Visual discrimination improves with training, a phenomenon that is thought to reflect plastic changes in the responses of neurons in primary visual cortex (V1). However, the identity of the neurons that undergo change, the nature of the changes, and the consequences of these changes for other visual behaviors remain unclear. We used chronic in vivo 2-photon calcium imaging to monitor the responses of neurons in the V1 of tree shrews learning a Go/No-Go fine orientation discrimination task. We observed increases in neural population measures of discriminability for task-relevant stimuli that correlate with performance and depend on a select subset of neurons with preferred orientations that include the rewarded stimulus and nearby orientations biased away from the non-rewarded stimulus. Learning is accompanied by selective enhancement in the response of these neurons to the rewarded stimulus that further increases their ability to discriminate the task stimuli. These changes persist outside of the trained task and predict observed enhancement and impairment in performance of other discriminations, providing evidence for selective and persistent learning-induced plasticity in the V1, with significant consequences for perception.

For over 150 years, spectrally selective filters have been proposed to improve the vision of observers with color vision deficiencies [1]. About 6% of males and <1% of females have anomalies in their gene arrays coded on the X chromosome that result in significantly decreased spectral separation between their middle- (M-) and long- (L-) wave sensitive cone photoreceptors [2]. These shifts alter individuals' color-matching and chromatic discrimination such that they are classified as anomalous trichromats [3, 4]. Broad-band spectrally selective filters proposed to improve the vision of color-deficient observers principally modify the illuminant and are largely ineffective in enhancing discrimination or perception because they do not sufficiently change the relative activity of M- and L-photoreceptors [5, 6]. Properly tailored notch filters, by contrast, might increase the difference of anomalous M- and L-cone signals. Here, we evaluated the effects of long-term usage of a commercial filter designed for this purpose on luminance and chromatic contrast response, estimated with a signal detection-based scaling method. We found that sustained use over two weeks was accompanied by increased chromatic contrast response in anomalous trichromats. Importantly, these improvements were observed when tested without the filters, thereby demonstrating an adaptive visual response. Normal observers and a placebo control showed no such changes in contrast response. These findings demonstrate a boosted chromatic response from exposure to enhanced chromatic contrasts in observers with reduced spectral discrimination. They invite the suggestion that modifications of photoreceptor signals activate a plastic post-receptoral substrate that could potentially be exploited for visual rehabilitation.

Mirror invariance is a visual mechanism that enables a prompt recognition of mirror images. This visual capacity emerges early in human development, is useful to recognize objects, faces, and places from both left and right perspectives, and is also present in primates, pigeons, and cephalopods. Notwithstanding, the same visual mechanism has been suspected to be the source of a specific difficulty for a relatively recent human invention-reading-by creating confusion between mirror letters (e.g., b-d in the Latin alphabet). Using an ecologically valid school-based design, we show here that mirror invariance represents indeed a major leash for reading fluency acquisition in first graders. Our causal approach, which specifically targeted mirror invariance inhibition for letters, in a synergic combination with post-training sleep to increase learning consolidation, revealed unprecedented improvement in reading fluency, which became two-times faster. This gain was obtained with as little as 7.5 h of multisensory-motor training to distinguish mirror letters, such as "b" versus "d." The magnitude, automaticity, and duration of this mirror discrimination learning were greatly enhanced by sleep, which keeps the gains perfectly intact even after 4 months. The results were consistently replicated in three randomized controlled trials. They not only reveal an extreme case of cognitive plasticity in humans (i.e., the inhibition in just 3 weeks of a ∼25-million-year-old visual mechanism), that allows adaptation to a cultural activity (reading), but at the same time also show a simple and cost-effective way to unleash the reading fluency potential of millions of children worldwide.

