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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Du, Yijuan; Grace, Anthony A (2016) Amygdala Hyperactivity in MAM Model of Schizophrenia is Normalized by Peripubertal Diazepam Administration. Neuropsychopharmacology 41:2455-62
Grace, Anthony A (2016) Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci 17:524-32
Du, Yijuan; Grace, Anthony A (2016) Loss of Parvalbumin in the Hippocampus of MAM Schizophrenia Model Rats Is Attenuated by Peripubertal Diazepam. Int J Neuropsychopharmacol 19:
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
Deserno, Lorenz; Huys, Quentin J M; Boehme, Rebecca et al. (2015) Ventral striatal dopamine reflects behavioral and neural signatures of model-based control during sequential decision making. Proc Natl Acad Sci U S A 112:1595-600
Modinos, Gemma; Allen, Paul; Grace, Anthony A et al. (2015) Translating the MAM model of psychosis to humans. Trends Neurosci 38:129-38
Belujon, Pauline; Grace, Anthony A (2015) Regulation of dopamine system responsivity and its adaptive and pathological response to stress. Proc Biol Sci 282:
Deserno, Lorenz; Beck, Anne; Huys, Quentin J M et al. (2015) Chronic alcohol intake abolishes the relationship between dopamine synthesis capacity and learning signals in the ventral striatum. Eur J Neurosci 41:477-86
Chase, Henry W; Clos, Mareike; Dibble, Sofia et al. (2015) Evidence for an anterior-posterior differentiation in the human hippocampal formation revealed by meta-analytic parcellation of fMRI coordinate maps: focus on the subiculum. Neuroimage 113:44-60

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