The fish brain has a unique feature of vertebrates—it grows with the growth of body over a lifetime. In this regard, fishes are a convenient model for the study of embryonic and postembryonic development of the central nervous system and of the influence of different factors on these processes. Currently, the mechanisms of adult brain morphogenesis of fish, which retain larval stage for a long time, are poorly understood. This is particularly true for participation of radial glia during morphogenesis of the brain, as well as the presence and distribution of the proliferative zone in the adult fish brain. Another interesting and little known aspect is the posttraumatic ability of fish to form active neurogenic niches. Investigation of the structural organizations of neurogenic niches and special conditions of the extracellular environment, as well as the interactions between neighboring cells in a neurogenic niche, is interesting and relevant direction in the study of the neuronal stem cells biology. Injury of fish brain creates special conditions for the implementation of genetic programs aimed at strengthening the proliferation of progenitor cells, as well as the activation and proliferation activity in the neuronal stem cells.
- adult neurogenesis
- neurogenic niche
- radial glia
- reparative neurogenesis
- neuroal differentiation
- teleost fishes
- matrix areas of brain
- neuroprotective factors
- neural stem cells
Among vertebrates, fishes are known to be able to effectively restore the structure of cells and fibers after damage of the central nervous system (CNS). They have the ability to restore the number of damaged cells by production of new cells in the matrix areas of the brain and neurogenic niches and the ability to restore the structure of damaged axons of neurons in the spinal cord pathways . However, it is currently unknown how this process is related to the neurogenesis in the adult brain and what elements of the matrix areas of the brain are involved in the reparative neurogenesis in fish. The evolutionarily ancient animal groups are often used as a convenient model for neurogenic studies in adults. The brain of such animals has a large number of periventricular proliferative zones and active zones of secondary neurogenesis [2, 3]. In contrast to the mammalian brain, numerous proliferative regions have been found in adult fish. The presence of such regions was described in
The regenerative processes in the brain of fish after the damaging impact are determined by a number of factors, which distinguish the dynamics of this process from that in other vertebrates, particularly mammals and humans [10, 11]. It is known that the brain injury in the mammalian brain results in a number of pathological changes associated with the development of an inflammatory response to the toxic effects of glutamate and other inflammatory mediators, and further pathological changes associated with processes of secondary inflammation and involve massive cell death [12, 13]. As a result of CNS trauma, the mammalian cells are exposed to severe necrosis and only a small part of them is eliminated via apoptosis . In the fish brain, the cellular response to the trauma develops in a different scenario. Apoptosis is observed 5 min after the injury, which progresses in the next few days . The elimination of damaged cells is carried out by phagocytes (microglia/macrophages), which remove damaged cells very effectively and provide a «clean» cell death without the remaining damaged cellular material and the development of secondary inflammation . The replacement of the large amounts of dead cells resulted from the damage in the fish brain appears from various sources: the radial glia, centers of primary and secondary proliferation, and neurogenic zones. The high regenerative potential in the central nervous system of fish is provided by the activation of specific regenerative factors  and the effect of neuroprotective factors protecting damaged cells and providing long-term survival of cells formed as a result of reparative neurogenesis.
2. Adult neurogenesis and neural regeneration in fish brain
Neuroregenerative properties were investigated in various parts of the fish brain: retina , optical tectum , spinal cord , and cerebellum . According to the «Lesion paradigm» formulated by Zupanc and his colleagues , a high regenerative potential of the central nervous system of fish is determined by a number of different processes, including the response of the central nervous system after a damaging effect.
The first few reports related to the development of this theory have been derived from studies on European carp
Significant progress in understanding the basic signs of successful regeneration after amputation of the caudal portion of the spinal cord has been made in research on electric fish
On the second day, the number of cells gradually declined, reaching the background level after approximately 3 weeks. During this period, only some cells underwent necrosis. An elimination of damaged cells by apoptosis in the brain of fish differs significantly from that of mammals . In contrast, the main process of elimination of damaged cells to the injured area of mammals is necrosis . Apoptosis also affects the small part of cells in the areas surrounding injury. The prevalence of necrosis in the mammalian brain after injury is one of the causes of subsequent secondary inflammation in the lesion , which in turn causes a further increase in response of necrotic injuries, resulting in the formation of larger cavities deprived of cells. These cavities are usually restricted area of reactive astrocytes, creating both mechanical and biochemical barriers that impede the growth of nerve fibers and cell migration into the damaged area. Unlike necrosis, apoptotic cells characteristically show overall compression, condensation of the nucleus, and the formation of vesicles, which are subsequently destroyed by the macrophages/microglia .
