Astrocyte subdomains respond independently in vivo
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Abstract Astrocytes contact thousands of synapses throughout the territory covered by its fine bushy processes. Astrocytes respond to neuronal activity with an increase in calcium concentration that is in turn linked to their capacity to modulate neuronal activity. It remains unclear whether astrocytes behave as a single functional unit that integrates all of these inputs, or if multiple functional subdomains reside within an individual astrocyte. We utilized the topographic organization of ferret visual cortex to test whether local neuronal activity can elicit spatially restricted events within an individual astrocyte. We monitored calcium activity throughout the extent of astrocytes in ferret visual cortex while presenting visual stimuli that elicit coordinated neuronal activity spatially restricted to functional columns. We found visually-driven calcium responses throughout the entire astrocyte that was largely independent in individual subdomains, often responding to different visual stimulus orientations. A model of the spatial interaction of astrocytes and neuronal orientation maps recapitulated these measurements, consistent with the hypothesis that astrocyte subdomains integrate local neuronal activity. Together, these results suggest that astrocyte responses to neural circuit activity are dominated by functional subdomains that respond locally and independently to neuronal activity.Keywords:
Premovement neuronal activity
Calcium imaging
Stimulus (psychology)
Biological neural network
Nerve net
In neuroscience, it's one of the central goals to decipher neuronal ensembles' function in the neural circuits. Recently, the progress of probes for optogenetic actuators and calcium indicators afford the probability for simultaneous optical manipulation and imaging of neuronal ensembles. Although with point-scanning imaging and localized optical stimulation, previous work had achieved all-optical interrogation of neural circuits in the local brain areas of mice and zebrafish larvae, no attempt was made to optical interrogate neuronal ensembles' function across the whole-brain. Here, we combined the fast volumetric imaging technique, light-sheet microscopy which was an order of magnitude faster than the point-scanning method, with digital laser beam shaping device, digital micromirror device (DMD), to learn about neuronal activities across the whole brain of behaving larval zebrafish. Using the spectrally separated calcium indicator, GCaMP6f, and activity actuator, ChrimsonR, we can simultaneously image and manipulate neuronal ensembles with minimal spectral cross-talk. Besides, to monitor the behavior of zebrafish larvae, a high-speed camera was introduced into the system. To demonstrate the system's function, arbitrarily selected neurons was stimulated during the whole-brain neuronal activities' imaging, which effectively activated the synaptic connections and brain-wide downstream neural circuits and evoked stereotyped behaviors. These results demonstrate the system's ability in studying the function of brain-wide neuronal ensembles in small animals.
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The ability to map functional connectivity is necessary for the study of the flow of activity in neuronal circuits. Optical imaging of calcium indicators, including FRET-based genetically encoded indicators and extrinsic dyes, is an important adjunct to electrophysiology and is widely used to visualize neuronal activity. However, techniques for mapping functional connectivities with calcium imaging data have been lacking. We present a procedure to compute reduced functional couplings between neuronal ensembles undergoing seizure activity from ratiometric calcium imaging data in three steps: (1) calculation of calcium concentrations and neuronal firing rates from ratiometric data; (2) identification of putative neuronal populations from spatio-temporal time-series of neural bursting activity; and then, (3) derivation of reduced connectivity matrices that represent neuronal population interactions. We apply our method to the larval zebrafish central nervous system undergoing chemoconvulsant-induced seizures. These seizures generate propagating, central nervous system-wide neural activity from which population connectivities may be calculated. This automatic functional connectivity mapping procedure provides a practical and user-independent means for summarizing the flow of activity between neuronal ensembles.
Calcium imaging
Biological neural network
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Bursting
Nerve net
Functional Imaging
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Abstract Astrocytes contact thousands of synapses throughout the territory covered by its fine bushy processes. Astrocytes respond to neuronal activity with an increase in calcium concentration that is in turn linked to their capacity to modulate neuronal activity. It remains unclear whether astrocytes behave as a single functional unit that integrates all of these inputs, or if multiple functional subdomains reside within an individual astrocyte. We utilized the topographic organization of ferret visual cortex to test whether local neuronal activity can elicit spatially restricted events within an individual astrocyte. We monitored calcium activity throughout the extent of astrocytes in ferret visual cortex while presenting visual stimuli that elicit coordinated neuronal activity spatially restricted to functional columns. We found visually-driven calcium responses throughout the entire astrocyte that was largely independent in individual subdomains, often responding to different visual stimulus orientations. A model of the spatial interaction of astrocytes and neuronal orientation maps recapitulated these measurements, consistent with the hypothesis that astrocyte subdomains integrate local neuronal activity. Together, these results suggest that astrocyte responses to neural circuit activity are dominated by functional subdomains that respond locally and independently to neuronal activity.
