Cristopher M. Niell

Modulation of Visual Responses by Behavioral State in Mouse Visual Cortex

Studies of visual processing in rodents have conventionally been performed on anesthetized animals, precluding examination of the effects of behavior on visually evoked responses. We have now studied the response properties of neurons in primary visual cortex of awake mice that were allowed to run on a freely rotating spherical treadmill with their heads fixed. Most neurons showed more than a doubling of visually evoked firing rate as the animal transitioned from standing still to running, without changes in spontaneous firing or stimulus selectivity. Tuning properties in the awake animal were similar to those measured previously in anesthetized animals. Response magnitude in the lateral geniculate nucleus did not increase with locomotion, demonstrating that the striking change in responsiveness did not result from peripheral effects at the eye. Interestingly, some narrow-spiking cells were spontaneously active during running but suppressed by visual stimuli. These results demonstrate powerful cell-type-specific modulation of visual processing by behavioral state in awake mice.

Highly Selective Receptive Fields in Mouse Visual Cortex

Genetic methods available in mice are likely to be powerful tools in dissecting cortical circuits. However, the visual cortex, in which sensory coding has been most thoroughly studied in other species, has essentially been neglected in mice perhaps because of their poor spatial acuity and the lack of columnar organization such as orientation maps. We have now applied quantitative methods to characterize visual receptive fields in mouse primary visual cortex V1 by making extracellular recordings with silicon electrode arrays in anesthetized mice. We used current source density analysis to determine laminar location and spike waveforms to discriminate putative excitatory and inhibitory units. We find that, although the spatial scale of mouse receptive fields is up to one or two orders of magnitude larger, neurons show selectivity for stimulus parameters such as orientation and spatial frequency that is near to that found in other species. Furthermore, typical response properties such as linear versus nonlinear spatial summation (i.e., simple and complex cells) and contrastinvariant tuning are also present in mouse V1 and correlate with laminar position and cell type. Interestingly, we find that putative inhibitory neurons generally have less selective, and nonlinear, responses. This quantitative description of receptive field properties should facilitate the use of mouse visual cortex as a system to address longstanding questions of visual neuroscience and cortical processing.

Diverse visual features encoded in mouse lateral geniculate nucleus

The thalamus is crucial in determining the sensory information conveyed to cortex. In the visual system, the thalamic lateral geniculate nucleus (LGN) is generally thought to encode simple center-surround receptive fields, which are combined into more sophisticated features in cortex, such as orientation and direction selectivity. However, recent evidence suggests that a more diverse set of retinal ganglion cells projects to the LGN. We therefore used multisite extracellular recordings to define the repertoire of visual features represented in the LGN of mouse, an emerging model for visual processing. In addition to center-surround cells, we discovered a substantial population with more selective coding properties, including direction and orientation selectivity, as well as neurons that signal absence of contrast in a visual scene. The direction and orientation selective neurons were enriched in regions that match the termination zones of direction selective ganglion cells from the retina, suggesting a source for their tuning. Together, these data demonstrate that the mouse LGN contains a far more elaborate representation of the visual scene than current models posit. These findings should therefore have a significant impact on our understanding of the computations performed in mouse visual cortex.

What can mice tell us about how vision works

Understanding the neural basis of visual perception is a long-standing fundamental goal of neuroscience. Historically, most vision studies were carried out on humans, macaques and cats. Over the past 5 years, however, a growing number of researchers have begun using mice to parse the mechanisms underlying visual processing; the rationale is that, despite having relatively poor acuity, mice are unmatched in terms of the variety and sophistication of tools available to label, monitor and manipulate specific cell types and circuits. In this review, we discuss recent advances in understanding the mouse visual system at the anatomical, receptive field and perceptual level, focusing on the opportunities and constraints those features provide toward the goal of understanding how vision works.

Identification of a Brainstem Circuit Regulating Visual Cortical State in Parallel with Locomotion

Sensory processing is dependent upon behavioral state. In mice, locomotion is accompanied by changes in cortical state and enhanced visual responses. Although recent studies have begun to elucidate intrinsic cortical mechanisms underlying this effect, the neural circuits that initially couple locomotion to cortical processing are unknown. The mesencephalic locomotor region (MLR) has been shown to be capable of initiating running and is associated with the ascending reticular activating system. Here, we find that optogenetic stimulation of the MLR in awake, head-fixed mice can induce both locomotion and increases in the gain of cortical responses. MLR stimulation below the threshold for overt movement similarly changed cortical processing, revealing that MLRs effects on cortex are dissociable from locomotion. Likewise, stimulation of MLR projections to the basal forebrain also enhanced cortical responses, suggesting a pathway linking the MLR to cortex. These studies demonstrate that the MLR regulates cortical state in parallel with locomotion.

Selective disruption of one Cartesian axis of cortical maps and receptive fields by deficiency in ephrin-As and structured activity.

The topographic representation of visual space is preserved from retina to thalamus to cortex. We have previously shown that precise mapping of thalamocortical projections requires both molecular cues and structured retinal activity. To probe the interaction between these two mechanisms, we studied mice deficient in both ephrin-As and retinal waves. Functional and anatomical cortical maps in these mice were nearly abolished along the nasotemporal (azimuth) axis of the visual space. Both the structure of single-cell receptive fields and large-scale topography were severely distorted. These results demonstrate that ephrin-As and structured neuronal activity are two distinct pathways that mediate map formation in the visual cortex and together account almost completely for the formation of the azimuth map. Despite the dramatic disruption of azimuthal topography, the dorsoventral (elevation) map was relatively normal, indicating that the two axes of the cortical map are organized by separate mechanisms.

