAL ABSTRACT AND HIGHLIGHTS: Whisker touch evokes both early- and late-traveling waves in the barrel cortex over 100's of millisecondsReward reinforcement modulates wave dynamics Late wave emergence coincides with network sparsity in L23 and time-locked L5 dendritic Ca 2+ spikes Experimental and computational results link motor feedback to distinct translaminar spacetime patterns.
ABSTRACT
Working memory (WM) is the ability to maintain and manipulate information 'in mind'. The neural codes underlying WM have been a matter of debate. We simultaneously recorded the activity of hundreds of neurons in the lateral prefrontal cortex of male macaque monkeys during a visuospatial WM task that required navigation in a virtual 3D environment. Here, we demonstrate distinct neuronal activation sequences (NASs) that encode remembered target locations in the virtual environment. This NAS code outperformed the persistent firing code for remembered locations during the virtual reality task, but not during a classical WM task using stationary stimuli and constraining eye movements. Finally, blocking NMDA receptors using low doses of ketamine deteriorated the NAS code and behavioral performance selectively during the WM task. These results reveal the versatility and adaptability of neural codes supporting working memory function in the primate lateral prefrontal cortex.
Subject(s)
Macaca mulatta , Memory, Short-Term , Neurons , Prefrontal Cortex , Animals , Prefrontal Cortex/physiology , Memory, Short-Term/physiology , Male , Neurons/physiology , Virtual Reality , Ketamine/pharmacology , Spatial Navigation/physiology , Receptors, N-Methyl-D-Aspartate/metabolismABSTRACT
Although temporal coding through spike-time patterns has long been of interest in neuroscience, the specific structures that could be useful for spike-time codes remain highly unclear. Here, we introduce an analytical approach, using techniques from discrete mathematics, to study spike-time codes. As an initial example, we focus on the phenomenon of "phase precession" in the rodent hippocampus. During navigation and learning on a physical track, specific cells in a rodent's brain form a highly structured pattern relative to the oscillation of population activity in this region. Studies of phase precession largely focus on its role in precisely ordering spike times for synaptic plasticity, as the role of phase precession in memory formation is well established. Comparatively less attention has been paid to the fact that phase precession represents one of the best candidates for a spike-time neural code. The precise nature of this code remains an open question. Here, we derive an analytical expression for a function mapping points in physical space to complex-valued spikes by representing individual spike times as complex numbers. The properties of this function make explicit a specific relationship between past and future in spike patterns of the hippocampus. Importantly, this mathematical approach generalizes beyond the specific phenomenon studied here, providing a technique to study the neural codes within precise spike-time sequences found during sensory coding and motor behavior. We then introduce a spike-based decoding algorithm, based on this function, that successfully decodes a simulated animal's trajectory using only the animal's initial position and a pattern of spike times. This decoder is robust to noise in spike times and works on a timescale almost an order of magnitude shorter than typically used with decoders that work on average firing rate. These results illustrate the utility of a discrete approach, based on the structure and symmetries in spike patterns across finite sets of cells, to provide insight into the structure and function of neural systems.
Subject(s)
Brain , Hippocampus , Animals , Action Potentials , Algorithms , Models, NeurologicalABSTRACT
Recent analyses have found waves of neural activity traveling across entire visual cortical areas in awake animals. These traveling waves modulate the excitability of local networks and perceptual sensitivity. The general computational role of these spatiotemporal patterns in the visual system, however, remains unclear. Here, we hypothesize that traveling waves endow the visual system with the capacity to predict complex and naturalistic inputs. We present a network model whose connections can be rapidly and efficiently trained to predict individual natural movies. After training, a few input frames from a movie trigger complex wave patterns that drive accurate predictions many frames into the future solely from the network's connections. When the recurrent connections that drive waves are randomly shuffled, both traveling waves and the ability to predict are eliminated. These results suggest traveling waves may play an essential computational role in the visual system by embedding continuous spatiotemporal structures over spatial maps.
Subject(s)
Visual Cortex , Wakefulness , Animals , Visual Cortex/physiologyABSTRACT
The cortical column is one of the fundamental computational circuits in the brain. In order to understand the role neurons in different layers of this circuit play in cortical function it is necessary to identify the boundaries that separate the laminar compartments. While histological approaches can reveal ground truth they are not a practical means of identifying cortical layers in vivo. The gold standard for identifying laminar compartments in electrophysiological recordings is current-source density (CSD) analysis. However, laminar CSD analysis requires averaging across reliably evoked responses that target the input layer in cortex, which may be difficult to generate in less well-studied cortical regions. Further, the analysis can be susceptible to noise on individual channels resulting in errors in assigning laminar boundaries. Here, we have analyzed linear array recordings in multiple cortical areas in both the common marmoset and the rhesus macaque. We describe a pattern of laminar spike-field phase relationships that reliably identifies the transition between input and deep layers in cortical recordings from multiple cortical areas in two different non-human primate species. This measure corresponds well to estimates of the location of the input layer using CSDs, but does not require averaging or specific evoked activity. Laminar identity can be estimated rapidly with as little as a minute of ongoing data and is invariant to many experimental parameters. This method may serve to validate CSD measurements that might otherwise be unreliable or to estimate laminar boundaries when other methods are not practical.
