Visual circuits get the VIP treatment.

Behavioral state, specifically locomotion, has been shown to enhance sensory responses in primary visual cortex. In this issue of Cell, Fu et al. reveal the circuit elements that mediate this plasticity and suggest that these circuits may serve a general modulatory function across primary sensory areas.

DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity.

Precision pharmacology aims to manipulate specific cellular interactions within complex tissues. In this pursuit, we introduce DART.2 (drug acutely restricted by tethering), a second-generation cell-specific pharmacology technology. The core advance is optimized cellular specificity-up to 3,000-fold in 15 min-enabling the targeted delivery of even epileptogenic drugs without off-target effects. Additionally, we introduce brain-wide dosing methods as an alternative to local cannulation and tracer reagents for brain-wide dose quantification. We describe four pharmaceuticals-two that antagonize excitatory and inhibitory postsynaptic receptors, and two that allosterically potentiate these receptors. Their versatility is showcased across multiple mouse-brain regions, including cerebellum, striatum, visual cortex and retina. Finally, in the ventral tegmental area, we find that blocking inhibitory inputs to dopamine neurons accelerates locomotion, contrasting with previous optogenetic and pharmacological findings. Beyond enabling the bidirectional perturbation of chemical synapses, these reagents offer intersectional precision-between genetically defined postsynaptic cells and neurotransmitter-defined presynaptic partners.

Unique Spatial Integration in Mouse Primary Visual Cortex and Higher Visual Areas.

Neurons in the visual system integrate over a wide range of spatial scales. This diversity is thought to enable both local and global computations. To understand how spatial information is encoded across the mouse visual system, we use two-photon imaging to measure receptive fields (RFs) and size-tuning in primary visual cortex (V1) and three downstream higher visual areas (HVAs: LM (lateromedial), AL (anterolateral), and PM (posteromedial)) in mice of both sexes. Neurons in PM, compared with V1 or the other HVAs, have significantly larger RF sizes and less surround suppression, independent of stimulus eccentricity or contrast. To understand how this specialization of RFs arises in the HVAs, we measured the spatial properties of V1 inputs to each area. Spatial integration of V1 axons was remarkably similar across areas and significantly different from the tuning of neurons in their target HVAs. Thus, unlike other visual features studied in this system, specialization of spatial integration in PM cannot be explained by specific projections from V1 to the HVAs. Further, the differences in RF properties could not be explained by differences in convergence of V1 inputs to the HVAs. Instead, our data suggest that distinct inputs from other areas or connectivity within PM may support the area's unique ability to encode global features of the visual scene, whereas V1, LM, and AL may be more specialized for processing local features.SIGNIFICANCE STATEMENT Surround suppression is a common feature of visual processing whereby large stimuli are less effective at driving neuronal responses than smaller stimuli. This is thought to enhance efficiency in the population code and enable higher-order processing of visual information, such as figure-ground segregation. However, this comes at the expense of global computations. Here we find that surround suppression is not equally represented across mouse visual areas: primary visual cortex has substantially more surround suppression than higher visual areas, and one higher area has significantly less suppression than two others examined, suggesting that these areas have distinct functional roles. Thus, we have identified a novel dimension of specialization in the mouse visual cortex that may enable both local and global computations.

Contribution of Sensory Encoding to Measured Bias.

Signal detection theory (SDT) is a widely used theoretical framework that describes how variable sensory signals are integrated with a decision criterion to support perceptual decision-making. SDT provides two key measurements: sensitivity (d') and bias (c), which reflect the separability of decision variable distributions (signal and noise) and the position of the decision criterion relative to optimal, respectively. Although changes in the subject's decision criterion can be reflected in changes in bias, decision criterion placement is not the sole contributor to measured bias. Indeed, neuronal representations of bias have been observed in sensory areas, suggesting that some changes in bias are because of effects on sensory encoding. To directly test whether the sensory encoding process can influence bias, we optogenetically manipulated neuronal excitability in primary visual cortex (V1) in mice of both sexes during either an orientation discrimination or a contrast detection task. Increasing excitability in V1 significantly decreased behavioral bias, whereas decreasing excitability had the opposite effect. To determine whether this change in bias is consistent with effects on sensory encoding, we made extracellular recordings from V1 neurons in passively viewing mice. Indeed, we found that optogenetic manipulation of excitability shifted the neuronal bias in the same direction as the behavioral bias. Moreover, manipulating the quality of V1 encoding by changing stimulus contrast or interstimulus interval also resulted in consistent changes in both behavioral and neuronal bias. Thus, changes in sensory encoding are sufficient to drive changes in bias measured using SDT.SIGNIFICANCE STATEMENT Perceptual decision-making involves sensory integration followed by application of a cognitive criterion. Using signal detection theory, one can extract features of the underlying decision variables and rule: sensitivity (d') and bias (c). Because bias is measured as the difference between the optimal and actual criterion, it is sensitive to both the sensory encoding processes and the placement of the decision criterion. Here, we use behavioral and electrophysiological approaches to demonstrate that measures of bias depend on sensory processes. Optogenetic manipulations of V1 in mice bidirectionally affect both behavioral and neuronal measures of bias with little effect on sensitivity. Thus, changes in sensory encoding influence bias, and the absence of changes in sensitivity do not preclude changes in sensory encoding.

