ABSTRACT
Predictive processing is a computational framework that aims to explain how the brain processes sensory information by making predictions about the environment and minimizing prediction errors. It can also be used to explain some of the key symptoms of psychotic disorders such as schizophrenia. In recent years, substantial advances have been made in our understanding of the neuronal circuitry that underlies predictive processing in cortex. In this review, we summarize these findings and how they might relate to psychosis and to observed cell type-specific effects of antipsychotic drugs. We argue that quantifying the effects of antipsychotic drugs on specific neuronal circuit elements is a promising approach to understanding not only the mechanism of action of antipsychotic drugs but also psychosis. Finally, we outline some of the key experiments that should be done. The aims of this review are to provide an overview of the current circuit-based approaches to psychosis and to encourage further research in this direction.
Subject(s)
Psychotic Disorders , Humans , Psychotic Disorders/physiopathology , Animals , Antipsychotic Agents/therapeutic use , Antipsychotic Agents/pharmacology , Brain/physiopathology , Brain/physiology , Nerve Net/physiopathology , Nerve Net/physiology , Schizophrenia/physiopathology , Neural Pathways/physiopathology , Neural Pathways/physiology , Models, NeurologicalABSTRACT
The emergence of sensory-guided behavior depends on sensorimotor coupling during development. How sensorimotor experience shapes neural processing is unclear. Here, we show that the coupling between motor output and visual feedback is necessary for the functional development of visual processing in layer 2/3 (L2/3) of primary visual cortex (V1) of the mouse. Using a virtual reality system, we reared mice in conditions of normal or random visuomotor coupling. We recorded the activity of identified excitatory and inhibitory L2/3 neurons in response to transient visuomotor mismatches in both groups of mice. Mismatch responses in excitatory neurons were strongly experience dependent and driven by a transient release from inhibition mediated by somatostatin-positive interneurons. These data are consistent with a model in which L2/3 of V1 computes a difference between an inhibitory visual input and an excitatory locomotion-related input, where the balance between these two inputs is finely tuned by visuomotor experience.
Subject(s)
Psychomotor Performance , Visual Cortex/physiology , Animals , Feedback, Sensory , Female , Interneurons/cytology , Male , Mice , Mice, Inbred C57BL , Neurons/cytology , Optogenetics , Photic Stimulation , Visual Cortex/cytology , Visual PerceptionABSTRACT
What cortical inputs are provided to motor control areas while they drive complex learned behaviors? We study this question in the nucleus interface of the nidopallium (NIf), which is required for normal birdsong production and provides the main source of auditory input to HVC, the driver of adult song. In juvenile and adult zebra finches, we find that spikes in NIf projection neurons precede vocalizations by several tens of milliseconds and are insensitive to distortions of auditory feedback. We identify a local isometry between NIf output and vocalizations: quasi-identical notes produced in different syllables are preceded by highly similar NIf spike patterns. NIf multiunit firing during song precedes responses in auditory cortical neurons by about 50 ms, revealing delayed congruence between NIf spiking and a neural representation of auditory feedback. Our findings suggest that NIf codes for imminent acoustic events within vocal performance.
Subject(s)
Finches/physiology , Vocalization, Animal/physiology , Action Potentials , Animals , Auditory Perception , MaleABSTRACT
Songbirds are capable of vocal learning and communication and are ideally suited to the study of neural mechanisms of complex sensory and motor processing. Vocal communication in a noisy bird colony and vocal learning of a specific song template both require the ability to monitor auditory feedback to distinguish self-generated vocalizations from external sounds and to identify mismatches between the developing song and a memorized template acquired from a tutor. However, neurons that respond to auditory feedback from vocal output have not been found in song-control areas despite intensive searching. Here we investigate feedback processing outside the traditional song system, in single auditory forebrain neurons of juvenile zebra finches that were in a late developmental stage of song learning. Overall, we found similarity of spike responses during singing and during playback of the bird's own song, with song responses commonly leading by a few milliseconds. However, brief time-locked acoustic perturbations of auditory feedback revealed complex sensitivity that could not be predicted from passive playback responses. Some neurons that responded to playback perturbations did not respond to song perturbations, which is reminiscent of sensory-motor mirror neurons. By contrast, some neurons were highly feedback sensitive in that they responded vigorously to song perturbations, but not to unperturbed songs or perturbed playback. These findings suggest that a computational function of forebrain auditory areas may be to detect errors between actual feedback and mirrored feedback deriving from an internal model of the bird's own song or that of its tutor. Such feedback-sensitive spikes could constitute the key signals that trigger adaptive motor responses to song disruptions or reinforce exploratory motor gestures for vocal learning.
