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The modulatory aminergic neurotransmitters are involved in practically all important physiological systems in the brain, and many of them are also involved in human central nervous system diseases, including Parkinson's disease, schizophrenia, Alzheimer's disease, and depression. The zebrafish brain aminergic systems share many structural properties with the mammalian systems. The noradrenergic, serotonergic, and histaminergic systems are highly similar. The dopaminergic systems also show similarities with the major difference being the lack of dopaminergic neurons in zebrafish mesencephalon. Development of automated quantitative behavioral analysis methods for zebrafish and imaging systems of complete brain neurotransmitter networks have enabled comprehensive studies on these systems in normal and pathological conditions. It is possible to visualize complete neurotransmitter systems in the whole zebrafish brain at an age when the fish already displays all major vital behaviors except reproduction. Alterations of brain dopaminergic systems with MPTP, the neurotoxin that in humans and rodents induces Parkinson's disease, induces both changes in zebrafish dopaminergic system and quantifiable abnormalities in motor behavior. Chemically-induced brain histamine deficiency causes an identifiable alteration in histaminergic neurons and terminal networks, and a clear change in swimming behavior and long-term memory. Combining the imaging techniques and behavioral methods with zebrafish genetics is likely to help reveal how the modulatory transmitter systems interact to produce important behaviors, and how they are regulated in pathophysiological conditions and diseases.

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The localization of glial cell line-derived neurotrophic factor (GDNF) mRNA was studied by in situ hybridization in rat from embryonic (E) day E10 to E15. At E10, GDNF mRNA is found in the urogenital field and the cranial part of the gut. At E11, the most abundant expression of GDNF mRNA is seen in the epithelial cells of the second, third and fourth pharyngeal pouches, the third and fourth pharyngeal arches and pharynx. Also mesenchymal cells of the gut and mesonephric tubules contain GDNF mRNA. At E13, expression is observed in the mesenchymal cell layers of the oesophagus, intestine and stomach, the mesenchymal cells around the condensing cartilages and metanephric kidney mesenchyme. Also, the epithelia of Rathke's pouch and pharynx are intensely labelled. High expression of GDNF mRNA continues at E15 in kidney, gastrointestinal tract and cartilage. At that stage, GDNF mRNA is seen also in whisker pad and skeletal muscles. The distribution of GDNF mRNA in embryonic rat suggests important roles for GDNF in the early differentiation of the kidney tubules, the innervation of the gastrointestinal tract and the differentiation process of the cartilage and muscle. Our results indicate novel functions for GDNF outside the nervous system.

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Because the neurotrophic system has not been systematically studied in developing heart, we studied the expression of mRNAs for neurotrophins and their high- and low-affinity receptors by radioactive in situ hybridization in the rat heart from embryonic day 9 (E9) to parturition. The neurotrophin-3 (NT-3) transcripts were seen in the group of Leu-7 immunoreactive cells in the ventricular region from E11 to parturition, suggesting that NT-3 is expressed in the part of the developing conduction system, mRNAs for truncated trk receptors, trkC.TK- and trkB.T1, were expressed in the outflow tract at E12 and in the walls of developing aorta and pulmonary trunk from E13 to parturition, whereas the mRNA for catalytic trkC.TK+ was revealed in the walls of aorta and pulmonary trunk from E13 to parturition and in the cardiac ganglion neurons from E14 to adult stage. Transcripts for low-affinity neurotrophin receptor (p75) were transiently seen in the distal outflow tract from E11 to E13, declining by E14. At E18, p75 transcripts were also seen in the cardiac ganglia. Transcripts for nerve growth factor, neurotrophin-4/5, trkA, or trkB.TK+ were not detected. Expression of NT-3 mRNA in the developing conduction system and of trkC.TK + mRNA in the cardiac neurons suggests a role for NT-3 in the innervation of the conduction system. Expression of trkC.TK+ in the wall of aorta and pulmonary trunk suggests that NT-3 also may affect the development of the smooth muscle cells.

We have investigated the eects of the truncated trkB receptor isoform T1 (trkB.T1) by transient transfection into mouse N2a neuroblastoma cells. We observed that expression of trkB.T1 leads to a striking change in cell morphology characterized by outgrowth of ®lopodia and processes. A similar morphological response was also observed in SH-SY5Y human neuroblastoma cells and NIH3T3 ®broblasts transfected with trkB.T1. N2a cells lack endogenous expression of trkB isoforms, but express barely detectable amounts of its ligands, brainderived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4). The morphological change was ligand-independent, since addition of exogenous BDNF or NT-4 or blockade of endogenous trkB ligands did not in¯uence this response. Filopodia and process outgrowth was signi®cantly suppressed when full-length trkB.TK+ was cotransfected together with trkB.T1 and this inhibitory eect was blocked by tyrosine kinase inhibitor K252a. Transfection of trkB.T1 deletion mutants showed that the morphological response is dependent on the extracellular, but not the intracellular domain of the receptor. Our results suggest a novel ligand-independent role for truncated trkB in the regulation of cellular morphology.