Neuronal Adaptation Reveals a Suboptimal Decoding of Orientation Tuned Populations in the Mouse Visual Cortex.

Sensory information is encoded by populations of cortical neurons. Yet, it is unknown how this information is used for even simple perceptual choices such as discriminating orientation. To determine the computation underlying this perceptual choice, we took advantage of the robust visual adaptation in mouse primary visual cortex (V1). We first designed a stimulus paradigm in which we could vary the degree of neuronal adaptation measured in V1 during an orientation discrimination task. We then determined how adaptation affects task performance for mice of both sexes and tested which neuronal computations are most consistent with the behavioral results given the adapted population responses in V1. Despite increasing the reliability of the population representation of orientation among neurons, and improving the ability of a variety of optimal decoders to discriminate target from distractor orientations, adaptation increases animals' behavioral thresholds. Decoding the animals' choice from neuronal activity revealed that this unexpected effect on behavior could be explained by an overreliance of the perceptual choice circuit on target preferring neurons and a failure to appropriately discount the activity of neurons that prefer the distractor. Consistent with this all-positive computation, we find that animals' task performance is susceptible to subtle perturbations of distractor orientation and optogenetic suppression of neuronal activity in V1. This suggests that to solve this task the circuit has adopted a suboptimal and task-specific computation that discards important task-related information.SIGNIFICANCE STATEMENT A major goal in systems neuroscience is to understand how sensory signals are used to guide behavior. This requires determining what information in sensory cortical areas is used, and how it is combined, by downstream perceptual choice circuits. Here we demonstrate that when performing a go/no-go orientation discrimination task, mice suboptimally integrate signals from orientation tuned visual cortical neurons. While they appropriately positively weight target-preferring neurons, they fail to negatively weight distractor-preferring neurons. We propose that this all-positive computation may be adopted because of its simple learning rules and faster processing, and may be a common approach to perceptual decision-making when task conditions allow.

Magnitude, time course, and specificity of rapid adaptation across mouse visual areas.

Adaptation is a ubiquitous feature of sensory processing whereby recent experience shapes future responses. The mouse primary visual cortex (V1) is particularly sensitive to recent experience, where a brief stimulus can suppress subsequent responses for seconds. This rapid adaptation profoundly impacts perception, suggesting that its effects are propagated along the visual hierarchy. To understand how rapid adaptation influences sensory processing, we measured its effects at key nodes in the visual system: in V1, three higher visual areas (HVAs: lateromedial, anterolateral, and posteromedial), and the superior colliculus (SC) in awake mice of both sexes using single-unit recordings. Consistent with the feed-forward propagation of adaptation along the visual hierarchy, we find that neurons in layer 4 adapt less strongly than those in other layers of V1. Furthermore, neurons in the HVAs adapt more strongly, and recover more slowly, than those in V1. The magnitude and time course of adaptation was comparable in each of the HVAs and in the SC, suggesting that adaptation may not linearly accumulate along the feed-forward visual processing hierarchy. Despite the increase in adaptation in the HVAs compared with V1, the effects were similarly orientation specific across all areas. These data reveal that adaptation profoundly shapes cortical processing, with increasing impact at higher levels in the cortical hierarchy, and also strongly influencing computations in the SC. Thus, we find robust, brain-wide effects of rapid adaptation on sensory processing.NEW & NOTEWORTHY Rapid adaptation dynamically alters sensory signals to account for recent experience. To understand how adaptation affects sensory processing and perception, we must determine how it impacts the diverse set of cortical and subcortical areas along the hierarchy of the mouse visual system. We find that rapid adaptation strongly impacts neurons in primary visual cortex, the higher visual areas, and the colliculus, consistent with its profound effects on behavior.

