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Brightness illusions are a powerful tool in studying vision, yet their neural correlates are poorly understood. Based on a human paradigm, we presented illusory drifting gratings to mice. Primary visual cortex (V1) neurons responded to illusory gratings, matching their direction selectivity for real gratings, and they tracked the spatial phase offset between illusory and real gratings. Illusion responses were delayed compared to real gratings, in line with the theory that processing illusions requires feedback from higher visual areas (HVAs). We provide support for this theory by showing a reduced V1 response to illusions, but not real gratings, following HVAs optogenetic inhibition. Finally, we used the pupil response (PR) as an indirect perceptual report and showed that the mouse PR matches the human PR to perceived luminance changes. Our findings resolve debates over whether V1 neurons are involved in processing illusions and highlight the involvement of feedback from HVAs. The neural mechanisms underpinning visual illusions remains poorly understood. Here, the authors recorded the neural responses of mouse primary visual cortex to illusory grating and found delayed responses to illusory brightness, showing that optogenetic inhibition of higher visual areas reduced V1 response to illusions but not to real gratings.

The noradrenergic locus coeruleus (LC) is a controller of brain and behavioral states. Activating LC neurons en masse by electrical or optogenetic stimulation promotes a stereotypical “activated” cortical state of high-frequency oscillations. However, it has been recently reported that spontaneous activity of LC cell pairs has sparse yet structured time-averaged cross-correlations, which is unlike the highly synchronous neuronal activity evoked by stimulation. Therefore, LC population activity could consist of distinct multicell ensembles each with unique temporal evolution of activity. We used nonnegative matrix factorization (NMF) to analyze large populations of simultaneously recorded LC single units in the rat LC. NMF identified ensembles of spontaneously coactive LC neurons and their activation time courses. Since LC neurons selectively project to specific forebrain regions, we hypothesized that distinct ensembles activate during different cortical states. To test this hypothesis, we calculated band-limited power and spectrograms of local field potentials in cortical area 24a aligned to spontaneous activations of distinct LC ensembles. A diversity of state modulations occurred around activation of different LC ensembles, including a typical activated state with increased highfrequency power as well as other states including decreased high-frequency power. Thus—in contrast to the stereotypical activated brain state evoked by en masse LC stimulation—spontaneous activation of distinct LC ensembles is associated with a multitude of cortical states.

Rationale Shifting to a new rule is a form of behavioral flexibility that is impaired in numerous psychiatric and neurological illnesses. Animal studies have revealed that this form of flexibility depends upon norepinephrine (NE) neurotransmission. Atomoxetine, a NE reuptake inhibitor, improves performance of humans in set shifting tasks. Objective Our objective was to validate its effects in a rodent set shifting task. Methods We tested the drug effect using an operant task that required a shift from a visual cue-guided behavior to a novel location-guided rule. Results A 1.0-mg/kg dose significantly accelerated rule shifting without affecting learning strategies, such as win-stay or lose-shift. Fitting behavioral performance with a learning function provided a measure of learning rate. Conclusion This novel analysis revealed that atomoxetine accelerated shifting to the new rule without affecting learning rate.

Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N-methyl-D-aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABA(A) receptors. The present study used a rodent model to compare the inhibition of NMDA and GABA(A) receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing. Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats. Reducing GABA(A) receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 μg, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC. These data demonstrate that, while tonic stimulation of NMDA and GABA(A) receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission.

Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N-methyl-d-aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABA^sub A^ receptors. The present study used a rodent model to compare the inhibition of NMDA and GABA^sub A^ receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing. Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats. Reducing GABA^sub A^ receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 [mu]g, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC. These data demonstrate that, while tonic stimulation of NMDA and GABA^sub A^ receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission.[PUBLICATION ABSTRACT]

Rationale Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N -methyl- d -aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABA A receptors. Objective The present study used a rodent model to compare the inhibition of NMDA and GABA A receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing. Methods Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats. Results Reducing GABA A receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 μg, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC. Conclusions These data demonstrate that, while tonic stimulation of NMDA and GABA A receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission.

