Zebrafish, Medaka And Turquoise Killifish For Understanding Human Neurodegenerative/Neurodevelopmental Disorders Part 2

The cerebellum has climbing fibers and parallel fibers, and the cell groups present are similar to those of humans, including Purkinje neurons and granule cells [13,14].

There is a positive relationship between climbing fibers and memory. During the process of climbing fibers, we need to stay awake and think calmly. This state of mind can promote the improvement of memory.

The activity of climbing fibers requires physical coordination and the cooperation of all parts of the body, especially the coordination of hands and feet. In the process of climbing fibers, we need to adjust the posture and position of the body many times. This adjustment process can promote the brain's thinking ability and improve our attention and concentration.

In addition, during the process of climbing fibers, we can enjoy a physical and psychological sense of pleasure, which can activate hormones such as dopamine in the brain, improve our mood, and make us more positive.

Therefore, climbing fiber can be used as an effective method to exercise and improve memory. It can make us more confident, brave, and tenacious, allowing us to constantly surpass ourselves and pursue higher and further goals. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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 Although zebrafish do not have structures corresponding to the deep cerebellar nuclei, cells called eurydendroid cells receive Purkinje cell projections and send efferent projections to various brain regions. 

Therefore, eurydendroid cells are thought to be functionally homologous to the deep cerebellar nuclei of mammals [15]. In humans, the cerebellum is divided into the vestibulocerebellum, spinocerebellum, and pontocerebellum in terms of phylogeny and functional localization, while the cerebellum of small fishes is mostly regarded as the vestibulocerebellum. 

We created a functional map of the zebrafish cerebellum and showed that the zebrafish cerebellum contains at least the vestibulocerebellum and spinocerebellum, the details of which can be found in a reference [16]. 

It is very interesting to determine if there are also cerebellum regions controlling higher brain functions within the telencephalon in small fishes. Zebrafish also have a telencephalon that corresponds to the human cerebrum, with regions corresponding to the hippocampus and amygdala, which are involved in memory learning and emotional behavior, respectively [17]. 

In humans, during development, the ventral and dorsal sides of the neural tube form a median constriction, whereas in zebrafish, the dorsal side of the neural tube forms an outward folding [18]. However, unlike humans, zebrafish do not have cortical layer structures. It is important to note that this does not mean that the fish brain does not have structures and functions equivalent to the mammalian cerebral cortex. 

The blood–brain barrier (BBB) is also present in zebrafish. Angiogenesis in the hindbrain begins at approximately 20 hpf, and pericytes and glia are found around the vessels by 60 hpf, but the BBB is incomplete until approximately 5–8 dpf (days post-fertilization), allowing various drugs to penetrate the central nervous system [19,20]. The drug can be administered orally or intracorporeally or it can be dissolved in the maintenance water of the larvae and infiltrated into the body tissue by water immersion. This feature is very useful for high-throughput screening using zebrafish larvae. 

For example, embryos or larvae are individually deposited in each well of 96- and 384-well plates and various compounds can be dissolved in the water. Thereafter, each fish can be evaluated by gene expression patterns, developmental changes, or behavioral analysis. 

This is less time-consuming and less expensive than the same screening procedure using mammalian models such as mice [21]. One of the major differences between zebrafish and humans is the ability to regenerate the central nervous system, including neurons. 

When zebrafish are artificially injured in the spinal cord, functional recovery and motor neuron repopulation are observed within 6 to 8 weeks [22,23]. In addition, tissue regeneration of the central nervous system has been observed after artificial damage, even in the telencephalon [24]. 

The increased regeneration ability of fish, even in the central nervous system, needs to be recognized when using fish as models of human neurological disorders. Many lines of evidence have been shown using zebrafish. 

Because zebrafish, medaka, and turquoise killifish are closely related teleosts, their major structures in the central nervous system are comparable. A review of these three model fishes including the description of their central nervous system is available [25].

3. Ease of Laboratory Management and Experimentation with Zebrafish, Medaka, and Turquoise Killifish

3.1. Visibility and Light Transmission in Small Fishes

One of the important characteristics of small fishes is their high tissue transparency during embryogenesis and the larval stages. In zebrafish and medaka, the developmental process can be observed outside the body of the parent fish, and the embryos and larvae are transparent, making it easy to observe the developmental process and internal structure. 

In addition, several mutant lines of zebrafish and medaka are available that are more transparent than the wild type, allowing the internal structure of the fish to be seen, even in the adult stage [26]. 

This characteristic allows direct observation of the development and tissue and cell activity, which is compatible with live imaging, and allows us to capture developmental and structural changes in the nervous system in greater detail in vivo. 

When fluorescent proteins are expressed specifically on the cell of interest, it is possible to observe the development and morphological changes of the neurons of interest over time. Chemical or genetically encoded Ca sensors expressed in neurons allow us to observe the activity of neurons with high temporal and spatial resolution [27]. For example, we showed that cerebellar neural activity during behavior can be observed at the cellular level [16]. 

A very exciting study has also been reported that expresses Ca sensors in neurons of the whole brain and utilizes the sensor signals as in electroencephalography [28]. Using optogenetics techniques, it is also theoretically possible to activate or suppress the neuronal activity of target neurons at any site [16,29]. A unique method to analyze the pathogenesis of diseases by altering the subcellular localization of target proteins has also been reported [30]. 

In short, small fishes are unique vertebrates that provide, in a live state, macroscopic observation of the nervous system, microscopic observation of precise neural activity, and adaptation of light transmission for optogenetics and other applications.

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