Response sub-additivity and variability quenching in visual cortex.

Sub-additivity and variability are ubiquitous response motifs in the primary visual cortex (V1). Response sub-additivity enables the construction of useful interpretations of the visual environment, whereas response variability indicates the factors that limit the precision with which the brain can do this. There is increasing evidence that experimental manipulations that elicit response sub-additivity often also quench response variability. Here, we provide an overview of these phenomena and suggest that they may have common origins. We discuss empirical findings and recent model-based insights into the functional operations, computational objectives and circuit mechanisms underlying V1 activity. These different modelling approaches all predict that response sub-additivity and variability quenching often co-occur. The phenomenology of these two response motifs, as well as many of the insights obtained about them in V1, generalize to other cortical areas. Thus, the connection between response sub-additivity and variability quenching may be a canonical motif across the cortex.

Mice Discriminate Stereoscopic Surfaces Without Fixating in Depth.

Stereopsis is a ubiquitous feature of primate mammalian vision, but little is known about if and how rodents such as mice use stereoscopic vision. We used random dot stereograms to test for stereopsis in male and female mice, and they were able to discriminate near from far surfaces over a range of disparities, with diminishing performance for small and large binocular disparities. Based on two-photon measurements of disparity tuning, the range of disparities represented in the visual cortex aligns with the behavior and covers a broad range of disparities. When we examined their binocular eye movements, we found that, unlike primates, mice did not systematically vary relative eye positions or use vergence eye movements when presented with different disparities. Nonetheless, the representation of disparity tuning was wide enough to capture stereoscopic information over a range of potential vergence angles. Although mice share fundamental characteristics of stereoscopic vision with primates and carnivores, their lack of disparity-dependent vergence eye movements and wide neuronal representation suggests that they may use a distinct strategy for stereopsis.SIGNIFICANCE STATEMENT Binocular vision allows us to derive depth information by comparing right and left eye information. We characterized binocular integration in mice because tools exist in these animals to dissect the underlying neural circuitry for binocular vision. Using random dot stereograms, we find that behavior and disparity tuning in the visual cortex share fundamental characteristics with primates, but we did not observe any evidence of disparity-dependent changes in vergence angle. We propose that mice use a distinct strategy of stereopsis compared with primates by using a broad range of disparities to encode depth over a large field of view and to compensate for nonstereoscopic changes in vergence angle that arise during natural behavior.

Multiple Timescales Account for Adaptive Responses across Sensory Cortices.

Sensory systems encounter remarkably diverse stimuli in the external environment. Natural stimuli exhibit timescales and amplitudes of variation that span a wide range. Mechanisms of adaptation, a ubiquitous feature of sensory systems, allow for the accommodation of this range of scales. Are there common rules of adaptation across different sensory modalities? We measured the membrane potential responses of individual neurons in the visual, somatosensory, and auditory cortices of male and female mice to discrete, punctate stimuli delivered at a wide range of fixed and nonfixed frequencies. We find that the adaptive profile of the response is largely preserved across these three areas, exhibiting attenuation and responses to the cessation of stimulation, which are signatures of response to changes in stimulus statistics. We demonstrate that these adaptive responses can emerge from a simple model based on the integration of fixed filters operating over multiple time scales.SIGNIFICANCE STATEMENT Our recent sensations affect our current expectations and perceptions of the environment. Neural correlates of this process exist throughout the brain and are loosely termed adaptation. Adaptive processes have been described across sensory cortices, but direct comparisons of these processes have not been possible because paradigms have been tailored specifically for each modality. We developed a common stimulus set that was used to characterize adaptation in somatosensory, visual, and auditory cortex. We describe here the similarities and differences in adaptation across these cortical areas and demonstrate that adaptive responses may emerge from a set of static filters that operate over a broad range of timescales.

Interocular velocity cues elicit vergence eye movements in mice.

