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Oscillations of neural activity permeate sensory systems. In the visual system, broadband gamma oscillations (30-80 Hz) are thought to act as a communication mechanism underlying perception. However, these oscillations show widely varying frequency and phase, providing constraints for coordinating spike timing across areas. Here, we examined Allen Brain Observatory data and performed causal experiments to show that narrowband gamma (NBG) oscillations (50-70 Hz) propagate and synchronize throughout the awake mouse visual system. Lateral geniculate nucleus (LGN) neurons fired precisely relative to NBG phase in primary visual cortex (V1) and multiple higher visual areas (HVAs). NBG neurons across areas showed a higher likelihood of functional connectivity and stronger visual responses; remarkably, NBG neurons in LGN, preferring bright (ON) versus dark (OFF), fired at distinct NBG phases aligned across the cortical hierarchy. NBG oscillations may thus serve to coordinate spike timing across brain areas and facilitate communication of distinct visual features during perception., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The role of spatial attention for visual perception has been thoroughly studied in primates, but less so in mice. Several behavioral tasks in mice reveal spatial attentional effects, with similarities to observations in primates. Pairing these tasks with large-scale, cell-type-specific techniques could enable deeper access to underlying mechanisms, and help define the utility and limitations of resolving attentional effects on visual perception and neural activity in mice. In this Review, we evaluate behavioral and neural evidence for visual spatial attention in mice; assess how specializations of the mouse visual system and behavioral repertoire impact interpretation of spatial attentional effects; and outline how several measurement and manipulation techniques in mice could precisely test and refine models of attentional modulation across scales., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A fundamental task of the visual system is to respond to both increases and decreases of luminance with action potentials (ON and OFF responses 1-4 ). OFF responses are stronger, faster, and more salient than ON responses in primary visual cortex (V1) of both cats 5 , 6 and primates, 7 , 8 but in ferrets 9 and mice, 10 ON responses can be stronger, weaker, 11 or balanced 12 in comparison to OFF responses. These discrepancies could arise from differences in species, experimental techniques, or stimulus properties, particularly retinotopic location in the visual field, as has been speculated; 9 however, the role of retinotopy for ON/OFF dominance has not been systematically tested across multiple scales of neural activity within species. Here, we measured OFF versus ON responses across large portions of visual space with silicon probe and whole-cell patch-clamp recordings in mouse V1 and lateral geniculate nucleus (LGN). We found that OFF responses dominated in the central visual field, whereas ON and OFF responses were more balanced in the periphery. These findings were consistent across local field potential (LFP), spikes, and subthreshold membrane potential in V1, and were aligned with spatial biases in ON and OFF responses in LGN. Our findings reveal that retinotopy may provide a common organizing principle for spatial modulation of OFF versus ON processing in mammalian visual systems., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Sensory impairments are a core feature of autism spectrum disorder (ASD). These impairments affect visual perception and have been hypothesized to arise from imbalances in cortical excitatory and inhibitory activity. There is conflicting evidence for this hypothesis from several recent studies of transgenic mouse models of ASD; crucially, none have measured activity from identified excitatory and inhibitory neurons during simultaneous impairments of sensory perception. Here, we directly recorded putative excitatory and inhibitory population spiking in primary visual cortex (V1) while simultaneously measuring visual perceptual behavior in CNTNAP2-/- knockout (KO) mice. We observed quantitative impairments in the speed, accuracy, and contrast sensitivity of visual perception in KO mice. During these perceptual impairments, stimuli evoked more firing of inhibitory neurons and less firing of excitatory neurons, with reduced neural sensitivity to contrast. In addition, pervasive 3-10 Hz oscillations in superficial cortical layers 2/3 (L2/3) of KO mice degraded predictions of behavioral performance from neural activity. Our findings show that perceptual deficits relevant to ASD may be associated with elevated cortical inhibitory activity along with diminished and aberrant excitatory population activity in L2/3, a major source of feedforward projections to higher cortical regions., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Internal brain states strongly modulate sensory processing during behaviour. Studies of visual processing in primates show that attention to space selectively improves behavioural and neural responses to stimuli at the attended locations. Here we develop a visual spatial task for mice that elicits behavioural improvements consistent with the effects of spatial attention, and simultaneously measure network, cellular, and subthreshold activity in primary visual cortex. During trial-by-trial behavioural improvements, local field potential (LFP) responses to stimuli detected inside the receptive field (RF) strengthen. Moreover, detection inside the RF selectively enhances excitatory and inhibitory neuron responses to task-irrelevant stimuli and suppresses noise correlations and low frequency LFP fluctuations. Whole-cell patch-clamp recordings reveal that detection inside the RF increases synaptic activity that depolarizes membrane potential responses at the behaviorally relevant location. Our study establishes that mice display fundamental signatures of visual spatial attention spanning behavioral, network, cellular, and synaptic levels, providing new insight into rapid cognitive enhancement of sensory signals in visual cortex.

