Hallucinations and delusions can be explained as a misconfiguration of these internal models: inaccurate predictions of the sensory consequences of movements can result in self-generated activity that is not correctly distinguished from externally driven activity ( Fletcher and Frith, 2009 Frith, 2005). Internal models are the transformations between cortical areas and can be used to predict the sensory consequences of movement. This coupling is key to our brain’s ability to learn internal models of the world ( Jordan and Rumelhart, 1992). Locomotion, for example, is coupled to proprioceptive feedback from muscle movements, somatosensory and auditory feedback from touching the ground, vestibular feedback from translational acceleration, and visual feedback in the form of expanding visual flow. Under normal conditions, self-generated movements are coupled to sensory feedback in different modalities. This work will be of interest to neuroscientists working on visual processing and psychosis researchers. The evidence supporting the conclusions is solid, although the statistical testing of the data may be improved. This important study uses calcium imaging in mice to advance our understanding of the effect of antipsychotic drugs on neural functioning. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is an alteration of the activation of internal representations as a consequence of reduced long-range layer 5 mediated communication. 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. 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 then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. 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. Here we used widefield calcium imaging to determine the cell type specific functional effects of antipsychotic drugs in mouse dorsal cortex during visuomotor integration. How these drugs influence the function of cortical circuits, and in particular their ability to identify self-generated activity patterns, is still largely unclear. 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. Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns.
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