Subject(s)
Brain , Electrophysiological Phenomena , Animals , Macaca mulattaABSTRACT
The stress response necessitates an immediate boost in vital physiological functions from their homeostatic operation to an elevated emergency response. However, the neural mechanisms underlying this state-dependent change remain largely unknown. Using a combination of in vivo and ex vivo electrophysiology with computational modeling, we report that corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN), the effector neurons of hormonal stress response, rapidly transition between distinct activity states through recurrent inhibition. Specifically, in vivo optrode recording shows that under non-stress conditions, CRHPVN neurons often fire with rhythmic brief bursts (RB), which, somewhat counterintuitively, constrains firing rate due to long (~2 s) interburst intervals. Stressful stimuli rapidly switch RB to continuous single spiking (SS), permitting a large increase in firing rate. A spiking network model shows that recurrent inhibition can control this activity-state switch, and more broadly the gain of spiking responses to excitatory inputs. In biological CRHPVN neurons ex vivo, the injection of whole-cell currents derived from our computational model recreates the in vivo-like switch between RB and SS, providing direct evidence that physiologically relevant network inputs enable state-dependent computation in single neurons. Together, we present a novel mechanism for state-dependent activity dynamics in CRHPVN neurons.
Subject(s)
Corticotropin-Releasing Hormone , Paraventricular Hypothalamic Nucleus , Corticotropin-Releasing Hormone/metabolism , Hypothalamus/metabolism , Neurons/physiology , Paraventricular Hypothalamic Nucleus/metabolismABSTRACT
Sleep is generally considered to be a state of large-scale synchrony across thalamus and neocortex; however, recent work has challenged this idea by reporting isolated sleep rhythms such as slow oscillations and spindles. What is the spatial scale of sleep rhythms? To answer this question, we adapted deep learning algorithms initially developed for detecting earthquakes and gravitational waves in high-noise settings for analysis of neural recordings in sleep. We then studied sleep spindles in non-human primate electrocorticography (ECoG), human electroencephalogram (EEG), and clinical intracranial electroencephalogram (iEEG) recordings in the human. Within each recording type, we find widespread spindles occur much more frequently than previously reported. We then analyzed the spatiotemporal patterns of these large-scale, multi-area spindles and, in the EEG recordings, how spindle patterns change following a visual memory task. Our results reveal a potential role for widespread, multi-area spindles in consolidation of memories in networks widely distributed across primate cortex.
The brain processes memories as we sleep, generating rhythms of electrical activity called 'sleep spindles'. Sleep spindles were long thought to be a state where the entire brain was fully synchronized by this rhythm. This was based on EEG recordings, short for electroencephalogram, a technique that uses electrodes on the scalp to measure electrical activity in the outermost layer of the brain, the cortex. But more recent intracranial recordings of people undergoing brain surgery have challenged this idea and suggested that sleep spindles may not be a state of global brain synchronization, but rather localised to specific areas. Mofrad et al. sought to clarify the extent to which spindles co-occur at multiple sites in the brain, which could shed light on how networks of neurons coordinate memory storage during sleep. To analyse highly variable brain wave recordings, Mofrad et al. adapted deep learning algorithms initially developed for detecting earthquakes and gravitational waves. The resulting algorithm, designed to more sensitively detect spindles amongst other brain activity, was then applied to a range of sleep recordings from humans and macaque monkeys. The analyses revealed that widespread and complex patterns of spindle rhythms, spanning multiple areas in the cortex of the brain, actually appear much more frequently than previously thought. This finding was consistent across all the recordings analysed, even recordings under the skull, which provide the clearest window into brain circuits. Further analyses found that these multi-area spindles occurred more often in sleep after people had completed tasks that required holding many visual scenes in memory, as opposed to control conditions with fewer visual scenes. In summary, Mofrad et al. show that neuroscientists had previously not appreciated the complex and dynamic patterns in this sleep rhythm. These patterns in sleep spindles may be able to adapt based on the demands needed for memory storage, and this will be the subject of future work. Moreover, the findings support the idea that sleep spindles help coordinate the consolidation of memories in brain circuits that stretch across the cortex. Understanding this mechanism may provide insights into how memory falters in aging and sleep-related diseases, such as Alzheimer's disease. Lastly, the algorithm developed by Mofrad et al. stands to be a useful tool for analysing other rhythmic waveforms in noisy recordings.
Subject(s)
Deep Learning , Animals , Electrocorticography , Electroencephalography , Memory , SleepABSTRACT
Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by heterozygous loss-of-function mutations in the X-linked gene MECP2 that is a global transcriptional regulator. Mutations in the methyl-CpG binding domain (MBD) of MECP2 disrupt its interaction with methylated DNA. Here, we investigate the effect of a novel MECP2 L124W missense mutation in the MBD of an atypical RTT patient with preserved speech in comparison to severe MECP2 null mutations. L124W protein had a limited ability to disrupt heterochromatic chromocenters due to decreased binding dynamics. We isolated two pairs of isogenic WT and L124W induced pluripotent stem cells. L124W induced excitatory neurons expressed stable protein, exhibited increased input resistance and decreased voltage-gated Na+ and K+ currents, and their neuronal dysmorphology was limited to decreased dendritic complexity. Three isogenic pairs of MECP2 null neurons had the expected more extreme morphological and electrophysiological phenotypes. We examined development and maturation of L124W and MECP2 null excitatory neural network activity using micro-electrode arrays. Relative to isogenic controls, L124W neurons had an increase in synchronous network burst frequency, in contrast to MECP2 null neurons that suffered a significant decrease in synchronous network burst frequency and a transient extension of network burst duration. A biologically motivated computational neural network model shows the observed changes in network dynamics are explained by changes in intrinsic Na+ and K+ currents in individual neurons. Our multilevel results demonstrate that RTT excitatory neurons show a wide spectrum of morphological, electrophysiological and circuitry phenotypes that are dependent on the severity of the MECP2 mutation.