Initially, the numbers of phagocytes in the area of damage were small, but after about 3 days of injury, the number of macrophages begins to increase in the area of injury and in the adjacent areas . The main side effects of necrosis, associated with inflammation of the surrounding tissue, are completely absent in apoptotic “clean” method of elimination of cells. Thus, the prevalence of processes of “clean” cell death for the destruction of damaged cells is a key feature underlying the regenerative capacity of the adult fish brain.
An important aspect of promoting successful regeneration in the brain of the fish is the detection of specific neuroprotective factors which play a key role in maintaining the viability of neurons in the affected areas and prevent further cell death after injury . Such factors are being considered as different substances, in particular some of the calcium binding proteins, such as calbindin-28 and parvalbumin. Expression of these calcium-binding proteins in the cells briefly increases in granular layer of the cerebellum of
3. Apoptosis and cell migration after injury of cerebellum
We observed the apoptosis and migration of cells in the young masou salmon
We believe that it was mainly due to the migration process in neurogenic niches and dorsomedial area. The highest density of cells was detected in the vicinity of the puncture area, gradually decreasing with the distance from the area of injury. Near the area of injury, many TUNEL-labeled components corresponding to different stages of the apoptotic process were localized (Figure 1B). So, dense apoptotic bodies, which are the final stage of coarse chromatin condensation and apoptotic cell degradation, were found. The size of apoptotic bodies was about 8–10 μm. In areas of apoptotic fragments localization were found large cells with basophilic cytoplasm, the diameter of cells body is about 13 μm. These cells tend to have an irregular shape and had cytoplasmic outgrowths. Presumably, these structures correspond to regional microglia/macrophages involved in phagocytosis of apoptotic fragments and recycling. Along with individual elements, there also occurred small conglomerates, including up to three apoptotic bodies.
Another variety of apoptotic bodies were small TUNEL-labeled bodies representing degranulated fragments of damaged cells. In the most superficial parts of the molecular layer was observed a very large number of small cells lacking the morphological features of differentiation (Figure 1C). Such morphological pattern of surface of the molecular layer apparently reflects the intensity of the processes of cell migration from the superficial regions of the cerebellum to the zone of injury. The surface area which has been characterized by a high density of cells revealed TUNEL-labeled small elements corresponding to cell degranulation products in the area.
In our studies, some effects of the damaging of cerebellum were combined with complex morphogenetic background of the ongoing postembryonic development of the brain
Counting the number of cell nuclei stained with methyl green, which was carried out on the surface layer of the cerebellum, indicates the presence of a large number of undifferentiated cells with high nuclear-cytoplasmic ratio. Such cells based on morphological criteria can be referred as proliferating population and cell population at the early stages of differentiation and/or migration.
We believe that the proliferative response to damage the cerebellum in young
Large TUNEL-labeled bodies (Figure 1D) conform to the final stage of chromatin degradation in apoptotic cells. This stage is characterized by the formation of large condensed fragments of chromatin that cannot be disposed by macrophages/microglia. These apoptotic bodies were also identified in the morphogenetic studies in mammals . Other visible TUNEL-labeled elements are small weakly diffused particles, which are products of degranulation of cells that are eliminated by apoptosis. These “remnants” of the cells were identified over large areas, located in different parts of the cerebellum. These different types of TUNEL-labeled structures in the cerebellum of
In our studies on the second day from the date of injury to the cerebellum, intensity of TUNEL-labeling of apoptotic bodies was not very high . However, apoptosis in a zone adjacent to the areas of trauma has been well defined. This surely indicates a part of the mechanism in the process of disposing of damaged cells. In the mentioned period of time (2 days after injury) in the area of damage was revealed increased density of distribution undifferentiated cells. This fact indicates that the reparative process moved at a later stage. Apparently, the reparative processes of neurogenesis in juvenile salmonids implemented in earlier periods compared with what is commonly referred to in the literature [1, 27, 28]. This is likely due to the high intensity of the background morphogenetic activity in the cerebellum of young fishes as compared to that in adult animals.