We stabilize the dynamic visual world on our retina by moving our eyes in response to motion signals. Coordinated movements between the two eyes are characterized as version when both eyes move in the same direction and vergence when the two eyes move in opposite directions. Vergence eye movements are necessary to track objects in three dimensions. In primates they can be elicited by intraocular differences in either spatial signals (disparity) or velocity, requiring the integration of left and right eye inputs. Whether mice are capable of similar behaviors is not known. To address this issue, we measured vergence eye movements in mice using a stereoscopic stimulus known to elicit vergence eye movements in primates. We found that mice also exhibit vergence eye movements, although at a low gain and that the primary driver of these vergence eye movements is interocular motion. Spatial disparity cues alone are ineffective. We also found that the vergence eye movements we observed in mice were robust to silencing visual cortex and to manipulations that disrupt the normal development of binocularity in visual cortex. A sublinear combination of motor commands driven by monocular signals is sufficient to account for our results.NEW & NOTEWORTHY The visual system integrates signals from the left and right eye to generate a representation of the world in depth. The binocular integration of signals may be observed from the coordinated vergence eye movements elicited by object motion in depth. We explored the circuits and signals responsible for these vergence eye movements in rodent and find these vergence eye movements are generated by a comparison of the motion and not spatial visual signals.

Sensory stimulation shifts visual cortex from synchronous to asynchronous states.

In the mammalian cerebral cortex, neural responses are highly variable during spontaneous activity and sensory stimulation. To explain this variability, the cortex of alert animals has been proposed to be in an asynchronous high-conductance state in which irregular spiking arises from the convergence of large numbers of uncorrelated excitatory and inhibitory inputs onto individual neurons. Signatures of this state are that a neuron's membrane potential (Vm) hovers just below spike threshold, and its aggregate synaptic input is nearly Gaussian, arising from many uncorrelated inputs. Alternatively, irregular spiking could arise from infrequent correlated input events that elicit large fluctuations in Vm (refs 5, 6). To distinguish between these hypotheses, we developed a technique to perform whole-cell Vm measurements from the cortex of behaving monkeys, focusing on primary visual cortex (V1) of monkeys performing a visual fixation task. Here we show that, contrary to the predictions of an asynchronous state, mean Vm during fixation was far from threshold (14 mV) and spiking was triggered by occasional large spontaneous fluctuations. Distributions of Vm values were skewed beyond that expected for a range of Gaussian input, but were consistent with synaptic input arising from infrequent correlated events. Furthermore, spontaneous fluctuations in Vm were correlated with the surrounding network activity, as reflected in simultaneously recorded nearby local field potential. Visual stimulation, however, led to responses more consistent with an asynchronous state: mean Vm approached threshold, fluctuations became more Gaussian, and correlations between single neurons and the surrounding network were disrupted. These observations show that sensory drive can shift a common cortical circuitry from a synchronous to an asynchronous state.

Binocular Disparity Selectivity Weakened after Monocular Deprivation in Mouse V1.

Experiences during the critical period sculpt the circuitry within the neocortex, leading to changes in the functional responses of sensory neurons. Monocular deprivation (MD) during the visual critical period causes shifts in ocular preference, or dominance, toward the open eye in primary visual cortex (V1) and disrupts the normal development of acuity. In carnivores and primates, MD also disrupts the emergence of binocular disparity selectivity, a cue resulting from integrating ocular inputs. This disruption may be a result of the increase in neurons driven exclusively by the open eye that follows deprivation or a result of a mismatch in the convergence of ocular inputs. To distinguish between these possibilities, we measured the ocular dominance (OD) and disparity selectivity of neurons from male and female mouse V1 following MD. Normal mouse V1 neurons are dominated by contralateral eye input and contralateral eye deprivation shifts mouse V1 neurons toward more balanced responses between the eyes. This shift toward binocularity, as assayed by OD, decreased disparity sensitivity. MD did not alter the initial maturation of binocularity, as disparity selectivity before the MD was indistinguishable from normal mature animals. Decreased disparity tuning was most pronounced in binocular and ipsilaterally biased neurons, which are the populations that have undergone the largest shifts in OD. In concert with the decline in disparity selectivity, we observed a shift toward lower spatial frequency selectivity for the ipsilateral eye following MD. These results suggest an emergence of novel synaptic inputs during MD that disrupt the representation of disparity selectivity.SIGNIFICANCE STATEMENT We demonstrate that monocular deprivation during the developmental critical period impairs binocular integration in mouse primary visual cortex. This impairment occurs despite an increase in the degree to which neurons become more binocular. We further demonstrate that our deprivation did not impair the maturation of disparity selectivity. Disparity selectivity has already reached a matured level before the monocular deprivation. The loss of disparity tuning is primarily observed in neurons dominated by the open eye, suggesting a link between altered inputs and loss of disparity sensitivity. These results suggest that new inputs following deprivation may not maintain the precise spatial relationship between the two eye inputs required for disparity selectivity.