Subject(s)
Auditory Perception/physiology , Finches/physiology , Vocalization, Animal/physiology , Acoustic Stimulation , Action Potentials , Animals , Brain/cytology , Brain/physiology , Feedback, Physiological , Learning/physiology , MaleABSTRACT
Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic drugs are a class of small molecules with relatively broad binding affinity for a variety of neuromodulator receptors that, in humans, can prevent or ameliorate psychosis. How these drugs influence the function of cortical circuits, and in particular their ability to distinguish between externally and self-generated activity patterns, is still largely unclear. To have experimental control over self-generated sensory feedback, we used a virtual reality environment in which the coupling between movement and visual feedback can be altered. We then used widefield calcium imaging to determine the cell type-specific functional effects of antipsychotic drugs in mouse dorsal cortex under different conditions of visuomotor coupling. By comparing cell type-specific activation patterns between locomotion onsets that were experimentally coupled to self-generated visual feedback and locomotion onsets that were not coupled, we show that deep cortical layers were differentially activated in these two conditions. We then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. Given that one of the key components of visuomotor integration in cortex is long-range cortico-cortical connections, we tested whether the effect of clozapine was detectable in the correlation structure of activity patterns across dorsal cortex. We found that clozapine as well as two other antipsychotic drugs, aripiprazole and haloperidol, resulted in a strong reduction in correlations of layer 5 activity between cortical areas and impaired the spread of visuomotor prediction errors generated in visual cortex. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is a selective alteration of long-range layer 5-mediated communication.
Subject(s)
Antipsychotic Agents , Clozapine , Humans , Animals , Mice , Antipsychotic Agents/pharmacology , Clozapine/pharmacology , Haloperidol/pharmacology , Brain/physiology , Aripiprazole/pharmacologyABSTRACT
A new study leveraging advances in high-field fMRI provides evidence that superficial cortical layers in humans play a crucial role in signaling prediction errors, a finding that is consistent with the predictive processing framework.
Subject(s)
Magnetic Resonance Imaging , Humans , Cerebral Cortex/physiology , Cerebral Cortex/diagnostic imaging , Brain Mapping/methodsABSTRACT
Acetylcholine is released in visual cortex by axonal projections from the basal forebrain. The signals conveyed by these projections and their computational significance are still unclear. Using two-photon calcium imaging in behaving mice, we show that basal forebrain cholinergic axons in the mouse visual cortex provide a binary locomotion state signal. In these axons, we found no evidence of responses to visual stimuli or visuomotor prediction errors. While optogenetic activation of cholinergic axons in visual cortex in isolation did not drive local neuronal activity, when paired with visuomotor stimuli, it resulted in layer-specific increases of neuronal activity. Responses in layer 5 neurons to both top-down and bottom-up inputs were increased in amplitude and decreased in latency, whereas those in layer 2/3 neurons remained unchanged. Using opto- and chemogenetic manipulations of cholinergic activity, we found acetylcholine to underlie the locomotion-associated decorrelation of activity between neurons in both layer 2/3 and layer 5. Our results suggest that acetylcholine augments the responsiveness of layer 5 neurons to inputs from outside of the local network, possibly enabling faster switching between internal representations during locomotion.
Subject(s)
Acetylcholine , Optogenetics , Visual Cortex , Animals , Visual Cortex/physiology , Mice , Acetylcholine/metabolism , Cholinergic Neurons/physiology , Locomotion/physiology , Male , Photic Stimulation , Axons/physiology , Neurons/physiologyABSTRACT
Here, we present a sample collection protocol for single-cell RNA sequencing of functionally identified neuronal populations in vivo with a virally delivered activity-dependent labeling tool (CaMPARI2). We describe steps for photoconversion in mice during the onset of computationally relevant events in a virtual reality environment, followed by removal and dissociation of the photo-labeled tissue, and separation of differentially labeled groups with fluorescence-activated cell sorting (FACS). We then detail procedures for characterizing and examining functionally relevant groups using standard bioinformatic techniques. For complete details on the use and execution of this protocol, please refer to O'Toole et al.1.
