Studies conducted over the previous funding period were aimed at examining vSub-mPFC modulation of the NAc and how this affects dopamine (DA) neuron activity, and how this is disrupted in the MAM rat model of schizophrenia. Using the MAM model of schizophrenia, we found that these rats show hyper-responsivity to amphetamine that correlates with an increase in the number of dopamine neurons firing (i.e., dopamine neuron population activity). Moreover, this increase Is due to increased drive from the ventral subiculum of the hippocampus (vSub);a region that also shows decreased parvalbumin interneuron labeling. Forthe next 5 years ofthis grant, we plan to focus on several unique findings made during the initial funding period. Specifically, we plan to focus on plasticity and interactions of the hippocampus/prefrontal cortex interactions within the nucleus accumbens, and to now include the amygdala into this interaction based on growing evidence of Its importance in schizophrenia;to test whether the increase in hippocampal activity is correlated with a loss of parvalbumin interneurons or instead to a decrease in parvalbumin expression;to examine novel treatments for schizophrenia using our animal model;and to examine whether peripubertal inten/ention can prevent the transition to schizophrenia, and conversely whether stress during this interval will exacerbate the schizophrenia-like pathological changes. This will be accomplished by the following specific aims: 1. Examine how afferent drive and synaptic plasticity is altered in the MAM model within the vSub-mPFCamygdala- NAc circuit;2. Examine whether the increased vSub activity is due to loss of parvalbumin interneurons or decreased parvalbumin expression due to decreased interneuron drive, when this occurs in development, and if this can be reversed. 3. Examine potential novel treatments for schizophrenia based on restoration of function in the MAM model. 4. Examine whether peripubertal intervention can exacerbate or prevent the transition to experimental psychosis/pathophysiology in the MAM rat. We hope that this will provide novel information regarding the cellular dynamics underlying the pathological changes that occur In schizophrenia, novel targets for more effective treatment, and the potential for a preventive strategy.

Public Health Relevance

; Due to the lack of understanding ofthe cellular basis of schizophrenia, current treatment strategies have not been particularly effective in treating this disorder. Using a rat developmental model of schizophrenia that mimics many aspects of the disorder, we discovered the potential cellular basis for the psychotic symptoms of this disorder, which has led to new targets for more effectively treating schizophrenia as well as a potential strategy for prevention of the transition to schizophrenia in susceptible individuals.

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 (NSS)
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Meinecke, Douglas L
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University of Pittsburgh
Schools of Arts and Sciences
United States
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Gill, Kathryn M; Cook, James M; Poe, Michael M et al. (2014) Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia. Schizophr Bull 40:341-50
Chang, Chun-Hui; Grace, Anthony A (2014) Amygdala-ventral pallidum pathway decreases dopamine activity after chronic mild stress in rats. Biol Psychiatry 76:223-30
Gill, Kathryn M; Grace, Anthony A (2014) Corresponding decrease in neuronal markers signals progressive parvalbumin neuron loss in MAM schizophrenia model. Int J Neuropsychopharmacol 17:1609-19
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Ewing, Samuel G; Grace, Anthony A (2013) Evidence for impaired sound intensity processing during prepulse inhibition of the startle response in a rodent developmental disruption model of schizophrenia. J Psychiatr Res 47:1630-5
Du, Yijuan; Grace, Anthony A (2013) Peripubertal diazepam administration prevents the emergence of dopamine system hyperresponsivity in the MAM developmental disruption model of schizophrenia. Neuropsychopharmacology 38:1881-8
Zimmerman, Eric C; Bellaire, Mark; Ewing, Samuel G et al. (2013) Abnormal stress responsivity in a rodent developmental disruption model of schizophrenia. Neuropsychopharmacology 38:2131-9
Patton, Mary H; Bizup, Brandon T; Grace, Anthony A (2013) The infralimbic cortex bidirectionally modulates mesolimbic dopamine neuron activity via distinct neural pathways. J Neurosci 33:16865-73
Belujon, Pauline; Patton, Mary H; Grace, Anthony A (2013) Disruption of prefrontal cortical-hippocampal balance in a developmental model of schizophrenia: reversal by sulpiride. Int J Neuropsychopharmacol 16:507-12
Schlagenhauf, Florian; Rapp, Michael A; Huys, Quentin J M et al. (2013) Ventral striatal prediction error signaling is associated with dopamine synthesis capacity and fluid intelligence. Hum Brain Mapp 34:1490-9

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