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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH086781-04
Application #
8242104
Study Section
Special Emphasis Panel (ZMH1-ERB-L (05))
Program Officer
Meinecke, Douglas L
Project Start
2009-07-27
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$311,915
Indirect Cost
$113,915
Name
California Institute of Technology
Department
None
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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
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
Brown, Alan S; Patterson, Paul H (2011) Maternal infection and schizophrenia: implications for prevention. Schizophr Bull 37:284-90