Evidence suggests that scalp-recorded occipital alpha-band (8-13 Hz) oscillations reflect phasic information transfer in thalamocortical neurons projecting from lateral geniculate nucleus to visual cortex. In animals, the phase of ongoing alpha oscillations has been shown to modulate stimulus discrimination and neuronal spiking. Human research has shown that alpha phase predicts visual perception of near-threshold stimuli and subsequent neural activity and that the frequency of these oscillations predicts reaction times, as well as the maximum temporal interval necessary for perceived simultaneity. These phasic effects have led to the hypothesis that conscious perception occurs in discrete temporal windows, clocked by the frequency of alpha oscillations. Under this hypothesis, variation in the frequency of occipital alpha oscillations should predict variation in the temporal resolution of visual perception. Specifically, when two stimuli fall within the same alpha cycle, they may be perceived as a single stimulus, resulting in perception with lower temporal resolution when alpha frequency is lower. We tested this by assessing the relationship between two-flash fusion thresholds (a measure of the temporal resolution of visual perception) and the frequency of eyes-closed and task-related alpha rhythms. We found, both between and within subjects, that faster alpha frequencies predicted more accurate flash discrimination, providing novel evidence linking alpha frequency to the temporal resolution of perception.

Although it is well established that fronto-parietal regions are active during action observation, whether they play a causal role in the ability to infer others' intentions from visual kinematics remains undetermined. In the experiments reported here, we combined offline continuous theta burst stimulation (cTBS) with computational modeling to reveal and causally probe single-trial computations in the inferior parietal lobule (IPL) and inferior frontal gyrus (IFG). Participants received cTBS over the left anterior IPL and the left IFG pars orbitalis in separate sessions before completing an intention discrimination task (discriminate intention of observed reach-to-grasp acts) or a kinematic discrimination task unrelated to intention (discriminate peak wrist height of the same acts). We targeted intention-sensitive regions whose fMRI activity, recorded when observing the same reach-to-grasp acts, could accurately discriminate intention. We found that transient disruption of activity of the left IPL, but not the IFG, impaired the observer's ability to attribute intention to action. Kinematic discrimination unrelated to intention, in contrast, was largely unaffected. Computational analyses of how encoding (mapping of intention to movement kinematics) and readout (mapping of kinematics to intention choices) intersect at the single-trial level revealed that IPL cTBS did not diminish the overall sensitivity of intention readout to movement kinematics. Rather, it selectively misaligned intention readout with respect to encoding, deteriorating mapping from informative kinematic features to intention choices. These results provide causal evidence of how the left anterior IPL computes mapping from kinematics to intentions.

Learning and experience are critical for translating ambiguous sensory information from our environments to perceptual decisions. Yet evidence on how training molds the adult human brain remains controversial, as fMRI at standard resolution does not allow us to discern the finer scale mechanisms that underlie sensory plasticity. Here, we combine ultra-high-field (7T) functional imaging at sub-millimeter resolution with orientation discrimination training to interrogate experience-dependent plasticity across cortical depths that are known to support dissociable brain computations. We demonstrate that learning alters orientation-specific representations in superficial rather than middle or deeper V1 layers, consistent with recurrent plasticity mechanisms via horizontal connections. Further, learning increases feedforward rather than feedback layer-to-layer connectivity in occipito-parietal regions, suggesting that sensory plasticity gates perceptual decisions. Our findings reveal finer scale plasticity mechanisms that re-weight sensory signals to inform improved decisions, bridging the gap between micro- and macro-circuits of experience-dependent plasticity.

Discrimination between predictive and non-predictive threat stimuli decreases as threat intensity increases. The central mechanisms that mediate the transition from discriminatory to generalized threat responding remain poorly resolved. Here, we identify the stress- and dysphoria-associated kappa opioid receptor (KOR) and its ligand dynorphin (Dyn), acting in the ventral tegmental area (VTA), as a key substrate for regulating threat generalization. We identify several dynorphinergic inputs to the VTA and demonstrate that projections from the bed nucleus of the stria terminalis (BNST) and dorsal raphe nucleus (DRN) both contribute to anxiety-like behavior but differentially affect threat generalization. These data demonstrate that conditioned threat discrimination has an inverted "U" relationship with threat intensity and establish a role for KOR/Dyn signaling in the midbrain for promoting threat generalization.

