Molecular Biology of Mesocortical and Mesoaccumbens Dopamine Neurons (sponsored by NIH/NIEHS)
Aberrant dopamine neurotransmission has been implicated in schizophrenia with elevated mesoaccumbens (or subcortical) dopamine neurotransmission contributing to positive symptoms of schizophrenia (paranoia, hallucinations, delusions, and bizarre behavior) and attenuated mesocortical dopamine neurotransmission affecting negative symptoms (social withdrawal, blunted emotions, and cognitive deficits). Targeting the dopamine system has proven effective at treating positive symptoms of schizophrenia as all currently approved antipsychotics block the dopamine D2 receptor but the efficacy of antipsychotic at alleviating negative symptoms is limited. The mesocortical and mesoaccumbens dopamine neurons have distinct afferent innervation, pharmacology, neurochemistry and electrophysiology properties; however, there is an important gap in information about the differential genes expression that underlie the functional differences of these two dopamine neuron populations and how they are regulated. The specific aims of the current proposal are to elucidate differential gene expression between mesocortical and mesoaccumbens dopamine neurons and the effect of inactivation of the prefrontal cortex on regulation gene expression of these dopamine neurons. To achieve these aims, the combination of rapid tyrosine hydroxylase fluorescent immunocytochemistry and a fluorescently labeled retrograde tracer will be used to visualize specific populations of dopamine neurons and laser capture microdissection will be used to capture these neurons and isolate RNA. These experiments are expected to elucidate unique gene expression profiles and differential regulation of gene expression. Once we understand the features that distinguish these dopamine neuronal populations and how they are regulated, we can begin to investigate strategies to specifically target either of these systems to control abnormal dopamine neurotransmission in pathological conditions such as schizophrenia.