We aim to explore a novel experimental approach to understanding mental disease. Our long-term goal is to understand how schizophrenia affects information processing in the brain. To this end, I will apply high-density tetrode electrophysiology techniques to record in multiple animal models of schizophrenia, during free behavior. Much recent work in schizophrenia has focused on enhanced activity of the default mode network: brain regions which are particularly co-active during rest periods, and which include the hippocampus. This converges with recent work by myself and others investigating normal hippocampal function, and particularly, the phenomenon of awake replay, in which large numbers of hippocampal neurons fire in sequences that relate to ongoing task demands. For example, awake replay can "look-ahead" along spatial trajectories ahead of an exploring animal to explore hypothetical outcomes. We propose to investigate neural activity during movement and rest, in two different mouse models of schizophrenia, in order to (1) determine whether there are disruptions to rest period activity in particular, reminiscent of disruption to the default mode network, and (2) determine whether two distinct genetic mouse models of schizophrenia exhibit commonalities, especially with respect to rest period activity. Our preliminary data show that hippocampal neural activity is affected in a forebrain-specific calcineurin knockout mouse model, in a manner specific to rest periods. We are now in a position to determine the effect of these changes on awake replay. We will also consider a transgenic DISC1 mouse model, which exhibits reduced parvalbumin-immunoreactivity, as is also seen in schizophrenia patients. This is particularly interesting because parvalbumin-containing interneurons initiate and sculpt awake replay events in normal animals, and loss of such inhibition might be expected to lead to a similar outcome as observed in the calcineurin mouse. Determining how information processing in rest periods is disrupted is a key goal, which will make possible future studies to determine how disruptions to awake replay affect ongoing task performance, how heterogeneous disease mechanisms may lead to similar behavioral phenotypes, and ultimately how circuit level dysfunction may be treated therapeutically. PUBLIC HEALTH RELEVANCE: Schizophrenia is a psychiatric disorder that affects almost 1% of the world population, and represents the seventh most costly medical illness to society. This proposal seeks to explore a novel experimental approach to the disease, looking for commonalities between two genetically distinct animal models, and specifically targeting neural activity at the level of circuits using a cutting edge electrophysiological technique that allows for the simultaneous recording of hundreds of neurons in freely behaving animals. This work will pave the way for a better understanding of how similar circuit level phenotypes might arise out of diverse genetic models, and generate a novel understanding of the neural basis of mental phenomena that might be applied in the future to the diagnosis and treatment of human patients.