Functional characterization and spatial clustering of visual cortical neurons in the predatory grasshopper mouse Onychomys arenicola.

Mammalian neocortical circuits are functionally organized such that the selectivity of individual neurons systematically shifts across the cortical surface, forming a continuous map. Maps of the sensory space exist in cortex, such as retinotopic maps in the visual system or tonotopic maps in the auditory system, but other functional response properties also may be similarly organized. For example, many carnivores and primates possess a map for orientation selectivity in primary visual cortex (V1), whereas mice, rabbits, and the gray squirrel lack orientation maps. In this report we show that a carnivorous rodent with predatory behaviors, the grasshopper mouse (Onychomys arenicola), lacks a canonical columnar organization of orientation preference in V1; however, neighboring neurons within 50 µm exhibit related tuning preference. Using a combination of two-photon microscopy and extracellular electrophysiology, we demonstrate that the functional organization of visual cortical neurons in the grasshopper mouse is largely the same as in the C57/BL6 laboratory mouse. We also find similarity in the selectivity for stimulus orientation, direction, and spatial frequency. Our results suggest that the properties of V1 neurons across rodent species are largely conserved.NEW & NOTEWORTHY Carnivores and primates possess a map for orientation selectivity in primary visual cortex (V1), whereas rodents and lagomorphs lack this organization. We examine, for the first time, V1 of a wild carnivorous rodent with predatory behaviors, the grasshopper mouse (Onychomys arenicola). We demonstrate the cellular organization of V1 in the grasshopper mouse is largely the same as the C57/BL6 laboratory mouse, suggesting that V1 neuron properties across rodent species are largely conserved.

Orientation selectivity in the visual cortex of the nine-banded armadillo.

Orientation selectivity in primary visual cortex (V1) has been proposed to reflect a canonical computation performed by the neocortical circuitry. Although orientation selectivity has been reported in all mammals examined to date, the degree of selectivity and the functional organization of selectivity vary across mammalian clades. The differences in degree of orientation selectivity are large, from reports in marsupials that only a small subset of neurons are selective to studies in carnivores, in which it is rare to find a neuron lacking selectivity. Furthermore, the functional organization in cortex varies in that the primate and carnivore V1 is characterized by an organization in which nearby neurons share orientation preference while other mammals such as rodents and lagomorphs either lack or have only extremely weak clustering. To gain insight into the evolutionary emergence of orientation selectivity, we examined the nine-banded armadillo, a species within the early placental clade Xenarthra. Here we use a combination of neuroimaging, histological, and electrophysiological methods to identify the retinofugal pathways, locate V1, and for the first time examine the functional properties of V1 neurons in the armadillo (Dasypus novemcinctus) V1. Individual neurons were strongly sensitive to the orientation and often the direction of drifting gratings. We uncovered a wide range of orientation preferences but found a bias for horizontal gratings. The presence of strong orientation selectivity in armadillos suggests that the circuitry responsible for this computation is common to all placental mammals.NEW & NOTEWORTHY The current study shows that armadillo primary visual cortex (V1) neurons share the signature properties of V1 neurons of primates, carnivorans, and rodents. Furthermore, these neurons exhibit a degree of selectivity for stimulus orientation and motion direction similar to that found in primate V1. Our findings in armadillo visual cortex suggest that the functional properties of V1 neurons emerged early in the mammalian lineage, near the time of the divergence of marsupials.

Functional characterization of spikelet activity in the primary visual cortex.

