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Journal ArticleDOI

Differential connectivity and response dynamics of excitatory and inhibitory neurons in visual cortex.

TL;DR: Investigating the dependencies between synaptic connectivity, feature selectivity and network activity in pyramidal cells and fast-spiking parvalbumin-expressing interneurons in mouse visual cortex found that feedforward and recurrent network influences determine the activity of excitatory and inhibitory ensembles in fundamentally different ways.
Abstract: Neuronal responses during sensory processing are influenced by both the organization of intracortical connections and the statistical features of sensory stimuli. How these intrinsic and extrinsic factors govern the activity of excitatory and inhibitory populations is unclear. Using two-photon calcium imaging in vivo and intracellular recordings in vitro, we investigated the dependencies between synaptic connectivity, feature selectivity and network activity in pyramidal cells and fast-spiking parvalbumin-expressing (PV) interneurons in mouse visual cortex. In pyramidal cell populations, patterns of neuronal correlations were largely stimulus-dependent, indicating that their responses were not strongly dominated by functionally biased recurrent connectivity. By contrast, visual stimulation only weakly modified co-activation patterns of fast-spiking PV cells, consistent with the observation that these broadly tuned interneurons received very dense and strong synaptic input from nearby pyramidal cells with diverse feature selectivities. Therefore, feedforward and recurrent network influences determine the activity of excitatory and inhibitory ensembles in fundamentally different ways.

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Citations
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Journal ArticleDOI
18 Jul 2013-Nature
TL;DR: A family of ultrasensitive protein calcium sensors (GCaMP6) that outperformed other sensors in cultured neurons and in zebrafish, flies and mice in vivo are developed and provide new windows into the organization and dynamics of neural circuits over multiple spatial and temporal scales.
Abstract: Fluorescent calcium sensors are widely used to image neural activity. Using structure-based mutagenesis and neuron-based screening, we developed a family of ultrasensitive protein calcium sensors (GCaMP6) that outperformed other sensors in cultured neurons and in zebrafish, flies and mice in vivo. In layer 2/3 pyramidal neurons of the mouse visual cortex, GCaMP6 reliably detected single action potentials in neuronal somata and orientation-tuned synaptic calcium transients in individual dendritic spines. The orientation tuning of structurally persistent spines was largely stable over timescales of weeks. Orientation tuning averaged across spine populations predicted the tuning of their parent cell. Although the somata of GABAergic neurons showed little orientation tuning, their dendrites included highly tuned dendritic segments (5-40-µm long). GCaMP6 sensors thus provide new windows into the organization and dynamics of neural circuits over multiple spatial and temporal scales.

5,365 citations

Journal ArticleDOI
20 Jul 2016-Neuron
TL;DR: Current understanding of neocortical interneuron diversity and the properties that distinguish cell types are reviewed and it is illustrated how recent advances in the field have shed light onto the mechanisms by which GABAergic inhibition contributes to network operations.

1,358 citations

Journal ArticleDOI
01 Aug 2014-Science
TL;DR: Not only are PV+ interneurons involved in basic microcircuit functions, but they also play a role in complex network operations, including expansion of dynamic activity range, pattern separation, modulation of place and grid field shapes, phase precession, and gain modulation of sensory responses.
Abstract: The success story of fast-spiking, parvalbumin-positive (PV(+)) GABAergic interneurons (GABA, γ-aminobutyric acid) in the mammalian central nervous system is noteworthy. In 1995, the properties of these interneurons were completely unknown. Twenty years later, thanks to the massive use of subcellular patch-clamp techniques, simultaneous multiple-cell recording, optogenetics, in vivo measurements, and computational approaches, our knowledge about PV(+) interneurons became more extensive than for several types of pyramidal neurons. These findings have implications beyond the "small world" of basic research on GABAergic cells. For example, the results provide a first proof of principle that neuroscientists might be able to close the gaps between the molecular, cellular, network, and behavioral levels, representing one of the main challenges at the present time. Furthermore, the results may form the basis for PV(+) interneurons as therapeutic targets for brain disease in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will be able to use PV(+) interneurons for therapeutic purposes.

899 citations

Journal ArticleDOI
16 Dec 2011-Science
TL;DR: An essential role of inhibitory plasticity is suggested in the formation and maintenance of functional cortical circuitry that can accommodate synaptic memories with activity patterns that become indiscernible from the background state but can be reactivated by external stimuli.
Abstract: Cortical neurons receive balanced excitatory and inhibitory synaptic currents. Such a balance could be established and maintained in an experience-dependent manner by synaptic plasticity at inhibitory synapses. We show that this mechanism provides an explanation for the sparse firing patterns observed in response to natural stimuli and fits well with a recently observed interaction of excitatory and inhibitory receptive field plasticity. The introduction of inhibitory plasticity in suitable recurrent networks provides a homeostatic mechanism that leads to asynchronous irregular network states. Further, it can accommodate synaptic memories with activity patterns that become indiscernible from the background state but can be reactivated by external stimuli. Our results suggest an essential role of inhibitory plasticity in the formation and maintenance of functional cortical circuitry.

648 citations

Journal ArticleDOI
12 Jan 2012-Neuron
TL;DR: It is shown that parvalbumin-expressing cells strongly modulate layer 2/3 pyramidal cell spiking responses to visual stimuli while only modestly affecting their tuning properties, indicating that PV cells are ideally suited to modulate cortical gain.

581 citations


Cites result from "Differential connectivity and respo..."

  • ...…change in a consistent manner, despite clear increases in Pyr cell spiking, implies that recurrent excitatory connections between layer 2/3 Pyr cells contribute little to the overall excitatory input onto these cells during visual stimulation, as suggested by a recent study (Hofer et al., 2011)....

