Corollary Discharge in Genetic Mouse Models of Schizophrenia

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The goal of the proposal is to gain a deeper understanding of a sensory disturbance that has been reliably observed in schizophrenia patients, namely an impairment in distinguishing self-generated from externally generated stimuli. Many of the stimuli that impinge on our nervous system are caused directly by our own actions and need to be separated from stimuli arising from events in the external world. It has long been assumed that the brain solves this problem using corollary discharge, brain signals that represent the expected sensory consequences of the organisms actions. There is considerable evidence suggesting that these corollary discharge signals are impaired in schizophrenia patients and this disturbance has been hypothesized to underlie the hallucinations and delusions that are observed in the disease. The goal of this proposal is to deepen our understanding of corollary discharge deficits in schizophrenia in two ways: first, to examine in detail the neural circuit abnormalities underlying this deficit and second, to examine its relationship to known risk factors for the disease, in particular genetic mutations. To this end, we will examine corollary discharge in two mouse lines that have been genetically engineered to carry mutations that represent major risk factors for schizophrenia: the 22q11.2 microdeletion and the DISC1 mutation. Neural activity will be recorded simultaneously in multiple sites from both the auditory cortex and motor cortex of these mice while they trigger auditory stimuli by pressing a lever. The proposed experiments will thus help shed light on how mutations that predispose to schizophrenia affect corollary discharge and how their effects manifest themselves at the level of individual neurons and neural circuits. We hope that the results will further our understanding of how the brain processes self-generated stimuli in both healthy and diseased states.