KEY POINTS: In vivo whole-cell patch-clamp recordings in cat visual cortex revealed small deflections in the membrane potential of neurons, termed spikelets. Spikelet statistics and functional properties suggest these deflections originate from a single, nearby cell. Spikelets shared a number sensory selectivities with the principal neuron including orientation selectivity, receptive field location and eye preference. Principal neurons and spikelets did not, however, generally share preferences for depth (binocular disparity). Cross-correlation of spikelet activity and membrane potential revealed direct effects on the membrane potential of some principal neurons, suggesting that these cells were synaptically coupled or received common input from the cortical network. Other spikelet-neuron pairs revealed indirect effects, likely to be the result of correlated network events. ABSTRACT: Intracellular recordings in the neocortex reveal not only the membrane potential of neurons, but small unipolar or bipolar deflections that are termed spikelets. Spikelets have been proposed to originate from various sources, including active dendritic mechanisms, gap junctions and extracellular signals. Here we examined the functional characteristics of spikelets measured in neurons from cat primary visual cortex in vivo. Spiking statistics and our functional characterization of spikelet activity indicate that spikelets originate from a separate, nearby cell. Spikelet kinetics and lack of a direct effect on spikelet activity from hyperpolarizing current injection suggest they do not arise from electrical coupling to the principal neuron being recorded. Spikelets exhibited matched orientation tuning preference and ocular dominance to the principal neuron. In contrast, binocular disparity preferences of spikelets and the principal neuron were unrelated. Finally, we examined the impact of spikelets on the principal neuron's membrane potential; we did observe some records for which spikelets were correlated with the membrane potential of the principal neuron, suggesting that these neurons were synaptically coupled or received common input from the cortical network.

Motion dependence of smooth pursuit eye movements in the marmoset.

Smooth pursuit eye movements stabilize slow-moving objects on the retina by matching eye velocity with target velocity. Two critical components are required to generate smooth pursuit: first, because it is a voluntary eye movement, the subject must select a target to pursue to engage the tracking system; and second, generating smooth pursuit requires a moving stimulus. We examined whether this behavior also exists in the common marmoset, a New World primate that is increasingly attracting attention as a genetic model for mental disease and systems neuroscience. We measured smooth pursuit in two marmosets, previously trained to perform fixation tasks, using the standard Rashbass step-ramp pursuit paradigm. We first measured the aspects of visual motion that drive pursuit eye movements. Smooth eye movements were in the same direction as target motion, indicating that pursuit was driven by target movement rather than by displacement. Both the open-loop acceleration and closed-loop eye velocity exhibited a linear relationship with target velocity for slow-moving targets, but this relationship declined for higher speeds. We next examined whether marmoset pursuit eye movements depend on an active engagement of the pursuit system by measuring smooth eye movements evoked by small perturbations of motion from fixation or during pursuit. Pursuit eye movements were much larger during pursuit than from fixation, indicating that pursuit is actively gated. Several practical advantages of the marmoset brain, including the accessibility of the middle temporal (MT) area and frontal eye fields at the cortical surface, merit its utilization for studying pursuit movements.

Strabismus disrupts binocular synaptic integration in primary visual cortex.

Visual disruption early in development dramatically changes how primary visual cortex neurons integrate binocular inputs. The disruption is paradigmatic for investigating the synaptic basis of long-term changes in cortical function, because the primary visual cortex is the site of binocular convergence. The underlying alterations in circuitry by visual disruption remain poorly understood. Here we compare membrane potential responses, observed via whole-cell recordings in vivo, of primary visual cortex neurons in normal adult cats with those of cats in which strabismus was induced before the developmental critical period. In strabismic cats, we observed a dramatic shift in the ocular dominance distribution of simple cells, the first stage of visual cortical processing, toward responding to one eye instead of both, but not in complex cells, which receive inputs from simple cells. Both simple and complex cells no longer conveyed the binocular information needed for depth perception based on binocular cues. There was concomitant binocular suppression such that responses were weaker with binocular than with monocular stimulation. Our estimates of the excitatory and inhibitory input to single neurons indicate binocular suppression that was not evident in synaptic excitation, but arose de novo because of synaptic inhibition. Further constraints on circuit models of plasticity result from indications that the ratio of excitation to inhibition evoked by monocular stimulation decreased mainly for nonpreferred eye stimulation. Although we documented changes in synaptic input throughout primary visual cortex, a circuit model with plasticity at only thalamocortical synapses is sufficient to account for our observations.