Patch clamping is the gold standard measurement technique for cell-type characterization in vivo, but it has low throughput, is difficult to scale, and requires highly skilled operation. We developed an autonomous robot that can acquire multiple consecutive patch-clamp recordings in vivo. In practice, 40 pipettes loaded into a carousel are sequentially filled and inserted into the brain, localized to a cell, used for patch clamping, and disposed. Automated visual stimulation and electrophysiology software enables functional cell-type classification of whole cell-patched cells, as we show for 37 cells in the anesthetized mouse in visual cortex (V1) layer 5. We achieved 9% yield, with 5.3 min per attempt over hundreds of trials. The highly variable and low-yield nature of in vivo patch-clamp recordings will benefit from such a standardized, automated, quantitative approach, allowing development of optimal algorithms and enabling scaling required for large-scale studies and integration with complementary techniques. NEW & NOTEWORTHY In vivo patch-clamp is the gold standard for intracellular recordings, but it is a very manual and highly skilled technique. The robot in this work demonstrates the most automated in vivo patch-clamp experiment to date, by enabling production of multiple, serial intracellular recordings without human intervention. The robot automates pipette filling, wire threading, pipette positioning, neuron hunting, break-in, delivering sensory stimulus, and recording quality control, enabling in vivo cell-type characterization.

Many factors modulate the state of cortical activity, but the importance of cortical state variability for sensory perception remains debated. We trained mice to detect spatially localized visual stimuli and simultaneously measured local field potentials and excitatory and inhibitory neuron populations across layers of primary visual cortex (V1). Cortical states with low spontaneous firing and correlations in excitatory neurons, and suppression of 3- to 7-Hz oscillations in layer 4, accurately predicted single-trial visual detection. Our results show that cortical states exert strong effects at the initial stage of cortical processing in V1 and can play a prominent role for visual spatial behavior in mice., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Primary visual cortex exhibits two types of gamma rhythm: broadband activity in the 30-90 Hz range and a narrowband oscillation seen in mice at frequencies close to 60 Hz. We investigated the sources of the narrowband gamma oscillation, the factors modulating its strength, and its relationship to broadband gamma activity. Narrowband and broadband gamma power were uncorrelated. Increasing visual contrast had opposite effects on the two rhythms: it increased broadband activity, but suppressed the narrowband oscillation. The narrowband oscillation was strongest in layer 4 and was mediated primarily by excitatory currents entrained by the synchronous, rhythmic firing of neurons in the lateral geniculate nucleus (LGN). The power and peak frequency of the narrowband gamma oscillation increased with light intensity. Silencing the cortex optogenetically did not abolish the narrowband oscillation in either LGN firing or cortical excitatory currents, suggesting that this oscillation reflects unidirectional flow of signals from thalamus to cortex., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The cortical local field potential (LFP) is a common measure of population activity, but its relationship to synaptic activity in individual neurons is not fully established. This relationship has been typically studied during anesthesia and is obscured by shared slow fluctuations. Here, we used patch-clamp recordings in visual cortex of anesthetized and awake mice to measure intracellular activity; we then applied a simple method to reveal its coupling to the simultaneously recorded LFP. LFP predicted membrane potential as accurately as synaptic currents, indicating a major role for synaptic currents in the relationship between cortical LFP and intracellular activity. During anesthesia, cortical LFP predicted excitation far better than inhibition; during wakefulness, it predicted them equally well, and visual stimulation further enhanced predictions of inhibition. These findings reveal a central role for synaptic currents, and especially inhibition, in the relationship between the subthreshold activity of individual neurons and the cortical LFP during wakefulness., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Neurons in visual cortex are connected not only locally, but also through networks of distal connectivity. These distal networks recruit both excitatory and inhibitory synapses and result in divisive normalization. Normalization is traditionally thought to result from increases in synaptic inhibition. By combining optogenetic stimulation and intracellular recordings in mouse visual cortex, we found that, on the contrary, normalization is a result of a decrease in synaptic excitation.