High-fidelity optical excitation of cortico-cortical projections at physiological frequencies.

Optogenetic activation of axons is a powerful approach for determining the synaptic properties and impact of long-range projections both in vivo and in vitro. However, because of the difficulty of measuring activity in axons, our knowledge of the reliability of optogenetic axonal stimulation has relied on data from somatic recordings. Yet, there are many reasons why activation of axons may not be comparable to cell bodies. Thus we have developed an approach to more directly assess the fidelity of optogenetic activation of axonal projections. We expressed opsins (ChR2, Chronos, or oChIEF) in the mouse primary visual cortex (V1) and recorded extracellular, pharmacologically isolated presynaptic action potentials in response to axonal activation in the higher visual areas. Repetitive stimulation of axons with ChR2 resulted in a 70% reduction in the fiber volley amplitude and a 60% increase in the latency at all frequencies tested (10-40 Hz). Thus ChR2 cannot reliably recruit axons during repetitive stimulation, even at frequencies that are reliable for somatic stimulation, likely due to pronounced channel inactivation at the high light powers required to evoke action potentials. By comparison, oChIEF and Chronos evoked photocurrents that inactivated minimally and could produce reliable axon stimulation at frequencies up to 60 Hz. Our approach provides a more direct and accurate evaluation of the efficacy of new optogenetic tools and has identified Chronos and oChIEF as viable tools to interrogate the synaptic and circuit function of long-range projections.

Mouse primary visual cortex is used to detect both orientation and contrast changes.

In mammals, the lateral geniculate nucleus (LGN) and the superior colliculus (SC) are the major targets of visual inputs from the retina. The LGN projects mainly to primary visual cortex (V1) while the SC targets the thalamus and brainstem, providing two potential pathways for processing visual inputs. Indeed, cortical lesion experiments in rodents have yielded mixed results, leading to the hypothesis that performance of simple visual behaviors may involve computations performed entirely by this subcortical pathway through the SC. However, these previous experiments have been limited by both their assays of behavioral performance and their use of lesions to change cortical activity. To determine the contribution of V1 to these tasks, we trained mice to perform threshold detection tasks in which they reported changes in either the contrast or orientation of visual stimuli. We then reversibly inhibited V1 by optogenetically activating parvalbumin-expressing inhibitory neurons with channelrhodopsin-2. We found that suppressing activity in V1 substantially impaired performance in visual detection tasks. The behavioral deficit depended on the retinotopic position of the visual stimulus, confirming that the effect was due to the specific suppression of the visually driven V1 neurons. Behavioral effects were seen with only moderate changes in neuronal activity, as inactivation that raised neuronal contrast thresholds by a median of only 14% was associated with a doubling of behavioral contrast detection threshold. Thus, detection of changes in either orientation or contrast is dependent on, and highly sensitive to, the activity of neurons in V1.

Input-specific synaptic depression shapes temporal integration in mouse visual cortex.

Efficient sensory processing requires the nervous system to adjust to ongoing features of the environment. In primary visual cortex (V1), neuronal activity strongly depends on recent stimulus history. Existing models can explain effects of prolonged stimulus presentation, but remain insufficient for explaining effects observed after shorter durations commonly encountered under natural conditions. We investigated the mechanisms driving adaptation in response to brief (100 ms) stimuli in L2/3 V1 neurons by performing in vivo whole-cell recordings to measure membrane potential and synaptic inputs. We find that rapid adaptation is generated by stimulus-specific suppression of excitatory and inhibitory synaptic inputs. Targeted optogenetic experiments reveal that these synaptic effects are due to input-specific short-term depression of transmission between layers 4 and 2/3. Thus, distinct mechanisms are engaged following brief and prolonged stimulus presentation and together enable flexible control of sensory encoding across a wide range of time scales.

Input-specific synaptic depression shapes temporal integration in mouse visual cortex.

Efficient sensory processing requires the nervous system to adjust to ongoing features of the environment. In primary visual cortex (V1), neuronal activity strongly depends on recent stimulus history. Existing models can explain effects of prolonged stimulus presentation but remain insufficient for explaining effects observed after shorter durations commonly encountered under natural conditions. We investigated the mechanisms driving adaptation in response to brief (100 ms) stimuli in L2/3 V1 neurons by performing in vivo whole-cell recordings to measure membrane potential and synaptic inputs. We find that rapid adaptation is generated by stimulus-specific suppression of excitatory and inhibitory synaptic inputs. Targeted optogenetic experiments reveal that these synaptic effects are due to input-specific short-term depression of transmission between layers 4 and 2/3. Thus, brief stimulus presentation engages a distinct adaptation mechanism from that previously reported in response to prolonged stimuli, enabling flexible control of sensory encoding across a wide range of timescales.