Emergence of orientation selectivity in the Mammalian visual pathway.

Orientation selectivity is a property of mammalian primary visual cortex (V1) neurons, yet its emergence along the visual pathway varies across species. In carnivores and primates, elongated receptive fields first appear in V1, whereas in lagomorphs such receptive fields emerge earlier, in the retina. Here we examine the mouse visual pathway and reveal the existence of orientation selectivity in lateral geniculate nucleus (LGN) relay cells. Cortical inactivation does not reduce this orientation selectivity, indicating that cortical feedback is not its source. Orientation selectivity is similar for LGN relay cells spiking and subthreshold input to V1 neurons, suggesting that cortical orientation selectivity is inherited from the LGN in mouse. In contrast, orientation selectivity of cat LGN relay cells is small relative to subthreshold inputs onto V1 simple cells. Together, these differences show that although orientation selectivity exists in visual neurons of both rodents and carnivores, its emergence along the visual pathway, and thus its underlying neuronal circuitry, is fundamentally different.

Interactions between Saccades and Smooth Pursuit Eye Movements in Marmosets.

Animals use a combination of eye movements to track moving objects. These different eye movements need to be coordinated for successful tracking, requiring interactions between the systems involved. Here, we study the interaction between the saccadic and smooth pursuit eye movement systems in marmosets. Using a single-target pursuit task, we show that saccades cause an enhancement in pursuit following a saccade. Using a two-target pursuit task, we show that this enhancement in pursuit is selective toward the motion of the target selected by the saccade, irrespective of any biases in pursuit prior to the saccade. These experiments highlight the similarities in the functioning of saccadic and smooth pursuit eye movement systems across primates.

Interactions between saccades and smooth pursuit eye movements in marmosets.

Animals use a combination of eye movements to track moving objects. These different eye movements need to be coordinated for successful tracking, requiring interactions between the systems involved. Here, we study the interaction between the saccadic and smooth pursuit eye movement systems in marmosets. Using a single target pursuit task, we show that saccades cause an enhancement in pursuit following a saccade. Using a two-target pursuit task, we show that this enhancement in pursuit is selective towards the motion of the target selected by the saccade, irrespective of any biases in pursuit prior to the saccade. These experiments highlight the similarities in the functioning of saccadic and smooth pursuit eye movement systems across primates. SIGNIFICANCE STATEMENT: We study the coordination between the smooth-pursuit and saccadic eye movement systems in marmosets using single and multiple object motions. We find that saccade to a target increases pursuit velocity towards the target. If multiple objects are visible, saccade choice makes pursuit more selective towards the saccade target. Our results show that coordination between different eye movement systems to successfully track moving objects is similar between marmosets and primates.

Primate neocortex performs balanced sensory amplification.

The sensory cortex amplifies relevant features of external stimuli. This sensitivity and selectivity arise through the transformation of inputs by cortical circuitry. We characterize the circuit mechanisms and dynamics of cortical amplification by making large-scale simultaneous measurements of single cells in awake primates and testing computational models. By comparing network activity in both driven and spontaneous states with models, we identify the circuit as operating in a regime of non-normal balanced amplification. Incoming inputs are strongly but transiently amplified by strong recurrent feedback from the disruption of excitatory-inhibitory balance in the network. Strong inhibition rapidly quenches responses, thereby permitting the tracking of time-varying stimuli.

Exact Analysis of the Subthreshold Variability for Conductance-Based Neuronal Models with Synchronous Synaptic Inputs.