After mechanical trauma of the cerebellum, patterns of tangential and radial cell migration can be observed. The zones of cell migration are best expressed in the dorsal part of cerebellar body, as well as in the areas of secondary neurogenesis. In our experimental conditions, two groups of TUNEL-labeled structures were identified: large TUNEL-labeled bodies, corresponding to the final stage of degradation of apoptotic cells, and small, weakly condensed particles, which are apparently products of cells degranulation. In the matrix areas, areas of trauma, and intact areas of the cerebellum, different levels of apoptotic activity were observed. The highest value of apoptotic index (5%) after the traumatic impact on the cerebellum was observed in the molecular layer, which is the main area of radial migration of cells. Thus, the background morphogenetic processes and physiological repair processes dominate in the cerebellum of young
In vivo investigation of cell migration after mechanical injury
Microglia/macrophages have been identified within a few days after lesions in several divisions of the CNS of teleost fish—the cerebellum , the dorsal telencephalon [39, 40], and the retina . We used multiphoton confocal microscopy for the
Animal at the beginning of the experiment was lying on the back, was submerged in the aquarium water, the surface of the skull was tightly pressed to the bottom wall of the special POC-R chamber. The brain of the animal was examined as a whole, without opening the skull and removing pigmented primary brain tunic. Thus, the substance for the study of DiI-labeled cells initially represented structurally heterogeneous environment, including the bones of the skull, cerebrospinal fluid, primary brain tunic, and brain tissue. The observation was carried out with special planar lens with built-in color correction (Advanced Correction System) at 20x magnification. The sample of cells was carried out in the middle portion of the optical section at a depth of 200 μm. Since the observations were made in
After 30 min of exposure DiI to mesencephalon of juveniles
As a result of optical scanning, we observed DiI-labeled elements without outgrowths, which formed local clusters (after 2 days) and were presented by individual elements (after 30 min) (Figure 2B). After 2 days in the optical sections of damaged
Based on the analysis galleries of optical sections of the midbrain of juveniles
In our studies, DiI was used as a dye for vital fluorescent multiphoton confocal microscopy. It can be regarded as a possible method of identifying populations of phagocytic cells in the brain, as the effective molecular markers that allow selective identification of populations of macrophages and microglia in the brain of the fish have not been developed so far. We supposed that using multiphoton confocal microscopy
5. Cell proliferation, neural stem cells and neuronal differentiation after injury
A common feature of any regeneration-competent CNS system examined thus far is that cells lost to injury are replaced by new cells that differentiate into various cell types, including neurons. After the stab-wound lesion to the cerebellum of juvenile
In the DMZ of juvenile
After stab-wound damage to the cerebellum of juvenile
The intensity of proliferation depends on the nature of injury and the amount of damaged brain tissue. After the damaging effects in the cerebellum of
In the basal area of
Forebrain proliferative activity of juvenile
After mechanical injury in the telencephalon of
HuCD-immunopositive cells were identified as part external proliferative zones and in the deep layers of the telencephalon juvenile
We have identified four types of HuCD-labeled cells differing in morphological parameters (large and small size cell bodies) and optical density. Type 1 cells are the smallest undifferentiated cells with a high OD; Type 2 are larger oval cells with high and average value of OD; multipolar cells with high OD were the third type; and bipolar neurons with large high OD belong to the fourth type.
There are considerable changes in topography HuCD-immunopositive cells in the telencephalon
This evidence based on HuCD and PCNA marking shows us the intense persistent neurogenesis in proliferative zone of dorsal region telencephalon
6. Neuroprotective factors in damaged fish brain
Calbindin-D28k has been postulated to exert a neuroprotective function by buffering intracellular free Ca2+. This hypothesis is supported by the findings that calbindin-D28k-expressing neurons exhibit a relative resistance to neurotoxicity induced by glutamate, calcium ionophore, or acidosis  and that the rate of survival of neurons can be increased after various types of insults by overexpression of the gene for calbindin-D28k [45, 46].
