Despite the impact on society, and the demonstrated utility of animal models for understanding disease, relatively few researchers work on animal models of mental illness such as schizophrenia. A major stumbling block is, how does one know if a mouse is schizophrenic? Although it is possible to measure behaviors related to the negative symptoms of schizophrenia such as deficits in social interaction, cognitive flexibility and sensory-motor gating, it is said to be impossible to evaluate the positive symptoms of schizophrenia, hallucinations and delusions. Thus, this disorder is often considered to be """"""""uniquely human"""""""".
We aim to test this assertion by developing an assay for a positive symptom of schizophrenia. We have developed an animal model with relevance for schizophrenia that is based on epidemiological findings that the risk for this disorder is strongly increased by maternal infection. The offspring of mice given a respiratory infection at mid-pregnancy display deficits in a series of behaviors relevant to schizophrenia. These include social interaction, prepulse inhibition, latent inhibition, interaction with a novel object, as well as increased anxiety under mildly stressful conditions. Moreover, these offspring display neuropathology that is characteristic of schizophrenia. We propose a novel approach towards animal studies of a positive symptom of schizophrenia. This will require a major advance with broad implications: establishing functional magnetic resonance imaging (fMRI) in awake mice. Using surrogate histological measures of neuronal activity, it appears that the mouse brain responds to hallucinogens in a manner similar to the human. Moreover, preliminary experiments indicate that at least one strain of mice can be adapted to the restraining device, allowing fMRI scanning. If this procedure can be established reliably, we will test the offspring of infected mothers for sensitivity to subthreshold doses of hallucinogens, as well as for spontaneous hallucinations, as defined by activity in the visual or somatosensory cortices in the absence of sensory input.

Public Health Relevance

Even partial success in this project could open up several new fields of investigation, attracting investigators into the important area of mouse models of mental illness. Auditory hallucinations are reported by 50-70% of schizophrenia patients, and they are often associated with acts of violence and suicide. Since the cause is unknown, an appropriate animal model of hallucination-like brain activity would be extremely useful in exploring novel therapeutic avenues.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1-ERB-L (05))
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Meinecke, Douglas L
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California Institute of Technology
Schools of Arts and Sciences
United States
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Malkova, Natalia V; Gallagher, Joseph J; Yu, Collin Z et al. (2014) Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia. Proc Natl Acad Sci U S A 111:E2492-500
Malkova, Natalia V; Yu, Collin Z; Hsiao, Elaine Y et al. (2012) Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun 26:607-16
Brown, Alan S; Patterson, Paul H (2011) Maternal infection and schizophrenia: implications for prevention. Schizophr Bull 37:284-90
Patterson, Paul H (2011) Maternal infection and immune involvement in autism. Trends Mol Med 17:389-94
Patterson, Paul H (2011) Modeling autistic features in animals. Pediatr Res 69:34R-40R