Narrowband gamma oscillations propagate and synchronize throughout the mouse thalamocortical visual system.

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.

Optimizing intact skull intrinsic signal imaging for subsequent targeted electrophysiology across mouse visual cortex.

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.

Spatial modulation of dark versus bright stimulus responses in the mouse visual system.

A fundamental task of the visual system is to respond to both increases and decreases of luminance with action potentials (ON and OFF responses1-4). OFF responses are stronger, faster, and more salient than ON responses in primary visual cortex (V1) of both cats5,6 and primates,7,8 but in ferrets9 and mice,10 ON responses can be stronger, weaker,11 or balanced12 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.

Diminished Cortical Excitation and Elevated Inhibition During Perceptual Impairments in a Mouse Model of Autism.

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.

Spatial attention enhances network, cellular and subthreshold responses in mouse visual cortex.

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.

Cortical State Fluctuations across Layers of V1 during Visual Spatial Perception.

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.