Molecular biology of mesocortical and mesoaccumbens dopamine neurons

Mississippi State University, Mississippi State MS

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Abstract

DESCRIPTION (provided by applicant): 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 genes expressed by these two dopamine neuron populations and how they are regulated. The first part of our hypothesis is that mesocortical and mesoaccumbens dopamine neurons will have distinct expression profiles of neurotransmitter receptor, transcription factor and dopamine neurotransmission genes that underlie their differences in function. Additionally, we hypothesize that the prefrontal cortex will have opposing effects on gene expression between these two populations. Specifically, that inactivation of the prefrontal cortex will attenuate expression of transcription factors and dopamine neurotransmission genes in mesocortical dopamine neurons and elevate these parameters in mesoaccumbens dopamine neurons. This is based on the observation that pyramidal neurons from the prefrontal cortex make excitatory synapses on mesocortical dopamine neurons but inhibit mesoaccumbens dopamine neurons via an intermediate GABAergic neuron. The specific aims of the current proposal are: 1) Elucidate differential gene expression between mesocortical and mesoaccumbens dopamine neurons and 2) Determine prefrontal cortex regulation of mesocortical and mesoaccumbens dopamine neuron gene expression. To achieve these aims, the combination of rapid tyrosine hydroxylase fluorescent immunocytochemistry and the fluorescently labeled retrograde tracer cholera toxin subunit B will be used to visualize mesocortical and mesoaccumbens dopamine neurons and laser capture microdissection will be used to isolate RNA specifically from these dopamine neurons under basal conditions or after inactivation of the prefrontal cortex. Gene eXpress profiling (GeXP) multiplex capillary electrophoresis based quantitative PCR will be used to determine the expression profiles of mesocortical and mesoaccumbens dopamine neurons. 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. PUBLIC HEALTH RELEVANCE: Abnormalities in dopamine neurotransmission have been reported in schizophrenia patients;however, certain populations of dopamine neurons are affected differently. Current technology can now discriminate these separate dopamine neuron populations and examine the types of genes each expresses. By understanding the genes that contribute to the differences in function between these two populations of dopamine neurons, future experiments can investigate ways of specifically targeting each of these populations to normalize dopamine transmission in diseases like schizophrenia.