The activity of the cerebral cortex is thought to depend on the precise relationship between synaptic excitation and inhibition. In the visual cortex, in particular, intracellular measurements have related response selectivity to coordinated increases in excitation and inhibition. These measurements, however, have all been made during anaesthesia, which strongly influences cortical state and therefore sensory processing. The synaptic activity that is evoked by visual stimulation during wakefulness is unknown. Here we measured visually evoked responses--and the underlying synaptic conductances--in the visual cortex of anaesthetized and awake mice. Under anaesthesia, responses could be elicited from a large region of visual space and were prolonged. During wakefulness, responses were more spatially selective and much briefer. Whole-cell patch-clamp recordings of synaptic conductances showed a difference in synaptic inhibition between the two conditions. Under anaesthesia, inhibition tracked excitation in amplitude and spatial selectivity. By contrast, during wakefulness, inhibition was much stronger than excitation and had extremely broad spatial selectivity. We conclude that during wakefulness, cortical responses to visual stimulation are dominated by synaptic inhibition, restricting the spatial spread and temporal persistence of neural activity. These results provide a direct glimpse of synaptic mechanisms that control sensory responses in the awake cortex.

During natural vision, the entire visual field is stimulated by images rich in spatiotemporal structure. Although many visual system studies restrict stimuli to the classical receptive field (CRF), it is known that costimulation of the CRF and the surrounding nonclassical receptive field (nCRF) increases neuronal response sparseness. The cellular and network mechanisms underlying increased response sparseness remain largely unexplored. Here we show that combined CRF + nCRF stimulation increases the sparseness, reliability, and precision of spiking and membrane potential responses in classical regular spiking (RS(C)) pyramidal neurons of cat primary visual cortex. Conversely, fast-spiking interneurons exhibit increased activity and decreased selectivity during CRF + nCRF stimulation. The increased sparseness and reliability of RS(C) neuron spiking is associated with increased inhibitory barrages and narrower visually evoked synaptic potentials. Our experimental observations were replicated with a simple computational model, suggesting that network interactions among neuronal subtypes ultimately sharpen recurrent excitation, producing specific and reliable visual responses.

Spontaneous activity within local circuits affects the integrative properties of neurons and networks. We have previously shown that neocortical network activity exhibits a balance between excitatory and inhibitory synaptic potentials, and such activity has significant effects on synaptic transmission, action potential generation, and spike timing. However, whether such activity facilitates or reduces sensory responses has yet to be clearly determined. We examined this hypothesis in the primary visual cortex in vivo during slow oscillations in ketamine-xylazine anesthetized cats. We measured network activity (Up states) with extracellular recording, while simultaneously recording postsynaptic potentials (PSPs) and action potentials in nearby cells. Stimulating the receptive field revealed that spiking responses of both simple and complex cells were significantly enhanced (>2-fold) during network activity, as were spiking responses to intracellular injection of varying amplitude artificial conductance stimuli. Visually evoked PSPs were not significantly different in amplitude during network activity or quiescence; instead, spontaneous depolarization caused by network activity brought these evoked PSPs closer to firing threshold. Further examination revealed that visual responsiveness was gradually enhanced by progressive membrane potential depolarization. These spontaneous depolarizations enhanced responsiveness to stimuli of varying contrasts, resulting in an upward (multiplicative) scaling of the contrast response function. Our results suggest that small increases in ongoing balanced network activity that result in depolarization may provide a rapid and generalized mechanism to control the responsiveness (gain) of cortical neurons, such as occurs during shifts in spatial attention.

Understanding brain function requires repeatable measurements of neural activity across multiple scales and multiple brain areas. In mice, large scale cortical neural activity evokes hemodynamic changes readily observable with intrinsic signal imaging (ISI). Pairing ISI with visual stimulation allows identification of primary visual cortex (V1) and higher visual areas (HVAs), typically through cranial windows that thin or remove the skull. These procedures can diminish long-term mechanical and physiological stability required for delicate electrophysiological measurements made weeks to months after imaging (e.g., in subjects undergoing behavioral training). Here, we optimized and directly validated an intact skull ISI system in mice. We first assessed how imaging quality and duration affect reliability of retinotopic maps in V1 and HVAs. We then verified ISI map retinotopy in V1 and HVAs with targeted, multi-site electrophysiology several weeks after imaging. Reliable ISI maps of V1 and multiple HVAs emerged with ~ 60 trials of imaging (65 ± 6 min), and these showed strong correlation to local field potential (LFP) retinotopy in superficial cortical layers (r2 = 0.74–0.82). This system is thus well-suited for targeted, multi-area electrophysiology weeks to months after imaging. We provide detailed instructions and code for other researchers to implement this system. [ABSTRACT FROM AUTHOR]