The amygdala-prefrontal-cortex circuit has long occupied the center of the threat system,1 but new evidence has rapidly amassed to implicate threat processing outside this canonical circuit.2-4 Through nonhuman research, the sensory cortex has emerged as a critical substrate for long-term threat memory,5-9 underpinned by sensory cortical pattern separation/completion10,11 and tuning shift.12,13 In humans, research has begun to associate the human sensory cortex with long-term threat memory,14,15 but the lack of mechanistic insights obscures a direct linkage. Toward that end, we assessed human olfactory threat conditioning and long-term (9 days) threat memory, combining affective appraisal, olfactory psychophysics, and functional magnetic resonance imaging (fMRI) over a linear odor-morphing continuum (five levels of binary mixtures of the conditioned stimuli/CS+ and CS- odors). Affective ratings and olfactory perceptual discrimination confirmed (explicit) affective and perceptual learning and memory via conditioning. fMRI representational similarity analysis (RSA) and voxel-based tuning analysis further revealed associative plasticity in the human olfactory (piriform) cortex, including immediate and lasting pattern differentiation between CS and neighboring non-CS and a late onset, lasting tuning shift toward the CS. The two plastic processes were especially salient and lasting in anxious individuals, among whom they were further correlated. These findings thus support an evolutionarily conserved sensory cortical system of long-term threat representation, which can underpin threat perception and memory. Importantly, hyperfunctioning of this sensory mnemonic system of threat in anxiety further implicates a hitherto underappreciated sensory mechanism of anxiety.

In any given perceptual task, the visual system selectively weighs or filters incoming information. The particular set of weights or filters form a kind of template, which reveals the regions or types of information that are particularly useful for a given perceptual decision.1,2 Unfortunately, sensory input is noisy and ever changing. To compensate for these fluctuations, the visual system could adopt a strategy of biasing the templates such that they reflect a temporal smoothing of input, which would be a form of serial dependence.3-5 Here, we demonstrate that perceptual templates are, in fact, altered by serial dependence. Using a simple orientation detection task and classification-image technique, we found that perceptual templates are systematically biased toward previously seen, task-irrelevant orientations. The results of an orientation discrimination task suggest that this shift in perceptual template derives from a change in the perceptual appearance of orientation. Our study reveals how serial dependence biases internal templates of orientation and suggests that the sensitivity of classification-image techniques in general could be improved by taking into account history-dependent fluctuations in templates.

Orienting covert exogenous (involuntary) attention to a target location improves performance in many visual tasks [1, 2]. It is unknown whether early visual cortical areas are necessary for this improvement. To establish a causal link between these areas and attentional modulations, we used transcranial magnetic stimulation (TMS) to briefly alter cortical excitability and determine whether early visual areas mediate the effect of exogenous attention on performance. Observers performed an orientation discrimination task. After a peripheral valid, neutral, or invalid cue, two cortically magnified gratings were presented, one in the stimulated region and the other in the symmetric region in the opposite hemifield. Observers received two successive TMS pulses around their occipital pole while the stimuli were presented. Shortly after, a response cue indicated the grating whose orientation observers had to discriminate. The response cue either matched-target stimulated-or did not match-distractor stimulated-the stimulated side. Grating contrast was varied to measure contrast response functions (CRF) for all combinations of attention and TMS conditions. When the distractor was stimulated, exogenous attention yielded response gain-performance benefits in the valid-cue condition and costs in the invalid-cue condition compared with the neutral condition at the high contrast levels. Crucially, when the target was stimulated, this response gain was eliminated. Therefore, TMS extinguished the effect of exogenous attention. These results establish a causal link between early visual areas and the modulatory effect of exogenous attention on performance.

The hippocampal subfields perform distinct operations during acquisition, differentiation, and recollection of episodic memories, and deficits in pattern separation are among the first symptoms of Alzheimer's disease (AD). We investigated how hippocampal subfields contribute to pattern separation and how this is affected by Apolipoprotein-E (APOE), the strongest AD genetic risk factor. Using ultra-high-field (7T) functional magnetic resonance imaging (fMRI), APOE-ε3-ε3 carriers predominantly recruited cornu ammonis 3 (CA3) during a spatial mnemonic discrimination task, whereas APOE-ε3-ε4 and APOE-ε3-ε2 carriers engaged CA3 and dentate gyrus (DG) to the same degree. Specifically, APOE-ε3-ε4 carriers showed reduced pattern separation in CA3, whereas APOE-ε3-ε2 carriers exhibited increased effects in DG and pattern separation-related functional connectivity between DG and CA3. Collectively, these results demonstrate that AD genetic risk alters hemodynamic responses in young pre-symptomatic individuals, paving the way for development of biomarkers for preclinical AD.

