Corollary Discharge in Genetic Mouse Models of Schizophrenia
Biological Psychiatry
Final Report Abstract
Many of the stimuli that impinge on our senses are caused by our own actions (for example the sound of our footsteps) and must be distinguished from stimuli caused by external events (sound of someone else’s footsteps). Typically, neural responses to such self-generated stimuli are attenuated in amplitude and this is thought to reflect a “corollary discharge” signal representing the expected sensory consequences of our actions. In contrast to healthy individuals, schizophrenia patients show less attenuation of responses to self-generated stimuli and this has been hypothesized to contribute to the hallucinations and delusions that are characteristic symptoms of the disease. The overall goal of this project was to examine the cellular and neural circuit mechanisms underlying this sensory deficit and how it relates to the risk factors for schizophrenia using genetic mouse models of the disease. To this end, we established an experimental paradigm for measuring responses to self-generated sounds in mice and characterized for the first time how such sounds are processed by neurons in the mouse auditory cortex (AC). This revealed that, similar to what has been observed in human subjects, responses of AC neurons to self-generated sounds are reduced in magnitude. Among other things, we also showed that this effect was strongest in neurons in the deeper cortical layers and depended on the probability with which sounds were caused by behavior, indicating a predictive process. We next examined the processing of self-generated sounds in Df(16)A+/− mice, which carry one of the largest genetic risk factors for schizophrenia, the 22q11.2 microdeletion. We found that AC neurons in these mice showed weaker attenuation of their responses to self-generated sounds, reminiscent of findings observed in schizophrenia patients. To investigate possible circuit mechanisms underlying this deficit, we examined a projection from the secondary motor cortex (M2) to the AC, which can relay motor-related information to the AC for generating corollary discharge signals. Optogenetic experiments in wild-type mice showed that this pathway modulates the activity of AC neurons primarily in deeper cortical layers. Furthermore, retrograde tracing of inputs to the AC revealed fewer inputs In Df(16)A+/− mice from M2 and consistent with this, AC neurons showed weaker motor-related signals. These results suggest impaired corollary discharge signaling in these mice which could underlie their failure to attenuate responses to selfgenerated sounds. Overall, the project thus delivered important insights into how self-generated stimuli are processed in health and disease, demonstrating how a major genetic risk factor for schizophrenia disrupts the top-down processing of sensory information.
Publications
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Attenuation of Responses to Self-Generated Sounds in Auditory Cortical Neurons. The Journal of Neuroscience, 36(47), 12010-12026.
Rummell, Brian P.; Klee, Jan L. & Sigurdsson, Torfi
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Altered corollary discharge signaling in the auditory cortex of a mouse model of schizophrenia predisposition. Nature Communications, 14(1).
Rummell, Brian P.; Bikas, Solmaz; Babl, Susanne S.; Gogos, Joseph A. & Sigurdsson, Torfi
