We have recently discovered a promising candidate biomarker of antipsychotic drug function in cortex. The overarching aim of this research project is to establish the validity of this biomarker, understand its mechanism, and test its disease relevance. Antipsychotic drugs are a class of small molecules that act on a diverse set of neuromodulatory receptors and reduce or ameliorate psychosis in patients. While the receptor binding profiles of most of these drugs are well established, it is still unclear how they influence brain function and what their treatment-relevant functional effects are. Psychosis can be characterized as a diminished ability of the brain to distinguish internally and externally generated activity patterns. In humans, conscious perception likely occurs in cortex. We were investigating mechanisms by which cortical circuits in the mouse distinguish self-generated feedback from externally generated input, and how this process is influenced by substances known to interfere with conscious perception, such as antipsychotic drugs. We discovered that a key set of clinically relevant antipsychotic drugs all selectively alter the ability of layer 5 excitatory neurons to distinguish externally and internally generated stimuli, and decorrelate the activity of layer 5 neurons in different cortical areas. These effects were absent or much reduced in other cortical layers. The aims of this research project are first, to improve upon our original measurement method to enable higher throughput and test a wide variety of antipsychotic and hallucinogenic compounds. Second, to determine the mechanisms underlying the decorrelation effect on layer 5 neurons by probing both the influence of antipsychotic drugs on local cortical circuitry as well as on cortico-striatal-thalamic loops. Third and last, to test whether the antipsychotic influence on cortical layer 5 neurons might be disease relevant by probing layer specific functional alterations in mouse models of schizophrenia. The relevance of this research is two-fold. First, if the decorrelation of layer 5 is indeed a biomarker of antipsychotic efficacy, this would be useful as a screen for antipsychotic efficacy of novel compounds. Second, we suspect that the alteration of layer 5 activity is indeed disease relevant and a core mechanism involved in the etiology of schizophrenia. Currently, we have no clear understanding of the circuit alterations in schizophrenia and cannot design targeted circuit interventions. Thus, should we be able to confirm the layer 5 biomarker of antipsychotic drugs and establish its mechanism, this research would have a directly translatable impact on antipsychotic drug discovery.