This application is a competing continuation of a grant to investigate the basic science aspects of schizophrenia as it relates to limbic system function. Evidence implicates several structures, including the prefrontal cortex, hippocampus, and the nucleus accumbens, in schizophrenia pathophysiology. In addition, manipulation of the dopamine system has been shown to regulate the interactions of these systems, and to be disrupted in schizophrenia. This study uses in vivo electrophysiological, neurochemical, and behavioral techniques to examine the interactions of these systems as they relate to schizophrenia. A large body of evidence suggests that the hippocampus is hyperactive in schizophrenia, which is consistent with findings from our developmental disruption model of schizophrenia using prenatal administration of the mitotoxin methylazoxymethanol acetate. However, how hyperactivity translates into imbalances with respect to dopamine-limbic system balance are unknown. In this application, we will test the hypothesis that hyperactivity within the ventral subiculum drives much of the pathophysiology of limbic system function characteristic of schizophrenia. This will be done along 4 specific aims: 1) examine the impact of sustained ventral subicular activity on the activity and interaction of neurons in the nucleus accumbens and medial prefrontal cortex., 2) examine the role of the medial prefrontal cortex in regulating ventral subiculum-nucleus accumbens interactions, 3) examine how ventral subicular activation modulates dopamine neuron firing and 4) examine the state of these systems interactions in the developmental model, with emphasis on how inactivation of the ventral subiculum can restore these parameters to normal. In this way, we hope to provide important insights into the pathophysiology of schizophrenia and propose a novel therapeutic target for its alleviation. Relevance to public health issues: Schizophrenia is a devastating disorder that incapacitates 1% of the world population, costing hundreds of billions of dollars in health care and lost income annually. This study examines the basic biology of systems with known involvement in schizophrenia, based on the developmental nature of the disorder. The results will provide important new information regarding how these systems interact in normal and pathological states, and how function may be restored to a disordered dopamine system.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-BDCN-A (90))
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Meinecke, Douglas L
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University of Pittsburgh
Schools of Arts and Sciences
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Bortz, David M; Grace, Anthony A (2018) Medial septum differentially regulates dopamine neuron activity in the rat ventral tegmental area and substantia nigra via distinct pathways. Neuropsychopharmacology 43:2093-2100
Uliana, Daniela L; Resstel, Leonardo B M; Grace, Anthony A (2018) Fear extinction disruption in a developmental rodent model of schizophrenia correlates with an impairment in basolateral amygdala-medial prefrontal cortex plasticity. Neuropsychopharmacology 43:2459-2467
Neves, Gilda A; Grace, Anthony A (2018) ?7 Nicotinic receptor-modulating agents reverse the hyperdopaminergic tone in the MAM model of schizophrenia. Neuropsychopharmacology 43:1712-1720
Bortz, David M; Grace, Anthony A (2018) Medial septum activation produces opposite effects on dopamine neuron activity in the ventral tegmental area and substantia nigra in MAM vs. normal rats. NPJ Schizophr 4:17
Gill, Kathryn M; Miller, Sarah A; Grace, Anthony A (2018) Impaired contextual fear-conditioning in MAM rodent model of schizophrenia. Schizophr Res 195:343-352
Zhu, Xiyu; Gomes, Felipe V; Grace, Anthony A (2017) The methylazoxymethanol acetate rat model: molecular and epigenetic effect in the developing prefrontal cortex: An Editorial Highlight for 'Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM J Neurochem 143:264-267
Grace, Anthony A (2017) Dopamine System Dysregulation and the Pathophysiology of Schizophrenia: Insights From the Methylazoxymethanol Acetate Model. Biol Psychiatry 81:5-8
Zimmerman, Eric C; Grace, Anthony A (2016) The Nucleus Reuniens of the Midline Thalamus Gates Prefrontal-Hippocampal Modulation of Ventral Tegmental Area Dopamine Neuron Activity. J Neurosci 36:8977-84
Gomes, Felipe V; Rincón-Cortés, Millie; Grace, Anthony A (2016) Adolescence as a period of vulnerability and intervention in schizophrenia: Insights from the MAM model. Neurosci Biobehav Rev 70:260-270
Harun, Rashed; Hare, Kristin M; Brough, Elizabeth M et al. (2016) Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent, regionally selective bimodal effects on striatal dopamine kinetics in vivo. J Neurochem 136:1270-1283

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