    [...]

  • ...The fact that synaptic excitation did not change in a consistent manner, despite clear increases in Pyr cell spiking, implies that recurrent excitatory connections between layer 2/3 Pyr cells contribute little to the overall excitatory input onto these cells during visual stimulation, as suggested by a recent study (Hofer et al., 2011)....

    [...]

  • ...Consistent with earlier reports, however, these responses were barely modulated by stimulus orientation (Sohya et al., 2007; Niell and Stryker, 2008; Kerlin et al., 2010; Zariwala et al., 2011; Ma et al., 2010; Bock et al., 2011; Hofer et al., 2011)....

    [...]

References
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Journal ArticleDOI
TL;DR: The Psychophysics Toolbox is a software package that supports visual psychophysics and its routines provide an interface between a high-level interpreted language and the video display hardware.
Abstract: The Psychophysics Toolbox is a software package that supports visual psychophysics. Its routines provide an interface between a high-level interpreted language (MATLAB on the Macintosh) and the video display hardware. A set of example programs is included with the Toolbox distribution.

16,594 citations

Journal ArticleDOI
TL;DR: A set of Cre reporter mice with strong, ubiquitous expression of fluorescent proteins of different spectra is generated and enables direct visualization of fine dendritic structures and axonal projections of the labeled neurons, which is useful in mapping neuronal circuitry, imaging and tracking specific cell populations in vivo.
Abstract: The Cre/lox system is widely used in mice to achieve cell-type-specific gene expression. However, a strong and universally responding system to express genes under Cre control is still lacking. We have generated a set of Cre reporter mice with strong, ubiquitous expression of fluorescent proteins of different spectra. The robust native fluorescence of these reporters enables direct visualization of fine dendritic structures and axonal projections of the labeled neurons, which is useful in mapping neuronal circuitry, imaging and tracking specific cell populations in vivo. Using these reporters and a high-throughput in situ hybridization platform, we are systematically profiling Cre-directed gene expression throughout the mouse brain in several Cre-driver lines, including new Cre lines targeting different cell types in the cortex. Our expression data are displayed in a public online database to help researchers assess the utility of various Cre-driver lines for cell-type-specific genetic manipulation.

5,365 citations

Journal ArticleDOI
TL;DR: This review focuses on the organizing principles that govern the diversity of inhibitory interneurons and their circuits.
Abstract: Mammals adapt to a rapidly changing world because of the sophisticated cognitive functions that are supported by the neocortex. The neocortex, which forms almost 80% of the human brain, seems to have arisen from repeated duplication of a stereotypical microcircuit template with subtle specializations for different brain regions and species. The quest to unravel the blueprint of this template started more than a century ago and has revealed an immensely intricate design. The largest obstacle is the daunting variety of inhibitory interneurons that are found in the circuit. This review focuses on the organizing principles that govern the diversity of inhibitory interneurons and their circuits.

2,854 citations

Journal ArticleDOI
04 Nov 1999-Nature
TL;DR: Two functionally distinct inhibitory networks comprising either fast-spiking (FS) or low-threshold spiking (LTS) neurons are described, which may allow each inhibitory network to function independently.
Abstract: Inhibitory interneurons are critical to sensory transformations, plasticity and synchronous activity in the neocortex There are many types of inhibitory neurons, but their synaptic organization is poorly understood Here we describe two functionally distinct inhibitory networks comprising either fast-spiking (FS) or low-threshold spiking (LTS) neurons Paired-cell recordings showed that inhibitory neurons of the same type were strongly interconnected by electrical synapses, but electrical synapses between different inhibitory cell types were rare The electrical synapses were strong enough to synchronize spikes in coupled interneurons Inhibitory chemical synapses were also common between FS cells, and between FS and LTS cells, but LTS cells rarely inhibited one another Thalamocortical synapses, which convey sensory information to the cortex, specifically and strongly excited only the FS cell network The electrical and chemical synaptic connections of different types of inhibitory neurons are specific, and may allow each inhibitory network to function independently

1,437 citations

Journal ArticleDOI
TL;DR: In vivo two-photon calcium imaging recordings indicated that whisker deflection-evoked Ca2+ transients occur in a subset of layer 2/3 neurons of the barrel cortex, demonstrating the suitability of this technique for real-time analyses of intact neuronal circuits with the resolution of individual cells.
Abstract: Two-photon calcium imaging is a powerful means for monitoring the activity of distinct neurons in brain tissue in vivo. In the mammalian brain, such imaging studies have been restricted largely to calcium recordings from neurons that were individually dye-loaded through microelectrodes. Previous attempts to use membrane-permeant forms of fluorometric calcium indicators to load populations of neurons have yielded satisfactory results only in cell cultures or in slices of immature brain tissue. Here we introduce a versatile approach for loading membrane-permeant fluorescent indicator dyes in large populations of cells. We established a pressure ejection-based local dye delivery protocol that can be used for a large spectrum of membrane-permeant indicator dyes, including calcium green-1 acetoxymethyl (AM) ester, Fura-2 AM, Fluo-4 AM, and Indo-1 AM. We applied this dye-loading protocol successfully in mouse brain tissue at any developmental stage from newborn to adult in vivo and in vitro. In vivo two-photon Ca2+ recordings, obtained by imaging through the intact skull, indicated that whisker deflection-evoked Ca2+ transients occur in a subset of layer 2/3 neurons of the barrel cortex. Thus, our results demonstrate the suitability of this technique for real-time analyses of intact neuronal circuits with the resolution of individual cells.

1,366 citations