Layer-Specific Refinement of Visual Cortex Function after Eye Opening in the Awake Mouse

The laminar structure and conserved cellular organization of mouse visual cortex provide a useful model to determine the mechanisms underlying the development of visual system function. However, the normal development of many receptive field properties has not yet been thoroughly quantified, particularly with respect to layer identity and in the absence of anesthesia. Here, we use multisite electrophysiological recording in the awake mouse across an extended period of development, starting at eye opening, to measure receptive field properties and behavioral-state modulation of responsiveness. We find selective responses for orientation, direction, and spatial frequency at eye opening, which are similar across cortical layers. After this initial similarity, we observe layer-specific maturation of orientation selectivity, direction selectivity, and linearity over the following week. Developmental increases in selectivity are most robust and similar between layers 2–4, whereas layers 5 and 6 undergo distinct refinement patterns. Finally, we studied layer-specific behavioral-state modulation of cortical activity and observed a striking reorganization in the effects of running on response gain. During week 1 after eye opening, running increases responsiveness in layers 4 and 5, whereas in adulthood, the effects of running are most pronounced in layer 2/3. Together, these data demonstrate that response selectivity is present in all layers of the primary visual cortex (V1) at eye opening in the awake mouse and identify the features of basic V1 function that are further shaped over this early developmental period in a layer-specific manner.

Vision Drives Accurate Approach Behavior during Prey Capture in Laboratory Mice

The ability to genetically identify and manipulate neural circuits in the mouse is rapidly advancing our understanding of visual processing in the mammalian brain [1, 2]. However, studies investigating the circuitry that underlies complex ethologically relevant visual behaviors in the mouse have been primarily restricted to fear responses [3-5]. Here, we show that a laboratory strain of mouse (Mus musculus, C57BL/6J) robustly pursues, captures, and consumes live insect prey and that vision is necessary for mice to perform the accurate orienting and approach behaviors leading to capture. Specifically, we differentially perturbed visual or auditory input in mice and determined that visual input is required for accurate approach, allowing maintenance of bearing to within 11° of the target on average during pursuit. While mice were able to capture prey without vision, the accuracy of their approaches and capture rate dramatically declined. To better explore the contribution of vision to this behavior, we developed a simple assay that isolated visual cues and simplified analysis of the visually guided approach. Together, our results demonstrate that laboratory mice are capable of exhibiting dynamic and accurate visually guided approach behaviors and provide a means to estimate the visual features that drive behavior within an ethological context.

Cell Types, Circuits, and Receptive Fields in the Mouse Visual Cortex

Over the past decade, the mouse has emerged as an important model system for studying cortical function, owing to the advent of powerful tools that can record and manipulate neural activity in intact neural circuits. This advance has been particularly prominent in the visual cortex, where studies in the mouse have begun to bridge the gap between cortical structure and function, allowing investigators to determine the circuits that underlie specific visual computations. This review describes the advances in our understanding of the mouse visual cortex, including neural coding, the role of different cell types, and links between vision and behavior, and discusses how recent findings and new approaches can guide future studies.

Reduced Cortical Activity Impairs Development and Plasticity after Neonatal Hypoxia Ischemia

Survivors of preterm birth are at high risk of pervasive cognitive and learning impairments, suggesting disrupted early brain development. The limits of viability for preterm birth encompass the third trimester of pregnancy, a “precritical period” of activity-dependent development characterized by the onset of spontaneous and evoked patterned electrical activity that drives neuronal maturation and formation of cortical circuits. Reduced background activity on electroencephalogram (EEG) is a sensitive marker of brain injury in human preterm infants that predicts poor neurodevelopmental outcome. We studied a rodent model of very early hypoxic–ischemic brain injury to investigate effects of injury on both general background and specific patterns of cortical activity measured with EEG. EEG background activity is depressed transiently after moderate hypoxia–ischemia with associated loss of spindle bursts. Depressed activity, in turn, is associated with delayed expression of glutamate receptor subunits and transporters. Cortical pyramidal neurons show reduced dendrite development and spine formation. Complementing previous observations in this model of impaired visual cortical plasticity, we find reduced somatosensory whisker barrel plasticity. Finally, EEG recordings from human premature newborns with brain injury demonstrate similar depressed background activity and loss of bursts in the spindle frequency band. Together, these findings suggest that abnormal development after early brain injury may result in part from disruption of specific forms of brain activity necessary for activity-dependent circuit development. SIGNIFICANCE STATEMENT Preterm birth and term birth asphyxia result in brain injury from inadequate oxygen delivery and constitute a major and growing worldwide health problem. Poor outcomes are noted in a majority of very premature (<25 weeks gestation) newborns, resulting in death or life-long morbidity with motor, sensory, learning, behavioral, and language disabilities that limit academic achievement and well-being. Limited progress has been made to develop therapies that improve neurologic outcomes. The overall objective of this study is to understand the effect of early brain injury on activity-dependent brain development and cortical plasticity to develop new treatments that will optimize repair and recovery after brain injury.