Schizophrenia negatively impacts the lives of approximately 3 million Americans, and represents a major global health burden. The identification of susceptibility factors relevant to the pathogenesis of schizophrenia in conjunction with animal modelling will likely accelerate the development of novel treatment strategies with improved efficacy, safety, and tolerability. There is a beurgoning body of evidence from epidemiological, clinical, neuroanatomical, neurochemical, and neurodevelopmental studies that implicate omega-3 (n-3) fatty acid deficiency as an important susceptibility factor in schizophrenia pathogenesis. The objective of this application is to test the central hypothesis that n-3 fatty acid deficiency will reproduce in rats the neuroanatomical, behavioral, and neurochemical abnormalities observed in other putative animal models of schizophrenia. The rationale for the proposed studies is that their completion is anticipated to produce proof- of-concept data regarding the face, construct, and predictive validity of a novel animal model of schizophrenia. The model's face and construct validity will be evaluated by determining the effect of n-3 fatty acid deficiency in rat on: (1) neuroanatomical features by magnetic resonance imaging: volume reductions in white matter, gray matter, amygdala-hippocampus complex, thalamus, cerebellar vermis, and corpus callossum volume, volume increases in lateral and third ventricular, and basal ganglia, and postmortem regional reductions in N-acetyl aspartate levels (Specific Aim 1), (2) behavioral/neuropsychological features: latent inhibition (attention), prepulse inhibition (sensorimotor gating), hippocampus- and prefrontal cortex- dependent learning (declarative and working memory), social interaction (social withdrawal), and sucrose preference (anhedonia)(Specific Aim 2), and (3) neurochemical features: increased sensitivity to dopamine- agonist- (amphetamine) and the NMDA receptor antagonist- (MK-801) induced locomotor activity and stereotypy (Specific Aim 3). The model's predictive validity will be evaluated by determining the capacity of prior chronic antipsychotic treatment to attenuate n-3 fatty acid deficiency-induced deficits. These experiments are innovative and the results will be significant because they are anticipated to establish the face, construct, and predictive validity of a novel animal model of schizophrenia created via the manipulation of a candidate non-genomic susceptibility factor, n-3 fatty acid deficiency. ? ?
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