Inversion of pop-out for a distracting feature dimension in monkey visual cortex.

During visual search, it is important to reduce the interference of distracting objects in the scene. The neuronal responses elicited by the search target stimulus are typically enhanced. However, it is equally important to suppress the representations of distracting stimuli, especially if they are salient and capture attention. We trained monkeys to make an eye movement to a unique "pop-out" shape stimulus among an array of distracting stimuli. One of these distractors had a salient color that varied across trials and differed from the color of the other stimuli, causing it to also pop-out. The monkeys were able to select the pop-out shape target with high accuracy and actively avoided the pop-out color distractor. This behavioral pattern was reflected in the activity of neurons in area V4. Responses to the shape targets were enhanced, while the activity evoked by the pop-out color distractor was only briefly enhanced, directly followed by a sustained period of pronounced suppression. These behavioral and neuronal results demonstrate a cortical selection mechanism that rapidly inverts a pop-out signal to "pop-in" for an entire feature dimension thereby facilitating goal-directed visual search in the presence of salient distractors.

A Direct Comparison of Spatial Attention and Stimulus-Response Compatibility between Mice and Humans.

Mice are becoming an increasingly popular model for investigating the neural substrates of visual processing and higher cognitive functions. To validate the translation of mouse visual attention and sensorimotor processing to humans, we compared their performance in the same visual task. Mice and human participants judged the orientation of a grating presented on either the right or left side in the visual field. To induce shifts of spatial attention, we varied the stimulus probability on each side. As expected, human participants showed faster RTs and a higher accuracy for the side with a higher probability, a well-established effect of visual attention. The attentional effect was only present in mice when their response was slow. Although the task demanded a judgment of grating orientation, the accuracy of the mice was strongly affected by whether the side of the stimulus corresponded to the side of the behavioral response. This stimulus-response compatibility (Simon) effect was much weaker in humans and only significant for their fastest responses. Both species exhibited a speed-accuracy trade-off in their responses, because slower responses were more accurate than faster responses. We found that mice typically respond very fast, which contributes to the stronger stimulus-response compatibility and weaker attentional effects, which were only apparent in the trials with slowest responses. Humans responded slower and had stronger attentional effects, combined with a weak influence of stimulus-response compatibility, which was only apparent in trials with fast responses. We conclude that spatial attention and stimulus-response compatibility influence the responses of humans and mice but that strategy differences between species determine the dominance of these effects.

Orientation-tuned surround suppression in mouse visual cortex.

The firing rates of neurons in primary visual cortex (V1) are suppressed by large stimuli, an effect known as surround suppression. In cats and monkeys, the strength of suppression is sensitive to orientation; responses to regions containing uniform orientations are more suppressed than those containing orientation contrast. This effect is thought to be important for scene segmentation, but the underlying neural mechanisms are poorly understood. We asked whether it is possible to study these mechanisms in the visual cortex of mice, because of recent advances in technology for studying the cortical circuitry in mice. It is unknown whether neurons in mouse V1 are sensitive to orientation contrast. We measured the orientation selectivity of surround suppression in the different layers of mouse V1. We found strong surround suppression in layer 4 and the superficial layers, part of which was orientation tuned: iso-oriented surrounds caused more suppression than cross-oriented surrounds. Surround suppression was delayed relative to the visual response and orientation-tuned suppression was delayed further, suggesting two separate suppressive mechanisms. Previous studies proposed that surround suppression depends on the activity of inhibitory somatostatin-positive interneurons in the superficial layers. To test the involvement of the superficial layers we topically applied lidocaine. Silencing of the superficial layers did not prevent orientation-tuned suppression in layer 4. These results show that neurons in mouse V1, which lacks orientation columns, show orientation-dependent surround suppression in layer 4 and the superficial layers and that surround suppression in layer 4 does not require contributions from neurons in the superficial layers.

Dynamic Weighting of Time-Varying Visual and Auditory Evidence During Multisensory Decision Making.