Subject(s)
Flow Cytometry , Neurons , Sequence Analysis, RNA , Single-Cell Analysis , Animals , Single-Cell Analysis/methods , Mice , Neurons/cytology , Neurons/metabolism , Sequence Analysis, RNA/methods , Flow Cytometry/methodsABSTRACT
Prediction errors are differences between expected and actual sensory input and are thought to be key computational signals that drive learning related plasticity. One way that prediction errors could drive learning is by activating neuromodulatory systems to gate plasticity. The catecholaminergic locus coeruleus (LC) is a major neuromodulatory system involved in neuronal plasticity in the cortex. Using two-photon calcium imaging in mice exploring a virtual environment, we found that the activity of LC axons in the cortex correlated with the magnitude of unsigned visuomotor prediction errors. LC response profiles were similar in both motor and visual cortical areas, indicating that LC axons broadcast prediction errors throughout the dorsal cortex. While imaging calcium activity in layer 2/3 of the primary visual cortex, we found that optogenetic stimulation of LC axons facilitated learning of a stimulus-specific suppression of visual responses during locomotion. This plasticity - induced by minutes of LC stimulation - recapitulated the effect of visuomotor learning on a scale that is normally observed during visuomotor development across days. We conclude that prediction errors drive LC activity, and that LC activity facilitates sensorimotor plasticity in the cortex, consistent with a role in modulating learning rates.
Subject(s)
Locus Coeruleus , Visual Cortex , Mice , Animals , Locus Coeruleus/physiology , Calcium , Learning/physiologyABSTRACT
The aim of this work is to provide a comment on a recent paper by Muzzu and Saleem (2021), which claims that visuomotor mismatch responses in mouse visual cortex can be explained by a locomotion-induced gain of visual halt responses. Our primary concern is that without directly comparing these responses with mismatch responses, the claim that one response can explain the other appears difficult to uphold, more so because previous work finds that a uniform locomotion-induced gain cannot explain mismatch responses. To support these arguments, we analyze layer 2/3 calcium imaging datasets and show that coupling between visual flow and locomotion greatly enhances mismatch responses in an experience-dependent manner compared with halts in non-coupled visual flow. This is consistent with mismatch responses representing visuomotor prediction errors. Thus, we conclude that while feature selectivity might contribute to mismatch responses in mouse visual cortex, it cannot explain these responses.
Subject(s)
Primary Visual Cortex , Visual Cortex , Mice , Animals , Locomotion/physiology , Visual Cortex/physiology , Calcium , Photic Stimulation/methodsABSTRACT
Predictive processing postulates the existence of prediction error neurons in cortex. Neurons with both negative and positive prediction error response properties have been identified in layer 2/3 of visual cortex, but whether they correspond to transcriptionally defined subpopulations is unclear. Here we used the activity-dependent, photoconvertible marker CaMPARI2 to tag neurons in layer 2/3 of mouse visual cortex during stimuli and behaviors designed to evoke prediction errors. We performed single-cell RNA-sequencing on these populations and found that previously annotated Adamts2 and Rrad layer 2/3 transcriptional cell types were enriched when photolabeling during stimuli that drive negative or positive prediction error responses, respectively. Finally, we validated these results functionally by designing artificial promoters for use in AAV vectors to express genetically encoded calcium indicators. Thus, transcriptionally distinct cell types in layer 2/3 that can be targeted using AAV vectors exhibit distinguishable negative and positive prediction error responses.
Subject(s)
Neurons , Visual Cortex , Animals , Mice , Cerebral Cortex , Promoter Regions, GeneticABSTRACT
Learned associations between stimuli in different sensory modalities can shape the way we perceive these stimuli. However, it is not well understood how these interactions are mediated or at what level of the processing hierarchy they occur. Here we describe a neural mechanism by which an auditory input can shape visual representations of behaviorally relevant stimuli through direct interactions between auditory and visual cortices in mice. We show that the association of an auditory stimulus with a visual stimulus in a behaviorally relevant context leads to experience-dependent suppression of visual responses in primary visual cortex (V1). Auditory cortex axons carry a mixture of auditory and retinotopically matched visual input to V1, and optogenetic stimulation of these axons selectively suppresses V1 neurons that are responsive to the associated visual stimulus after, but not before, learning. Our results suggest that cross-modal associations can be communicated by long-range cortical connections and that, with learning, these cross-modal connections function to suppress responses to predictable input.
