Effective Disconnection of Intrinsic Networks in the Prefrontal Cortex: Convergence across Primate and Mouse Models of Schizophrenia

Abstract

Individuals who are afflicted with schizophrenia experience a disorienting array of symptoms that include sensations of nonexistent stimuli (hallucinations), fixed beliefs not grounded in reality (delusions), emotional disturbances, and a generalized disorganization of thought. Some of the most fundamental aspects of consciousness can be disrupted in schizophrenia, such as the capacity to maintain a continuous thought process, plan and predict future actions and consequences, discern threatening from beneficial stimuli, and consciously inhibit impulsive or harmful behavior. Descriptions of the subjective experience of schizophrenia often revolve around the idea that the executive “self” of an individual is disconnected or no longer whole. Executive functions are thought to be distributed throughout cortical and subcortical networks, but to the extent that they can be localized they tend to depend on proper functioning of regions within the prefrontal cortex. In particular, the dorsolateral prefrontal cortex (DLPFC) of primates is considered to be vital in the process of organizing thought, and likewise the disorganization of thought in schizophrenia is linked to dysfunction in this region. For example, the DLPFC contains a densely interconnected circuit of pyramidal neurons that can sustain neural activity in the absence of sensory input, which is thought to underlie our ability to maintain a concept “in mind” after it has disappeared. What happens when these fundamental processes are disrupted? The manifestations can range from subtle disturbances in the integration of sensory input to a failure to distinguish reality from imagination. In this dissertation, I describe the contributions I have made to the understanding of schizophrenia during the course of my graduate school training. I was given the opportunity to begin my work on this project by analyzing preexisting neural data obtained from the DLPFC in a pharmacological primate model of schizophrenia . From there, I developed a surgical and recording protocol that allowed me to generate comparable in vivo data from the prefrontal cortex of awake Dgcr8+/- mice, an established genetic model of schizophrenia. Despite the disparities between these two animal models, I report convergent patterns indicating a disruption of neuronal correlations in the prefrontal regions of both monkeys given dissociative drugs and mice carrying a schizophrenia-associated mutation. In both studies, I found evidence that neurons in the disease state were not synchronizing their activity with each other as effectively as in the control state. Furthermore, the effective transfer of information between pairs of neighboring neurons was reduced. These results suggest that the intrinsic circuitry of the prefrontal cortex may be disconnected in schizophrenia, and that this disconnection relates to a reduction in coincident spiking activity of neighboring neurons. It is plausible that such a dissolution of local prefrontal connectivity could result in a failure to achieve the cognitively demanding task of thought organization. While much is yet to be learned about the nature of schizophrenia, my findings have the potential to motivate the development of novel approaches to the restoration of function in this devastating disease.