Feedforward mechanisms of cross-orientation interactions in mouse V1.

Sensory neurons are modulated by context. For example, in mouse primary visual cortex (V1), neuronal responses to the preferred orientation are modulated by the presence of superimposed orientations ("plaids"). The effects of this modulation are diverse; some neurons are suppressed, while others have larger responses to a plaid than its components. We investigated whether this diversity could be explained by a unified circuit mechanism. We report that this masking is maintained during suppression of cortical activity, arguing against cortical mechanisms. Instead, the heterogeneity of plaid responses is explained by an interaction between stimulus geometry and orientation tuning. Highly selective neurons are uniformly suppressed by plaids, whereas the effects in weakly selective neurons depend on the spatial configuration of the stimulus, transitioning systematically between suppression and facilitation. Thus, the diverse responses emerge as a consequence of the spatial structure of feedforward inputs, with no need to invoke cortical interactions.

Supralinear increase of recurrent inhibition during sparse activity in the somatosensory cortex.

The balance between excitation and inhibition in the cortex is crucial in determining sensory processing. Because the amount of excitation varies, maintaining this balance is a dynamic process; yet the underlying mechanisms are poorly understood. We show here that the activity of even a single layer 2/3 pyramidal cell in the somatosensory cortex of the rat generates widespread inhibition that increases disproportionately with the number of active pyramidal neurons. This supralinear increase of inhibition results from the incremental recruitment of somatostatin-expressing inhibitory interneurons located in layers 2/3 and 5. The recruitment of these interneurons increases tenfold when they are excited by two pyramidal cells. A simple model demonstrates that the distribution of excitatory input amplitudes onto inhibitory neurons influences the sensitivity and dynamic range of the recurrent circuit. These data show that through a highly sensitive recurrent inhibitory circuit, cortical excitability can be modulated by one pyramidal cell.

Distinct recruitment of feedforward and recurrent pathways across higher-order areas of mouse visual cortex.

Cortical visual processing transforms features of the external world into increasingly complex and specialized neuronal representations. These transformations arise in part through target-specific routing of information; however, within-area computations may also contribute to area-specific function. Here, we sought to determine whether higher order visual cortical areas lateromedial (LM), anterolateral (AL), posteromedial (PM), and anteromedial (AM) have specialized anatomical and physiological properties by using a combination of whole-cell recordings and optogenetic stimulation of primary visual cortex (V1) axons in vitro. We discovered area-specific differences in the strength of recruitment of interneurons through feedforward and recurrent pathways, as well as differences in cell-intrinsic properties and interneuron densities. These differences were most striking when comparing across medial and lateral areas, suggesting that these areas have distinct profiles for net excitability and integration of V1 inputs. Thus, cortical areas are not defined simply by the information they receive but also by area-specific circuit properties that enable specialized filtering of these inputs.

Distinct timing in the activity of cannabinoid-sensitive and cannabinoid-insensitive basket cells.

Cannabinoids are powerful modulators of inhibition, yet the precise spike timing of cannabinoid receptor (CB1R)-expressing inhibitory neurons in relation to other neurons in the circuit is poorly understood. Here we found that the spike timing of CB1R-expressing basket cells, a major target for cannabinoids in the rat hippocampus, was distinct from the other main group of basket cells, the CB1R-negative. Despite receiving the same afferent inputs, the synaptic and biophysical properties of the two cell types were tuned to detect different features of activity. CB1R-negative basket cells responded reliably and immediately to subtle and repetitive excitation. In contrast, CB1R-positive basket cells responded later and did not follow repetitive activity, but were better suited to integrate the consecutive excitation of independent afferents. This temporal separation in the activity of the two basket cell types generated distinct epochs of somatic inhibition that were differentially affected by endocannabinoids.

Mouse Higher Visual Areas Provide Both Distributed and Specialized Contributions to Visually Guided Behaviors.

Cortical parallel processing streams segregate many diverse features of a sensory scene. However, some features are distributed across streams, begging the question of whether and how such distributed representations contribute to perception. We determined the necessity of the primary visual cortex (V1) and three key higher visual areas (lateromedial [LM], anterolateral [AL], and posteromedial [PM]) for perception of orientation and contrast, two features that are robustly encoded across all four areas. Suppressing V1, LM, or AL decreased sensitivity for both orientation discrimination and contrast detection, consistent with a role for these areas in sensory perception. In comparison, suppressing PM selectively increased false alarm (FA) rates during contrast detection, without any effect on orientation discrimination. This effect was not retinotopically specific, suggesting that suppression of PM altered sensory integration or the decision-making process rather than processing of local visual features. Thus, we find that distributed representations in the visual system can nonetheless support specialized perceptual roles for higher visual cortical areas.

