The long-term goal of this project is to develop a rat model for the neuropathological and behavioral deficits of schizophrenia that can be used to analyze the neurobiological basis of schizophrenia-like behavioral deficits and to identify novel targets for the development of new treatments. The proposed animal model is based on disruption of neurogenesis with the anti- mitotic drug, cytosine arabinoside (AraC). The rationale for the proposed model is based on the idea that subtle lesions in the developing nervous system will have significant effects on the subsequent development and plasticity of the neural circuits that regulate adult behaviors. In preliminary experiments, we determined that sensorimotor gating is selectively altered in adult rats following prenatal AraC injections; consistent and significant deficits in baseline PPI were found only following AraC injections at embryonic days 19 and 20. Preliminary anatomical studies suggest that the hippocampus is disrupted in the E19/20 AraC treated age group. The purpose of this R21 proposal is to initiate a new series of investigations based upon these initial findings. The goal of this application is to bring to bear a new set of tools to probe the value of the model as a research tool in schizophrenia. We will focus on analyzing the hippocampal- cortical circuitry and how the timing of disruptions in neurogenesis affect a range of behavioral, functional, and neuroanatomical end points. The study hypothesis is that specifically-timed injections of AraC will produce subtle alterations in hippocampal-cortical circuitry resulting in behavioral and neurophysiological disruptions dependent upon this circuitry. A cohort of rats will be exposed to AraC on embryonic days 17 and 18 or 19 and 20 or on postnatal days 0 and 1. In the first and second specific aims of this application, open-field exploration will be used to characterize general abnormalities while sensorimotor gating, spatial navigation, and cortical long-term potentiation will be used to assess hippocampal-cortical circuitry. In the third specific aim, neuroanatomical techniques, including neuronal birthdate labeling with BrdU, will be used to characterize the effects of perinatal inhibition of neurogenesis on the development of the hippocampal-cortical circuit and select other regions that modulate this circuit. The long-term goal of this project is to develop a rat model of neuropathological and behavioral deficits in schizophrenia based on perinatal disruption of neurogenesis with an antimitotic drug, cytosine arabinoside. The model will be used to analyze the neurobiological basis of schizophrenia-like behavioral deficits and to identify novel targets for the development of new treatments for this devastating mental illness. ? ? ?
| Brown, P Leon; Shepard, Paul D; Elmer, Greg I et al. (2012) Altered spatial learning, cortical plasticity and hippocampal anatomy in a neurodevelopmental model of schizophrenia-related endophenotypes. Eur J Neurosci 36:2773-81 |
| Sillitoe, Roy V; Vogel, Michael W (2008) Desire, disease, and the origins of the dopaminergic system. Schizophr Bull 34:212-9 |
