Schizophrenia is a prevalent and debilitating mental illness. The psychotic or positive symptoms of the disease can sometimes be addressed by treatment with antipsychotic medications. However, antipsychotic medications have limited effectiveness and treat only a subset of symptoms, deficiencies that have not been addressed since these medications were developed over 50 years ago. In addition, psychosis is observed in many other psychiatric illnesses, including schizotypal personality disorder, bipolar disorder, and temporal lobe epilepsy. The fact that antipsychotic medications act by blocking dopamine (DA), along with other lines of evidence, suggests that the symptoms schizophrenia might be caused by excess DA release in the brain. It has been proposed that this DA excess could be caused by dysfunction in afferent regions governing ventral tegmental area (VTA) DA neuron activity. However, these regions have not been fully characterized. My project is therefore designed to enhance our knowledge of afferent regions involved in controlling activity of VTA DA cells, and which of these afferent regions could contribute to the aberrant neurobiology seen in schizophrenia. Previous findings from our group and others have described a tripartite circuit containing the ventral subiculum (vSub), nucleus accumbens (NAc), and ventral pallidum (VP), which governs the proportion of VTA DA neurons that are spontaneously active, ie population activity. Population activity is a key parameter of VTA activity, because DA cells can only exhibit burst firing if they are spontaneously active. Recently, our group reported that inhibition of the infralimbic subdivision of the medial prefrontal cortex (ilPFC) increases population activit, and that this effect depends on vSub. However, there is no direct projection from ilPFC to the ventral hippocampus. We propose that communication between the two structures is mediated by the nucleus reuniens of the midline thalamus (RE). Several anatomical studies have characterized dense, reciprocal connections between RE and ilPFC/vSub. This suggests that RE could be involved in controlling VTA DA neuron population activity, and that ilPFC might exert its influence on VTA via RE. In addition, dysfunction in prefrontal cortex, hyperactivity in thalamus, and hyperactivity in ventral hippocampus have been proposed to underlie the psychotic symptoms of schizophrenia and other disorders. However, the idea that hyperactivity in RE could lead to overdrive of vSub and aberrantly high VTA DA neuron activity has never been tested directly. We will address these questions with the following specific aims: 1) Determine the role of RE in regulating VTA DA neuron population activity 2) Determine if ilPFC control of VTA DA population activity is mediated by RE 3) Determine how altered signaling in the ilPFC-RE-vSub circuit contributes to hyperdopaminergic states, using circuit-based electrophysiological and behavioral approaches.

Public Health Relevance

Schizophrenia is a prevalent and debilitating mental illness. Antipsychotic medications have limited effectiveness in treating schizophrenia and address only a subset of symptoms, deficiencies that have not been addressed since these medications were developed over 50 years ago. In this proposal we will investigate the function of circuits relevant to controlling dopamine release in the brain and to schizophrenia. Our findings could help make great strides towards the development of novel therapeutic interventions for patients experiencing psychosis not only in schizophrenia, but a variety of other psychiatric disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Van'T Veer, Ashlee V
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University of Pittsburgh
Schools of Arts and Sciences
United States
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