This proposal represents a competing continuation of a grant to investigate the basic science aspects of schizophrenia as it relates to limbic system function. Pharmacological evidence has implicated the dopamine (DA) system in schizophrenia; however, there is little evidence for a direct pathology within the DA system itself. Instead, evidence has amassed to suggest a primary deficit within limbic cortical structures, each of which supplies a glutamatergic input that overlaps with the DA system within the nucleus accumbens (NAc). Three regions in particular have been associated with several aspects of schizophrenia, including the prefrontal cortex, the hippocampus subiculum and the basolateral amygdala. In the previous proposal, we examined how each of these systems provides synaptic influences in the NAc. In the current proposal, we will extend this to examine, using in vivo intracellular recording methods, how tonic activation of these afferent systems affects the state of the neurons in the NAc, and moreover how these activity patterns are modulated by selective DA drugs administered locally via reverse dialysis. We will also investigate how the NAc system in turn modulates the FA system, and how these systems are altered in a developmental disruption model of schizophrenia. This will be done according to the following four specific aims: 1) Examine how tonic activation of NAc neuron afferents affects baseline activity and response of NAc neurons to afferent stimulation, 2) Examine the DA receptor subtypes involved in modulating afferent interactions within the NAc, 3) Examine how the NAc system modulates the activity of DA neurons in the ventral tegmental area and how this correlates with DA release, and 4) Examine the effects of developmental neurotoxic disruptions on the integration of information flow within the NAc and its projections to the ventral tegmental area, and how this differs in prepubertal vs postpubertal rats. In this way, we hope to extend our knowledge of cortical-subcortical interactions in modulating the state of NAc neurons, how this state is regulated in an interactive manner by the DA system, and how developmental disruptions lead to a reorganization of limbic systems during development in a manner that may contribute to the pathophysiology of schizophrenia in humans.
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