It has remained uncertain whether the mechanisms of visual perceptual learning (VPL)1-4 remain stable across the lifespan or undergo developmental changes. This uncertainty largely originates from missing results about the mechanisms of VPL in healthy children. We here investigated the mechanisms of task-irrelevant VPL in healthy elementary school age children (7-10 years old) and compared their results to healthy young adults (18-31 years old). Subjects performed a rapid-serial-visual-presentation (RSVP) task at central fixation over the course of several daily sessions while coherent motion was merely exposed as a task-irrelevant feature in the visual periphery either at threshold or suprathreshold levels for coherent motion detection. As a result of this repeated exposure, children and adults both showed enhanced discrimination performance for the threshold task-irrelevant feature as in previous studies with adults.5-8 However, adults demonstrated a decreased performance for the suprathreshold task-irrelevant feature whereas children increased performance. One possible explanation for this difference is that children cannot effectively suppress salient task-irrelevant features because of weaker selective attention ability compared to that of adults.9-11 However, our results revealed to the contrary that children with stronger selective attention ability, as measured by the useful field of view (UFOV) test, showed greater increases in performance for the suprathreshold task-irrelevant feature. Together, these results suggest that the mechanisms of VPL change dramatically from childhood to adulthood due to a change in the way learners handle salient task-irrelevant features.

People's assessments of the state of the world often deviate systematically from the information available to them [1]. Such biases can originate from people's own decisions: committing to a categorical proposition, or a course of action, biases subsequent judgment and decision-making. This phenomenon, called confirmation bias [2], has been explained as suppression of post-decisional dissonance [3, 4]. Here, we provide insights into the underlying mechanism. It is commonly held that decisions result from the accumulation of samples of evidence informing about the state of the world [5-8]. We hypothesized that choices bias the accumulation process by selectively altering the weighting (gain) of subsequent evidence, akin to selective attention. We developed a novel psychophysical task to test this idea. Participants viewed two successive random dot motion stimuli and made two motion-direction judgments: a categorical discrimination after the first stimulus and a continuous estimation of the overall direction across both stimuli after the second stimulus. Participants' sensitivity for the second stimulus was selectively enhanced when that stimulus was consistent with the initial choice (compared to both, first stimuli and choice-inconsistent second stimuli). A model entailing choice-dependent selective gain modulation explained this effect better than several alternative mechanisms. Choice-dependent gain modulation was also established in another task entailing averaging of numerical values instead of motion directions. We conclude that intermittent choices direct selective attention during the evaluation of subsequent evidence, possibly due to decision-related feedback in the brain [9]. Our results point to a recurrent interplay between decision-making and selective attention.

Sensory-driven decisions are formed by accumulating information over time. Although parietal cortex activity is thought to represent accumulated evidence for sensory-based decisions, recent perturbation studies in rodents and non-human primates have challenged the hypothesis that these representations actually influence behavior. Here, we asked whether the parietal cortex integrates acoustic features from auditory cortical inputs during a perceptual decision-making task. If so, we predicted that selective inactivation of this projection should impair subjects' ability to accumulate sensory evidence. We trained gerbils to perform an auditory discrimination task and obtained measures of integration time as a readout of evidence accumulation capability. Minimum integration time was calculated behaviorally as the shortest stimulus duration for which subjects could discriminate the acoustic signals. Direct pharmacological inactivation of parietal cortex increased minimum integration times, suggesting its role in the behavior. To determine the specific impact of sensory evidence, we chemogenetically inactivated the excitatory projections from auditory cortex to parietal cortex and found this was sufficient to increase minimum behavioral integration times. Our signal-detection-theory-based model accurately replicated behavioral outcomes and indicated that the deficits in task performance were plausibly explained by elevated sensory noise. Together, our findings provide causal evidence that parietal cortex plays a role in the network that integrates auditory features for perceptual judgments.