Illusions are a powerful tool for studying the single neuron correlates of perception. Here, we introduce the neon color spreading (NCS) illusion in mice and report the neuronal correlates of illusory brightness, which has heretofore only been studied using human fMRI. We designed a novel NCS paradigm to evoke the percept of an illusory drifting grating and analyzed the activity of 520 single units in the mouse primary visual cortex (V1). A substantial proportion of V1 single units (60.5%) responded to illusory gratings with direction tuning matched to their preferred direction, which was determined using physically presented luminance-defined gratings (LDG). Moreover, by presenting LDG gratings with a 180° phase shift relative to NCs gratings, we show that spatial phase tuning shifted 180° for most single units. This finding conclusively demonstrates that V1 single units respond to illusory brightness. Using this novel mouse paradigm, we show that responses to illusory gratings have a lower magnitude and are delayed relative to physical gratings. We determined where V1 single units fell in the V1 cellular hierarchy (based on their susceptibility to surround suppression, their putative classification as interneuron or pyramidal neuron, and designation as a simple or complex cell) and found that higher-level V1 single units are more responsive to NCS stimuli. These findings resolve the debate of whether V1 is involved in illusory brightness processing and reveal a V1 hierarchical organization in which higher-level neurons are pivotal to the processing of illusory qualities, such as brightness.

The brainstem region, locus coeruleus (LC), has been remarkably conserved across vertebrates. Evolution has woven the LC into wide-ranging neural circuits that influence functions as broad as autonomic systems, the stress response, nociception, sleep, and high-level cognition among others. Given this conservation, there is a strong possibility that LC activity is inherently similar across species, and furthermore that age, sex, and brain state influence LC activity similarly across species. The degree to which LC activity is homogenous across these factors, however, has never been assessed due to the small sample size of individual studies. Here, we pool data from 20 laboratories (1,855 neurons) and show diversity across both intrinsic and extrinsic factors such as species, age, sex and brain state. We use a negative binomial regression model to compare activity from male monkeys, and rats and mice of both sexes that were recorded across brain states from brain slices or under different anesthetics or during wakefulness . LC activity differed due to complex interactions of species, sex, and brain state. The LC became more active during aging, independent of sex. Finally, in contrast to the foundational principle that all species express two distinct LC firing modes (\"tonic\" or \"phasic\"), we discovered great diversity within spontaneous LC firing patterns. Different factors were associated with higher incidence of some firing modes. We conclude that the activity of the evolutionarily-ancient LC is not conserved. Inherent differences due to age and species-sex-brain state interactions have implications for understanding the role of LC in species-specific naturalistic behavior, as well as in psychiatric disorders, cardiovascular disease, immunology, and metabolic disorders.

Contemporary neuroscience and psychiatry suggest that attention to decision outcomes guides rule learning by adjusting stimulus-outcome associations. Separately, sensory neurophysiology conceptualizes attention as a ‘filter’ that improves perception. Here, we show that the contemporary view is incomplete by demonstrating an unconventional and novel effect of perceptual attention on subsequent outcome-based rule learning. Moreover, we show for the first time in rodents that, like in primates, this attentional process involves tuning of modality specific cortico-cortical interactions. We designed a novel head-fixed rat-on-a-treadmill apparatus and used it to train rats to discriminate auditory-visual stimuli using one modality and then reduced stimulus discriminability in that modality. We observed perceptual learning suggesting engagement of perceptual attention. Moreover, engaging visual perceptual attention resulted in more saccades and increased frontal-visual cortex EEG Granger causality relative to engaging auditory perceptual attention. We then presented novel and easily discriminable stimuli in both modalities and measured outcome-driven learning in the other modality. Learning was slower after engaging perceptual attention. Our work suggests that a more complete description of learning requires integrating these previously siloed concepts of attention. Moreover, treating impaired set-shifting as a trans-diagnostic symptom may require targeting different neural circuits for perceptual attention or outcome-based attention depending on which type of attention is impaired in each neuro-psychiatric disorder.