Premovement neuronal activity
Calcium imaging
Stimulus (psychology)
Biological neural network
Nerve net
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The neural code that relates the firing of neurons to the generation of behavior and mental states must be implemented by spatiotemporal patterns of activity across neuronal populations. These patterns engage selective groups of neurons, called neuronal ensembles, which are emergent building blocks of neural circuits. We review optical and computational methods, based on two-photon calcium imaging and two-photon optogenetics, to detect, characterize, and manipulate neuronal ensembles in three dimensions. We review data using these methods in the mammalian cortex that demonstrate the existence of neuronal ensembles in the spontaneous and evoked cortical activity in vitro and in vivo. Moreover, two-photon optogenetics enable the possibility of artificially imprinting neuronal ensembles into awake, behaving animals and of later recalling those ensembles selectively by stimulating individual cells. These methods could enable deciphering the neural code and also be used to understand the pathophysiology of and design novel therapies for neurological and mental diseases.
Calcium imaging
Biological neural network
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Two-photon excitation microscopy
Neural Activity
Systems neuroscience
Cellular neuroscience
Neuronal Circuits
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Calcium imaging
Channelrhodopsin
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Photostimulation
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Abstract Astrocytes are a direct target of neuromodulators and can influence neuronal activity on broad spatial and temporal scales in response to a rise in cytosolic calcium. However, our knowledge about how astrocytes are recruited during different animal behaviors remains limited. To measure astrocyte activity calcium in vivo during normative behaviors, we utilize a high-resolution, long working distance multicore fiber optic imaging system that allows visualization of individual astrocyte calcium transients in the cerebral cortex of freely moving mice. We define the spatiotemporal dynamics of astrocyte calcium changes during diverse behaviors, ranging from sleep-wake cycles to the exploration of novel objects, showing that their activity is more variable and less synchronous than apparent in head-immobilized imaging conditions. In accordance with their molecular diversity, individual astrocytes often exhibit distinct thresholds and activity patterns during explorative behaviors, allowing temporal encoding across the astrocyte network. Astrocyte calcium events were induced by noradrenergic and cholinergic systems and modulated by internal state. The distinct activity patterns exhibited by astrocytes provides a means to vary their neuromodulatory influence in different behavioral contexts and internal states.
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The functional role of astrocyte calcium signaling in brain information processing was intensely debated in recent decades. This interest was motivated by high resolution imaging techniques showing highly developed structure of distal astrocyte processes. Another point was the evidence of bi-directional astrocytic regulation of neuronal activity. To analyze the effects of interplay of calcium signals in processes and in soma mediating correlations between local signals and the cell-level response of the astrocyte we proposed spatially extended model of the astrocyte calcium dynamics. Specifically, we investigated how spatiotemporal properties of Ca2+ dynamics in spatially extended astrocyte model can coordinate (e.g., synchronize) networks of neurons and synapses.
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Nerve net
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Calcium imaging
Biological neural network
Premovement neuronal activity
Nerve net
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Developing neuronal systems intrinsically generate coordinated spontaneous activity that propagates by involving a large number of synchronously firing neurons. In vivo, waves of spikes transiently characterize the activity of developing brain circuits and are fundamental for activity-dependent circuit formation. In vitro, coordinated spontaneous spiking activity, or network bursts (NBs), interleaved within periods of asynchronous spikes emerge during the development of 2D and 3D neuronal cultures. Several studies have investigated this type of activity and its dynamics, but how a neuronal system generates these coordinated events remains unclear. Here, we investigate at a cellular level the generation of network bursts in spontaneously active neuronal cultures by exploiting high-resolution multielectrode array recordings and computational network modelling. Our analysis reveals that NBs are generated in specialized regions of the network (functional neuronal communities) that feature neuronal links with high cross-correlation peak values, sub-millisecond lags and that share very similar structural connectivity motifs providing recurrent interactions. We show that the particular properties of these local structures enable locally amplifying spontaneous asynchronous spikes and that this mechanism can lead to the initiation of NBs. Through the analysis of simulated and experimental data, we also show that AMPA currents drive the coordinated activity, while NMDA and GABA currents are only involved in shaping the dynamics of NBs. Overall, our results suggest that the presence of functional neuronal communities with recurrent local connections allows a neuronal system to generate spontaneous coordinated spiking activity events. As suggested by the rules used for implementing our computational model, such functional communities might naturally emerge during network development by following simple constraints on distance-based connectivity.
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Biological neural network
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Multielectrode array
Network Dynamics
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Neuronal networks in vitro are prominent systems to study the development of connections in living neuronal networks and the interplay between connectivity, activity and function. These cultured networks show a rich spontaneous activity that evolves concurrently with the connectivity of the underlying network. In this work we monitor the development of neuronal cultures, and record their activity using calcium fluorescence imaging. We use spectral analysis to characterize global dynamical and structural traits of the neuronal cultures. We first observe that the power spectrum can be used as a signature of the state of the network, for instance when inhibition is active or silent, as well as a measure of the network's connectivity strength. Second, the power spectrum identifies prominent developmental changes in the network such as GABAA switch. And third, the analysis of the spatial distribution of the spectral density, in experiments with a controlled disintegration of the network through CNQX, an AMPA-glutamate receptor antagonist in excitatory neurons, reveals the existence of communities of strongly connected, highly active neurons that display synchronous oscillations. Our work illustrates the interest of spectral analysis for the study of in vitro networks, and its potential use as a network-state indicator, for instance to compare healthy and diseased neuronal networks.
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Spectral Analysis
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