Complementary modulation of somatic inhibition by opioids and cannabinoids.

Somatic inhibition, which is critical for determining the spike output of principal cells, is mediated by two physiologically distinct classes of GABAergic interneurons called basket cells. In the hippocampus, despite both targeting the somatic membrane of CA1 pyramidal cells, these two classes of basket cells are active at different times. Differential modulation of these two types of basket cells could hence be important for regulating the activity patterns of CA1 pyramidal cells at very specific periods during ongoing activity. Indeed, cannabinoids selectively suppress the output of one class of basket cell. Whether opioids, another major modulator of inhibition in the hippocampus, also selectively suppress somatic inhibition is not known. Here, we show that basket cells are selectively modulated by either opioids or cannabinoids, but not both. We also find that basket cells are integrated into specific inhibitory subnetworks that are themselves under differential control of opioids and cannabinoids. Furthermore, because the two interneuron types are activated at different times, opioids and cannabinoids suppress different epochs of inhibition. This cell-type specific sensitivity to neuromodulators allows for a fine control of the temporal structure of hippocampal activity.

Visual Attention: Mice Can Use Spatial Cues Too.

The use of cues to predict the location of a visual target is an important cognitive strategy for primates. While mice are generally considered to be less dependent on vision than primates, new work shows that they can also use spatial cues to direct their visual attention.

Self-administering cannabinoids.

Endocannabinoids, which are typically released by principal cells in response to prolonged depolarization, act as retrograde messengers to inhibit synaptic transmission. A recent study shows that in a specific subtype of cortical interneuron, endocannabinoids released under similar circumstances can also act cell-autonomously. Here, endocannabinoids endow these neurons with a memory of their own activity in the form of a long-term change in excitability.

Higher-Order Areas of the Mouse Visual Cortex.

The brain has evolved to transform sensory information in the environment into neural representations that can be used for perception and action. Higher-order sensory cortical areas, with their increasingly complex receptive fields and integrative properties, are thought to be critical nodes for this function. This is especially true in the primate visual cortex, in which functionally specialized areas are engaged in parallel streams to support diverse computations. Recent anatomical and physiological studies of the mouse visual cortex have revealed a similarly complex network of specialized higher-order areas. This structure provides a useful model for determining the synaptic and circuit mechanisms through which information is transformed across distinct processing stages. In this review, we summarize the current knowledge on the layout, connectivity, and functional properties of the higher visual areas in the mouse. In addition, we speculate on the contribution of these areas to perception and action, and how knowledge of the mouse visual system can inform us about the principles that govern information processing in integrated networks.

Sensory neuron signaling to the brain: properties of transmitter release from olfactory nerve terminals.

Olfactory receptor neurons (ORNs) convey sensory information directly to the CNS via conventional glutamatergic synaptic contacts in olfactory bulb glomeruli. To better understand the process by which information contained in the odorant-evoked firing of ORNs is transmitted to the brain, we examined the properties of glutamate release from olfactory nerve (ON) terminals in slices of the rat olfactory bulb. We show that marked paired pulse depression is the same in simultaneously recorded periglomerular and tufted neurons, and that this form of short-term plasticity is attributable to a reduction of glutamate release from ON terminals. We used the progressive blockade of NMDA receptor (NMDAR) EPSCs by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine hydrogen maleate] and stationary fluctuation analysis of AMPA receptor (AMPAR) EPSCs to determine the probability of release (P(r)) of ON terminals; both approaches indicated that P(r) is unusually high (>/=0.8). The low-affinity glutamate receptor antagonists gamma-d-glutamylglycine and l-amino-5-phosphonovaleric acid blocked ON-evoked AMPAR- and NMDAR-mediated EPSCs, respectively, to the same extent under conditions of low and high P(r), suggesting that multivesicular release is not a feature of ON terminals. Although release from most synapses exhibits a highly nonlinear dependence on extracellular Ca(2+), we find that the relationship between glutamate release and extracellular Ca(2+) at ON terminals is nearly linear. Our results suggest that ON terminals have specialized features that may contribute to the reliable transmission of sensory information from nose to brain.