Subject(s)
Auditory Cortex , Visual Cortex , Acoustic Stimulation , Animals , Auditory Cortex/physiology , Learning , Mice , Photic Stimulation , Visual Cortex/physiologyABSTRACT
Homeostatic regulation is essential for stable neuronal function. Several synaptic mechanisms of homeostatic plasticity have been described, but the functional properties of synapses involved in homeostasis are unknown. We used longitudinal two-photon functional imaging of dendritic spine calcium signals in visual and retrosplenial cortices of awake adult mice to quantify the sensory deprivation-induced changes in the responses of functionally identified spines. We found that spines whose activity selectively correlated with intrinsic network activity underwent tumor necrosis factor alpha (TNF-α)-dependent homeostatic increases in their response amplitudes, but spines identified as responsive to sensory stimulation did not. We observed an increase in the global sensory-evoked responses following sensory deprivation, despite the fact that the identified sensory inputs did not strengthen. Instead, global sensory-evoked responses correlated with the strength of network-correlated inputs. Our results suggest that homeostatic regulation of global responses is mediated through changes to intrinsic network-correlated inputs rather than changes to identified sensory inputs thought to drive sensory processing.
Subject(s)
Neuronal Plasticity , Neurons , Mice , Animals , Neuronal Plasticity/physiology , Neurons/physiology , Homeostasis/physiology , Synapses/physiology , Sensory Deprivation/physiologyABSTRACT
During visual development, response properties of layer 2/3 neurons in visual cortex are shaped by experience. Both visual and visuomotor experience are necessary to co-ordinate the integration of bottom-up visual input and top-down motor-related input. Whether visual and visuomotor experience engage different plasticity mechanisms, possibly associated with the two separate input pathways, is still unclear. To begin addressing this, we measured the expression level of three different immediate early genes (IEG) (c-fos, egr1 or Arc) and neuronal activity in layer 2/3 neurons of visual cortex before and after a mouse's first visual exposure in life, and subsequent visuomotor learning. We found that expression levels of all three IEGs correlated positively with neuronal activity, but that first visual and first visuomotor exposure resulted in differential changes in IEG expression patterns. In addition, IEG expression levels differed depending on whether neurons exhibited primarily visually driven or motor-related activity. Neurons with strong motor-related activity preferentially expressed EGR1, while neurons that developed strong visually driven activity preferentially expressed Arc. Our findings are consistent with the interpretation that bottom-up visual input and top-down motor-related input are associated with different IEG expression patterns and hence possibly also with different plasticity pathways.
ABSTRACT
The experience of coupling between motor output and visual feedback is necessary for the development of visuomotor skills and shapes visuomotor integration in visual cortex. Whether these experience-dependent changes of responses in V1 depend on modifications of the local circuit or are the consequence of circuit changes outside of V1 remains unclear. Here, we probed the role of N-methyl-d-aspartate (NMDA) receptor-dependent signaling, which is known to be involved in neuronal plasticity, in mouse primary visual cortex (V1) during visuomotor development. We used a local knockout of NMDA receptors and a photoactivatable inhibition of CaMKII in V1 during the first visual experience to probe for changes in neuronal activity in V1 as well as the influence on performance in a visuomotor task. We found that a knockout of NMDA receptors before, but not after, first visuomotor experience reduced responses to unpredictable stimuli, diminished the suppression of predictable feedback in V1, and impaired visuomotor skill learning later in life. Our results demonstrate that NMDA receptor-dependent signaling in V1 is critical during the first visuomotor experience for shaping visuomotor integration and enabling visuomotor skill learning.
Subject(s)
Receptors, N-Methyl-D-Aspartate , Visual Cortex , Animals , Learning , Mice , Neuronal Plasticity/physiology , Neurons/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Visual Cortex/physiologyABSTRACT
The zebrafish is an important model in systems neuroscience but viral tools to dissect the structure and function of neuronal circuitry are not established. We developed methods for efficient gene transfer and retrograde tracing in adult and larval zebrafish by herpes simplex viruses (HSV1). HSV1 was combined with the Gal4/UAS system to target cell types with high spatial, temporal, and molecular specificity. We also established methods for efficient transneuronal tracing by modified rabies viruses in zebrafish. We demonstrate that HSV1 and rabies viruses can be used to visualize and manipulate genetically or anatomically identified neurons within and across different brain areas of adult and larval zebrafish. An expandable library of viruses is provided to express fluorescent proteins, calcium indicators, optogenetic probes, toxins and other molecular tools. This toolbox creates new opportunities to interrogate neuronal circuits in zebrafish through combinations of genetic and viral approaches.