Other calcium-binding protein like parvalbumin may also be involved in the neuroprotective properties of fish nervous system. The results of studies on young
According to Grosche et al. , glutamine synthetase (GS) is a specific glial protein performing the conversion of toxic glutamate into a non-toxic amino acid, glutamine. In normal conditions, this mechanism prevents accumulation of glutamate neurotoxicity in nerve tissue, protecting neurons from cell death. But after a brain injury in a mammalian brain, volume of synthesized GS is insufficient to neutralize the toxic effects of glutamate. This determines such effects as the development of primary and secondary inflammations and progressive neurodegenerative processes observed following injury of the CNS in mammals and human glutamine synthetase . In fish, the increased activity of GS is likely to provide an important mechanism for reducing the neurodegenerative effects caused by glutamate neurotoxicity. This assumption indicates the presence of certain ways that determine such strong differences in the regenerative potential of the two taxa of vertebrates .
The results of immunohistochemical analysis of GS indicate significant differences between the distribution of the enzyme in normal conditions and after stab-wound lesion to the cerebellum (Figure 5A, C). In both cases, enzyme activity was identified in cells and fibers. Densitometric analysis of enzyme activity in cells has shown that there are two levels of activity: intensive and moderate. The results of the morphological analysis and some literature data  indicate that cells containing the GS represent the population of astrocytes. Morphological studies of GS-ip cells in the cerebellum in young
After stab-wound lesion to the cerebellum, maximal number of GS-ip cells has been identified in the granular layer of cerebellum (Figure 5C, D). Redistribution of cells synthesizing GS, from the molecular to the granular layer, was revealed.
In the lateral and dorsal regions of the cerebellum of
From other hand, the high activity of GS in control suggests the involvement of glutamate in plastic processes, including morphogenesis taking place during persistent neurogenesis in normal fish cerebellum [1, 47].
We believe that metabolic glutamate which is presumably involved in morphogenic cerebellar functions in
The increase in the number of GS-ip cells in the granular layer and the high activity of GS in them on the second and third day are referred by us to as the astrocytic response observed after a damaging impact. However, the number of these cells is not high enough for response to the GS-ip cells as «reactive gliosis» appeared on central nervous system of mammals after damaging effects. In the mammalian brain, as is known, as a result of a traumatic impact, pool of reactive astrocytes formed morphological and biochemical barrier, features which significantly differ from those in normal astrocytes . The cellular mechanism associated with the transformation of a population of astrocytes and isolating a subpopulation of activated glia in the brain of the fish is currently poorly understood. Unlike mammalian brain, astrocytes in a fish brain do not form the astrocytic barrier, which is characteristic for the development of posttraumatic process in the mammalian brain. Nevertheless, changing GS synthesis is an unambiguous evidence in favor of the neuroprotective properties of the enzyme and increased production in the cerebellum
The fish brain has a unique feature of vertebrates—it grows with the growth of body over a lifetime. In this regard, fish is a convenient model for the study of embryonic and postembryonic development of the central nervous system and of the influence of different factors on these processes. Injury of fish brain creates special conditions for the implementation of genetic programs aimed at strengthening the proliferation of progenitor cells as well as activation and proliferation activity in the neuronal stem cells. Study of neurogenic activity, migration, and differentiation in the neurogenic niches contributes to a better understanding about how these structures operate, not only in fish but in other vertebrates as well.
This study was supported by a grant of the President of the Russian Federation (MD-4318.2015.4), Grant of Scientific Foundation (№ 10046–2016.4), and the “Far East” Program for Basic Research of the Far East Branch of the Russian Academy of Sciences 2015–2017 (project number 15-I-6-116, Section III).
We are grateful to Dr. Sachin Shukla Eye Research Centre (Hyderabad, India) for the participation in ELISA immunoassay and editing the text.
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