Interactions Between Dopamine Neurons and Radial Glial Cells In the Adult Goldfish Forebrain

Abstract

Aromatase is the only enzyme that converts androgens into estrogens, which is found in the brain, testes and ovaries. In teleosts, brain aromatase is exclusively expressed in radial glial cells, which are the abundant stem-like non-neuronal progenitors involved in neuroendocrine functions and neurogenesis in the central nervous system. With little information about radial glial cell regulation by neurotransmitters and neurohormones available, the overall goal of this thesis is to investigate the interactions between dopamine neurons and radial glial cells in the adult goldfish (Carassius auratus) forebrain. Immunocytochemistry and confocal imaging revealed a close anatomical relationship between dopamine neurons and radial glial cells along the ventricular surface in the telencephalon. Transcriptional regulation of brain aromatase by dopamine indicated a brain region-specific pattern and suggested the involvement of other regulators in the goldfish forebrain. A novel goldfish primary radial glial cell culture model was established and characterized for brain aromatase regulation studies. Pharmacological studies demonstrated that specific activation of dopamine D1 receptors up-regulates brain aromatase through a cAMP-dependent molecular mechanism, which can be enhanced or attenuated by the product of aromatase action, 17β-estradiol. Proteome profiling and the response following treatment with the specific dopamine D1 receptor agonist SKF 38393 revealed that proteins involved in cell proliferation and growth are regulated through small molecules- and transcription factors-mediated signaling pathways. Analysis of genes related to radial glial cell and dopamine neuron functions demonstrated that glial activation and dopamine neuron recovery are estrogen-dependent in a neurotoxin MPTP-induced goldfish model of Parkinson’s disease. This thesis illustrates novel molecular mechanisms underlying brain aromatase regulation as well as radial glial cell function regulation and provides a framework for future investigation of existing endocrine disruptors modulating neurosteroid levels in the teleost brain.