Despite their growing popularity as models of visual functions, it remains unclear whether rodents are capable of deploying advanced shape-processing strategies when engaged in visual object recognition. In rats, for instance, pattern vision has been reported to range from mere detection of overall object luminance to view-invariant processing of discriminative shape features. Here we sought to clarify how refined object vision is in rodents, and how variable the complexity of their visual processing strategy is across individuals. To this aim, we measured how well rats could discriminate a reference object from 11 distractors, which spanned a spectrum of image-level similarity to the reference. We also presented the animals with random variations of the reference, and processed their responses to these stimuli to derive subject-specific models of rat perceptual choices. Our models successfully captured the highly variable discrimination performance observed across subjects and object conditions. In particular, they revealed that the animals that succeeded with the most challenging distractors were those that integrated the wider variety of discriminative features into their perceptual strategies. Critically, these strategies were largely preserved when the rats were required to discriminate outlined and scaled versions of the stimuli, thus showing that rat object vision can be characterized as a transformation-tolerant, feature-based filtering process. Overall, these findings indicate that rats are capable of advanced processing of shape information, and point to the rodents as powerful models for investigating the neuronal underpinnings of visual object recognition and other high-level visual functions.

The ability to anticipate what others will do next is crucial for navigating social, interactive environments. Here, we develop an experimental and analytical framework to measure the implicit readout of prospective intention information from movement kinematics. Using a primed action categorization task, we first demonstrate implicit access to intention information by establishing a novel form of priming, which we term kinematic priming: subtle differences in movement kinematics prime action prediction. Next, using data collected from the same participants in a forced-choice intention discrimination task 1 h later, we quantify single-trial intention readout-the amount of intention information read by individual perceivers in individual kinematic primes-and assess whether it can be used to predict the amount of kinematic priming. We demonstrate that the amount of kinematic priming, as indexed by both response times (RTs) and initial fixations to a given probe, is directly proportional to the amount of intention information read by the individual perceiver at the single-trial level. These results demonstrate that human perceivers have rapid, implicit access to intention information encoded in movement kinematics and highlight the potential of our approach to reveal the computations that permit the readout of this information with single-subject, single-trial resolution.

During visual perception, the brain enhances the representations of image regions that belong to figures and suppresses those that belong to the background. Natural images contain many regions that initially appear to be part of a figure when analyzed locally (proto-objects) but are actually part of the background if the whole image is considered. These proto-grounds must be correctly assigned to the background to allow correct shape identification and guide behavior. To understand how the brain resolves this conflict between local and global processing, we recorded neuronal activity from the primary visual cortex (V1) of macaque monkeys while they discriminated between n/u shapes that have a central proto-ground region. We studied the fine-grained spatiotemporal profile of neural activity evoked by the n/u shape and found that neural representation of the object proceeded from a coarse-to-fine resolution. Approximately 100 ms after the stimulus onset, the representation of the proto-ground region was enhanced together with the rest of the n/u surface, but after ∼115 ms, the proto-ground was suppressed back to the level of the background. Suppression of the proto-ground was only present in animals that had been trained to perform the shape-discrimination task, and it predicted the choice of the animal on a trial-by-trial basis. Attention enhanced figure-ground modulation, but it had no effect on the strength of proto-ground suppression. The results indicate that the accuracy of scene segmentation is sharpened by a suppressive process that resolves local ambiguities by assigning proto-grounds to the background.

Recording action potentials extracellularly during behavior has led to fundamental discoveries regarding neural function-hippocampal neurons respond to locations in space,1 motor cortex neurons encode movement direction,2 and dopamine neurons signal reward prediction errors3-observations undergirding current theories of cognition,4 movement,5 and learning.6 Recently it has become possible to measure calcium flux, an internal cellular signal related to spiking. The ability to image calcium flux in anatomically7,8 or genetically9 identified neurons can extend our knowledge of neural circuit function by allowing activity to be monitored in specific cell types or projections, or in the same neurons across many days. However, while initial studies were grounded in prior unit recording work, it has become fashionable to assume that calcium is identical to spiking, even though the spike-to-fluorescence transformation is nonlinear, noisy, and unpredictable under real-world conditions.10 It remains an open question whether calcium provides a high-fidelity representation of single-unit activity in awake, behaving subjects. Here, we have addressed this question by recording both signals in the lateral orbitofrontal cortex (OFC) of rats during olfactory discrimination learning. Activity in the OFC during olfactory learning has been well-studied in humans,11,12,13,14 nonhuman primates,15,16 and rats,17,18,19,20,21 where it has been shown to signal information about both the sensory properties of odor cues and the rewards they predict. Our single-unit results replicated prior findings, whereas the calcium signal provided only a degraded estimate of the information available in the single-unit spiking, reflecting primarily reward value.