Perceptual decision-making in a dynamic environment requires two integration processes: integration of sensory evidence from multiple modalities to form a coherent representation of the environment, and integration of evidence across time to accurately make a decision. Only recently studies started to unravel how evidence from two modalities is accumulated across time to form a perceptual decision. One important question is whether information from individual senses contributes equally to multisensory decisions. We designed a new psychophysical task that measures how visual and auditory evidence is weighted across time. Participants were asked to discriminate between two visual gratings, and/or two sounds presented to the right and left ear based on respectively contrast and loudness. We varied the evidence, i.e., the contrast of the gratings and amplitude of the sound, over time. Results showed a significant increase in performance accuracy on multisensory trials compared to unisensory trials, indicating that discriminating between two sources is improved when multisensory information is available. Furthermore, we found that early evidence contributed most to sensory decisions. Weighting of unisensory information during audiovisual decision-making dynamically changed over time. A first epoch was characterized by both visual and auditory weighting, during the second epoch vision dominated and the third epoch finalized the weighting profile with auditory dominance. Our results suggest that during our task multisensory improvement is generated by a mechanism that requires cross-modal interactions but also dynamically evokes dominance switching.

Implied motion activation in cortical area MT can be explained by visual low-level features.

To investigate form-related activity in motion-sensitive cortical areas, we recorded cell responses to animate implied motion in macaque middle temporal (MT) and medial superior temporal (MST) cortex and investigated these areas using fMRI in humans. In the single-cell studies, we compared responses with static images of human or monkey figures walking or running left or right with responses to the same human and monkey figures standing or sitting still. We also investigated whether the view of the animate figure (facing left or right) that elicited the highest response was correlated with the preferred direction for moving random dot patterns. First, figures were presented inside the cell's receptive field. Subsequently, figures were presented at the fovea while a dynamic noise pattern was presented at the cell's receptive field location. The results show that MT neurons did not discriminate between figures on the basis of the implied motion content. Instead, response preferences for implied motion correlated with preferences for low-level visual features such as orientation and size. No correlation was found between the preferred view of figures implying motion and the preferred direction for moving random dot patterns. Similar findings were obtained in a smaller population of MST cortical neurons. Testing human MT+ responses with fMRI further corroborated the notion that low-level stimulus features might explain implied motion activation in human MT+. Together, these results suggest that prior human imaging studies demonstrating animate implied motion processing in area MT+ can be best explained by sensitivity for low-level features rather than sensitivity for the motion implied by animate figures.

Contribution of the mouse calyx of Held synapse to tone adaptation.

The calyx of Held synapse is a giant synapse in the medial nucleus of the trapezoid body (MNTB) of the ventral brainstem, which is involved in sound localization. Although it has many release sites, it can show transmission failures and display an increase in synaptic delay during high-frequency signalling. Its apparent lack of reliability and precision raises the question whether this synapse makes a sizeable contribution to tone adaptation, the decline in response to sustained or repetitive auditory stimuli. We observed evidence for the presence of both ipsilateral and contralateral inhibition, but these effects were already present in the inputs to the MNTB, suggesting that synaptic inhibition within the MNTB does not contribute to tone adaptation. During trains of brief tones at variable intervals, there were no clear changes in reliability or precision at tone intervals of 20 ms or longer. A progressive decrease in the number of spikes measured in the MNTB was observed at shorter tone intervals, but this decrease largely originated upstream from the MNTB. In addition, for tones with short intervals, during the train a progressive increase in first-spike latencies was observed, but much smaller changes were observed in the delay between excitatory postsynaptic potentials and postsynaptic action potentials within the MNTB. We conclude that despite the failures and variability in synaptic delay that are present at the calyx of Held synapse, their contribution to tone adaptation is relatively small compared with upstream factors.

The essential role of recurrent processing for figure-ground perception in mice.

The segregation of figures from the background is an important step in visual perception. In primary visual cortex, figures evoke stronger activity than backgrounds during a delayed phase of the neuronal responses, but it is unknown how this figure-ground modulation (FGM) arises and whether it is necessary for perception. Here, we show, using optogenetic silencing in mice, that the delayed V1 response phase is necessary for figure-ground segregation. Neurons in higher visual areas also exhibit FGM and optogenetic silencing of higher areas reduced FGM in V1. In V1, figures elicited higher activity of vasoactive intestinal peptide-expressing (VIP) interneurons than the background, whereas figures suppressed somatostatin-positive interneurons, resulting in an increased activation of pyramidal cells. Optogenetic silencing of VIP neurons reduced FGM in V1, indicating that disinhibitory circuits contribute to FGM. Our results provide insight into how lower and higher areas of the visual cortex interact to shape visual perception.

Reliability and precision of the mouse calyx of Held synapse.