Subject(s)
Rabies virus , Zebrafish , Animals , Gene Expression , Neurons/physiology , Optogenetics/methods , Rabies virus/genetics , Zebrafish/geneticsABSTRACT
To generate complex bilateral motor patterns such as those underlying birdsong, neural activity must be highly coordinated across the two cerebral hemispheres. However, it remains largely elusive how this coordination is achieved given that interhemispheric communication between song-control areas in the avian cerebrum is restricted to projections received from bilaterally connecting areas in the mid- and hindbrain. By electrically stimulating cerebral premotor areas in zebra finches, we find that behavioral effectiveness of stimulation rapidly switches between hemispheres. In time intervals in which stimulation in one hemisphere tends to distort songs, stimulation in the other hemisphere is mostly ineffective, revealing an idiosyncratic form of motor dominance that bounces back and forth between hemispheres like a virtual ping-pong ball. The intervals of lateralized effectiveness are broadly distributed and are unrelated to simple spectral and temporal song features. Such interhemispheric switching could be an important dynamical aspect of neural coordination that may have evolved from simpler pattern generator circuits.
Subject(s)
Brain/physiology , Finches/physiology , Vocalization, Animal/physiology , Animals , Brain/anatomy & histology , Functional Laterality/physiology , High Vocal Center/anatomy & histology , High Vocal Center/physiology , Male , Models, Anatomic , Sound SpectrographyABSTRACT
Processing in cortical circuits is driven by combinations of cortical and subcortical inputs. These inputs are often conceptually categorized as bottom-up, conveying sensory information, and top-down, conveying contextual information. Using intracellular recordings in mouse primary visual cortex, we measured neuronal responses to visual input, locomotion, and visuomotor mismatches. We show that layer 2/3 (L2/3) neurons compute a difference between top-down motor-related input and bottom-up visual flow input. Most L2/3 neurons responded to visuomotor mismatch with either hyperpolarization or depolarization, and the size of this response was correlated with distinct physiological properties. Consistent with a subtraction of bottom-up and top-down input, visual and motor-related inputs had opposing influence on L2/3 neurons. In infragranular neurons, we found no evidence of a difference computation and responses were consistent with positive integration of visuomotor inputs. Our results provide evidence that L2/3 functions as a bidirectional comparator of top-down and bottom-up input.
Subject(s)
Motor Activity/physiology , Neurons/physiology , Visual Cortex/physiology , Visual Pathways/physiology , Animals , Mice , Patch-Clamp Techniques , Photic Stimulation , Visual Perception/physiologyABSTRACT
This perspective describes predictive processing as a computational framework for understanding cortical function in the context of emerging evidence, with a focus on sensory processing. We discuss how the predictive processing framework may be implemented at the level of cortical circuits and how its implementation could be falsified experimentally. Lastly, we summarize the general implications of predictive processing on cortical function in healthy and diseased states.
Subject(s)
Computer Simulation , Models, Neurological , Neocortex/physiology , Sensation/physiology , Animals , HumansABSTRACT
Motor cortex (M1) lesions result in motor impairments, yet how M1 contributes to the control of movement remains controversial. To investigate the role of M1 in sensory guided motor coordination, we trained mice to navigate a virtual corridor using a spherical treadmill. This task required directional adjustments through spontaneous turning, while unexpected visual offset perturbations prompted induced turning. We found that M1 is essential for execution and learning of this visually guided task. Turn-selective layer 2/3 and layer 5 pyramidal tract (PT) neuron activation was shaped differentially with learning but scaled linearly with turn acceleration during spontaneous turns. During induced turns, however, layer 2/3 neurons were activated independent of behavioral response, while PT neurons still encoded behavioral response magnitude. Our results are consistent with a role of M1 in the detection of sensory perturbations that result in deviations from intended motor state and the initiation of an appropriate corrective response.