No abstract

Larval zebrafish offers a good model to approach brain disease mechanisms, as structural abnormalities of their small brains can be correlated to quantifiable behavior. In this study, the structural alterations in one diencephalic dopaminergic nucleus induced by 1-methyl-4-phenylpyridinium (MPP+), a toxin inducing Parkinson's disease in humans, and those found in several neuronal groups after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the pretoxin, were associated with decreased swimming speed. Detailed cell counts of dopaminergic groups indicated a transient decline of tyrosine hydroxylase expressing neurons up to about 50% after MPTP. The MPTP effect was partly sensitive to monoamine oxidase inhibitor deprenyl. Detailed analysis of the developing catecholaminergic cell groups suggests that the cell groups emerged at their final positions and no obvious significant migration from the original positions was seen. One 5-HT neuron group was also affected by MPTP treatment, whereas other groups remained intact, suggesting that the effect is selective. New nomenclature for developing catecholaminergic cell groups corresponding to adult groups is introduced. The diencephalic cell population consisting of groups 5,6 and 11 was sensitive to both MPTP and MPP+ and in this respect resembles mammalian substantia nigra. The results suggest that MPTP and MPP+ induce a transient functional deficit and motility disorder in larval zebrafish.

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.

The histaminergic and hypocretin/orexin (hcrt) neurotransmitter systems play crucial roles in alertness/wakefulness in rodents. We elucidated the role of histamine in wakefulness and the interaction of the histamine and hcrt systems in larval zebrafish. Translation inhibition of histidine decarboxylase (hdc) with morpholino oligonucleotides (MOs) led to a behaviorally measurable decline in light-associated activity, which was partially rescued by hdc mRNA injections and mimicked by histamine receptor H1 (Hrh1) antagonist pyrilamine treatment. Histamine-immunoreactive fibers targeted the dorsal telencephalon, an area that expresses histamine receptors hrh1 and hrh3 and contains predominantly glutamatergic neurons. Tract tracing with DiI revealed that projections from dorsal telencephalon innervate the hcrt and histaminergic neurons. Translation inhibition of hdc decreased the number of hcrt neurons in a Hrh1-dependent manner. The reduction was rescued by overexpression of hdc mRNA. hdc mRNA injection alone led to an up-regulation of hcrt neuron numbers. These results suggest that histamine is essential for the development of a functional and intact hcrt system and that histamine has a bidirectional effect on the development of the hcrt neurons. In summary, our findings provide evidence that these two systems are linked both functionally and developmentally, which may have important implications in sleep disorders and narcolepsy. development via histamine receptor H1 in zebrafish.

Serotonin (or 5‐hydroxytryptamine; 5‐HT) and monoamine oxidase (MAO) are involved in several physiological functions and pathological conditions. We show that the serotonergic system and its development in zebrafish are similar to those of other vertebrates rendering zebrafish a good model to study them. Development of MAO expression followed a similar time course as the 5‐HT system. MAO expression and activity were located in or adjacent to serotonergic nuclei and their targets, especially in the ventral hypothalamus. MAO mRNA was detected in the brain from 24 h post‐fertilization and histochemical enzyme activity from 42 h post‐fertilization. Deprenyl (100 μM) decreased MAO activity 34–74% depending on the age. Inhibition of MAO by deprenyl strongly increased 5‐HT but not dopamine and noradrenaline levels. Deprenyl decreased 5‐HT‐immunoreactivity in serotonergic neurons and induced novel ectopic 5‐HT‐immunoreactivity neurons in the diencephalon in a manner dependent on 5‐HT uptake. Deprenyl administration decreased locomotion, altered vertical positioning and increased heart rate. Treatment with p‐chlorophenylalanine normalized 5‐HT levels and rescued the behavioral alteration, indicating that the symptoms were 5‐HT dependent. These findings suggest that zebrafish MAO resembles mammalian MAO A more than MAO B, metabolizing mainly 5‐HT. Applications of this model of hyperserotonergism include pharmacological and genetic screenings.