Traditionally, the calyx of Held synapse is viewed as a highly reliable relay in the sound localization circuit of the auditory brainstem, with every presynaptic action potential triggering a postsynaptic action potential in vivo. However, this view is at odds with slice recordings that report large short-term depression (STD). To investigate the reliability and precision of this synapse, we compared slice and in vivo recordings from medial nucleus of the trapezoid body neurons of young adult mice. We show that the extracellularly recorded complex waveform can be used to estimate both presynaptic release and postsynaptic excitability. Whereas under standard slice conditions the synapse underwent large STD, both extracellular and whole-cell recordings indicated that in vivo the size of the EPSPs was independent of recent history. The estimated quantal content was typically <20 in vivo, much lower than in the resting synapse under standard slice conditions. However, due to the large quantal size and summation of EPSPs, the safety factor of this synapse was generally still sufficiently large and postsynaptic failures were observed only infrequently in vivo. When present, failures were typically due to stochastic fluctuations in EPSP size or postsynaptic spike depression. In vivo, the calyx of Held synapse thus functions as a tonic synapse. The price it pays for its low release probability is an increase in jitter and synaptic latency and occasional postsynaptic failures.

Towards a Unified View on Pathways and Functions of Neural Recurrent Processing.

There are three neural feedback pathways to the primary visual cortex (V1): corticocortical, pulvinocortical, and cholinergic. What are the respective functions of these three projections? Possible functions range from contextual modulation of stimulus processing and feedback of high-level information to predictive processing (PP). How are these functions subserved by different pathways and can they be integrated into an overarching theoretical framework? We propose that corticocortical and pulvinocortical connections are involved in all three functions, whereas the role of cholinergic projections is limited by their slow response to stimuli. PP provides a broad explanatory framework under which stimulus-context modulation and high-level processing are subsumed, involving multiple feedback pathways that provide mechanisms for inferring and interpreting what sensory inputs are about.

Activity in Lateral Visual Areas Contributes to Surround Suppression in Awake Mouse V1.

Neuronal response to sensory stimuli depends on the context. The response in primary visual cortex (V1), for instance, is reduced when a stimulus is surrounded by a similar stimulus [1-3]. The source of this surround suppression is partially known. In mouse, local horizontal integration by somatostatin-expressing interneurons contributes to surround suppression [4]. In primates, however, surround suppression arises too quickly to come from local horizontal integration alone, and myelinated axons from higher visual areas, where cells have larger receptive fields, are thought to provide additional surround suppression [5, 6]. Silencing higher visual areas indeed decreased surround suppression in the awake primate by increasing responses to large stimuli [7, 8], although not under anesthesia [9, 10]. In smaller mammals, like mice, fast surround suppression could be possible without feedback. Recent studies revealed a small reduction in V1 responses when silencing higher areas [11, 12] but have not investigated surround suppression. To determine whether higher visual areas contribute to V1 surround suppression, even when this is not necessary for fast processing, we inhibited the areas lateral to V1, particularly the lateromedial area (LM), a possible homolog of primate V2 [13], while recording in V1 of awake and anesthetized mice. We found that part of the surround suppression depends on activity from lateral visual areas in the awake, but not anesthetized, mouse. Inhibiting the lateral visual areas specifically increased responses in V1 to large stimuli. We present a model explaining how excitatory feedback to V1 can have these suppressive effects for large stimuli.

Disentangling neural structures for processing of high- and low-speed visual motion.

Human psychophysical and electrophysiological evidence suggests at least two separate visual motion pathways, one tuned to a lower and one tuned to a broader and partly overlapping range of higher speeds. It remains unclear whether these two different channels are represented by different cortical areas or by sub-populations within a single area. We recorded evoked potentials at 59 scalp locations to the onset of a slow (3.5 degrees /s) and fast (32 degrees /s) moving test pattern, preceded by either a slow or fast adapting pattern that moved in either the same direction or opposite to the test motion. Baseline potentials were recorded for slow and fast moving test patterns after adaptation to a static pattern. Comparison of adapted responses with baseline responses revealed that the N2 peak around 180 ms after test stimulus onset was modulated by the preceding adaptation. This modulation depended on both direction and speed. Source localization of baseline potentials as well as direction-independent motion adaptation revealed cortical areas activated by fast motion to be more dorsal, medial and posterior compared with neural structures underlying slow motion processing. For both speeds, the direction-dependent component of this adaptation modulation occurred in the same area, located significantly more dorsally compared with neural structures that were adapted in a direction-independent manner. These results demonstrate for the first time the cortical separation of more ventral areas selectively activated by visual motion at low speeds (and not high speeds) and dorsal motion-sensitive cortical areas that are activated by both high and low speeds.

Figure-ground perception in the awake mouse and neuronal activity elicited by figure-ground stimuli in primary visual cortex.