The spiking activity of neocortical neurons exhibits a striking level of variability, even when these networks are driven by identical stimuli. The approximately Poisson firing of neurons has led to the hypothesis that these neural networks operate in the asynchronous state. In the asynchronous state, neurons fire independently from one another, so that the probability that a neuron experience synchronous synaptic inputs is exceedingly low. While the models of asynchronous neurons lead to observed spiking variability, it is not clear whether the asynchronous state can also account for the level of subthreshold membrane potential variability. We propose a new analytical framework to rigorously quantify the subthreshold variability of a single conductance-based neuron in response to synaptic inputs with prescribed degrees of synchrony. Technically, we leverage the theory of exchangeability to model input synchrony via jump-process-based synaptic drives; we then perform a moment analysis of the stationary response of a neuronal model with all-or-none conductances that neglects postspiking reset. As a result, we produce exact, interpretable closed forms for the first two stationary moments of the membrane voltage, with explicit dependence on the input synaptic numbers, strengths, and synchrony. For biophysically relevant parameters, we find that the asynchronous regime yields realistic subthreshold variability (voltage variance ≃4-9 mV2) only when driven by a restricted number of large synapses, compatible with strong thalamic drive. By contrast, we find that achieving realistic subthreshold variability with dense cortico-cortical inputs requires including weak but nonzero input synchrony, consistent with measured pairwise spiking correlations. We also show that, without synchrony, the neural variability averages out to zero for all scaling limits with vanishing synaptic weights, independent of any balanced state hypothesis. This result challenges the theoretical basis for mean-field theories of the asynchronous state.

Mammals Achieve Common Neural Coverage of Visual Scenes Using Distinct Sampling Behaviors.

Most vertebrates use head and eye movements to quickly change gaze orientation and sample different portions of the environment with periods of stable fixation. Visual information must be integrated across fixations to construct a complete perspective of the visual environment. In concert with this sampling strategy, neurons adapt to unchanging input to conserve energy and ensure that only novel information from each fixation is processed. We demonstrate how adaptation recovery times and saccade properties interact and thus shape spatiotemporal tradeoffs observed in the motor and visual systems of mice, cats, marmosets, macaques, and humans. These tradeoffs predict that in order to achieve similar visual coverage over time, animals with smaller receptive field sizes require faster saccade rates. Indeed, we find comparable sampling of the visual environment by neuronal populations across mammals when integrating measurements of saccadic behavior with receptive field sizes and V1 neuronal density. We propose that these mammals share a common statistically driven strategy of maintaining coverage of their visual environment over time calibrated to their respective visual system characteristics.

A retinal source of spatial contrast gain control.

Sensory cortex is able to encode a broad range of stimulus features despite a great variation in signal strength. In cat primary visual cortex (V1), for example, neurons are able to extract stimulus features like orientation or spatial configuration over a wide range of stimulus contrasts. The contrast-invariant spatial tuning found in V1 neuron responses has been modeled as a gain control mechanism, but at which stage of the visual pathway it emerges has remained unclear. Here we describe our findings that contrast-invariant spatial tuning occurs not only in the responses of lateral geniculate nucleus (LGN) relay cells but also in their afferent retinal input. Our evidence suggests that a similar contrast-invariant mechanism is found throughout the stages of the early visual pathway, and that the contrast-invariant spatial selectivity is evident in both retinal ganglion cell and LGN cell responses.

Binocular integration and disparity selectivity in mouse primary visual cortex.

Signals from the two eyes are first integrated in primary visual cortex (V1). In many mammals, this binocular integration is an important first step in the development of stereopsis, the perception of depth from disparity. Neurons in the binocular zone of mouse V1 receive inputs from both eyes, but it is unclear how that binocular information is integrated and whether this integration has a function similar to that found in other mammals. Using extracellular recordings, we demonstrate that mouse V1 neurons are tuned for binocular disparities, or spatial differences, between the inputs from each eye, thus extracting signals potentially useful for estimating depth. The disparities encoded by mouse V1 are significantly larger than those encoded by cat and primate. Interestingly, these larger disparities correspond to distances that are likely to be ecologically relevant in natural viewing, given the stereo-geometry of the mouse visual system. Across mammalian species, it appears that binocular integration is a common cortical computation used to extract information relevant for estimating depth. As such, it is a prime example of how the integration of multiple sensory signals is used to generate accurate estimates of properties in our environment.