Figure-ground segregation is the process by which the visual system identifies image elements of figures and segregates them from the background. Previous studies examined figure-ground segregation in the visual cortex of monkeys where figures elicit stronger neuronal responses than backgrounds. It was demonstrated in anesthetized mice that neurons in the primary visual cortex (V1) of mice are sensitive to orientation contrast, but it is unknown whether mice can perceptually segregate figures from a background. Here, we examined figure-ground perception of mice and found that mice can detect figures defined by an orientation that differs from the background while the figure size, position or phase varied. Electrophysiological recordings in V1 of awake mice revealed that the responses elicited by figures were stronger than those elicited by the background and even stronger at the edge between figure and background. A figural response could even be evoked in the absence of a stimulus in the V1 receptive field. Current-source-density analysis suggested that the extra activity was caused by synaptic inputs into layer 2/3. We conclude that the neuronal mechanisms of figure-ground segregation in mice are similar to those in primates, enabling investigation with the powerful techniques for circuit analysis now available in mice.

The Formation of Hierarchical Decisions in the Visual Cortex.

Intelligence relies on our ability to find appropriate sequences of decisions in complex problem spaces. The efficiency of a problem solver depends on the speed of its individual decisions and the number of decisions it can explore in parallel. It remains unknown whether the primate brain can consider multiple decisions at the same time. We therefore trained monkeys to navigate through a decision tree with stochastic sensory evidence at multiple branching points and recorded neuronal activity in visual cortical areas V1 and V4. We found a first phase of decision making in which neuronal activity increased in parallel along multiple branches of the decision tree. This was followed by an integration phase where the optimal overall strategy crystallized as the result of interactions between local decisions. The results reveal how sensory evidence is integrated efficiently for hierarchical decisions and contribute to our understanding of the brain mechanisms that implement complex mental programs.

Directional hearing by linear summation of binaural inputs at the medial superior olive.

Neurons in the medial superior olive (MSO) enable sound localization by their remarkable sensitivity to submillisecond interaural time differences (ITDs). Each MSO neuron has its own "best ITD" to which it responds optimally. A difference in physical path length of the excitatory inputs from both ears cannot fully account for the ITD tuning of MSO neurons. As a result, it is still debated how these inputs interact and whether the segregation of inputs to opposite dendrites, well-timed synaptic inhibition, or asymmetries in synaptic potentials or cellular morphology further optimize coincidence detection or ITD tuning. Using in vivo whole-cell and juxtacellular recordings, we show here that ITD tuning of MSO neurons is determined by the timing of their excitatory inputs. The inputs from both ears sum linearly, whereas spike probability depends nonlinearly on the size of synaptic inputs. This simple coincidence detection scheme thus makes accurate sound localization possible.

Adaptation to real motion reveals direction-selective interactions between real and implied motion processing.

Viewing static pictures of running humans evokes neural activity in the dorsal motion-sensitive cortex. To establish whether this response arises from direction-selective neurons that are also involved in real motion processing, we measured the visually evoked potential to implied motion following adaptation to static or moving random dot patterns. The implied motion response was defined as the difference between evoked potentials to pictures with and without implied motion. Interaction between real and implied motion was found as a modulation of this difference response by the preceding motion adaptation. The amplitude of the implied motion response was significantly reduced after adaptation to motion in the same direction as the implied motion, compared to motion in the opposite direction. At 280 msec after stimulus onset, the average difference in amplitude reduction between opposite and same adapted direction was 0.5 muV on an average implied motion amplitude of 2.0 muV. These results indicate that the response to implied motion arises from direction-selective motion-sensitive neurons. This is consistent with interactions between real and implied motion processing at a neuronal level.

Delayed response to animate implied motion in human motion processing areas.

Viewing static photographs of objects in motion evokes higher fMRI activation in the human medial temporal complex (MT+) than looking at similar photographs without this implied motion. As MT+ is traditionally thought to be involved in motion perception (and not in form perception), this finding suggests feedback from object-recognition areas onto MT+. To investigate this hypothesis, we recorded extracranial potentials evoked by the sight of photographs of biological agents with and without implied motion. The difference in potential between responses to pictures with and without implied motion was maximal between 260 and 400 msec after stimulus onset. Source analysis of this difference revealed one bilateral, symmetrical dipole pair in the occipital lobe. This area also showed a response to real motion, but approximately 100 msec earlier than the implied motion response. The longer latency of the implied motion response in comparison to the real motion response is consistent with a feedback projection onto MT+ following object recognition in higher-level temporal areas.