Cellular Mechanisms Participating in Brain Repair of Adult Zebrafish and Mammals after Injury

Abstract

Adult neurogenesis is an evolutionary conserved process occurring in all vertebrates. However, striking differences are observed between the taxa, considering the number of neurogenic niches, the neural stem cell (NSC) identity, and brain plasticity under constitutive and injury-induced conditions. Zebrafish has become a popular model for the investigation of the molecular and cellular mechanisms involved in adult neurogenesis. Compared to mammals, the adult zebrafish displays a high number of neurogenic niches distributed throughout the brain. Furthermore, it exhibits a strong regenerative capacity without scar formation or any obvious disabilities. In this review, we will first discuss the similarities and differences regarding (i) the distribution of neurogenic niches in the brain of adult zebrafish and mammals (mainly mouse) and (ii) the nature of the neural stem cells within the main telencephalic niches. In the second part, we will describe the cascade of cellular events occurring after telencephalic injury in zebrafish and mouse. Our study clearly shows that most early events happening right after the brain injury are shared between zebrafish and mouse including cell death, microglia, and oligodendrocyte recruitment, as well as injury-induced neurogenesis. In mammals, one of the consequences following an injury is the formation of a glial scar that is persistent. This is not the case in zebrafish, which may be one of the main reasons that zebrafish display a higher regenerative capacity.

Keywords: adult neurogenesis; brain injury; mice; neural stem cell; regeneration; stroke; zebrafish.

Figure 1

Localization and cellular organization of the main neurogenic niches in the brain of adult zebrafish, mouse, and humans. (A,E,I): sagittal sections of zebrafish (A), mouse (E) and human (I) brains with the main proliferative regions (neurogenic niches) shown in red. The mammalian brain displays only two main neurogenic niches: the subventricular zone (SVZ) of the lateral ventricles and subgranular zone of the dentate gyrus (DG) of the hippocampus. Note that the mammalian hypothalamus (HYP) also exhibits discrete neurogenesis. The zebrafish brain displays numerous niches throughout the brain. (B–K): transversal sections through the brain, marking the main neurogenic niches of the respective species shown in (A,E,I). (D–L): Cell composition of the neurogenic niches in zebrafish, mice and humans. (D): The main neurogenic niches in the subpallial ventricular zone (VZ), the dorsolateral telencephalon (Dl) in zebrafish, and their respective homologues in mammals: the SVZ and the DG of the hippocampus in mouse and humans. In zebrafish, type 1 and type 2 cells are quiescent and proliferative radial glial cells (RGC), respectively (quiescent and proliferative neural stem cells (NSCs)). Type 3 cells are proliferative neuroblasts. The neuroepithelial cells are NSCs from the subpallium. (H,L): In mammals, the NSCs are shown in grey (B-cells and Type 1 -T1-), the transient amplifying cells in light green (C-Cells and Type -T2-) and the neuroblasts in dark green (A-cells and Type 3 -T3-). Note the hypocellular gap in the human SVZ compared to mice. Ce: cerebellum; Cx: cerebral cortex; Dl: lateral zone of the dorsal telencephalic area; DG: dentate gyrus of the hippocampus; Dp: posterior zone of dorsal telencephalic area; HYP: hypothalamus; MO: medulla oblongata; OB: Olfactory bulbs; RGC: radial glial cell; RMS: rostral migratory stream; SVZ: subventricular zone VZ: ventricular zone; TEL: telencephalon; TeO: optic tectum.

Figure 2

The telencephalon of adult zebrafish contains slow and fast cycling progenitors. The VZ of the dorsal telencephalon (pallium) is mainly composed of quiescent (type 1) or proliferative (type 2) RGCs corresponding to slow cycling progenitors. The ventral part of the telencephalon (subpallium) is composed of fast cycling progenitors (type 3 cells) identified as neuroblasts, grouped within a cluster and forming a rostral migratory like structure (RMS-like). Some neuroblasts are also observed scattered between RGC soma in the pallium. RGCs were identified as bona fide NSCs in the pallium and neuroepithelial cells could be NSCs in the subpallium. RGCs: radial glial cells.

Figure 3

Cellular events occurring after telencephalic injury in zebrafish and stroke in mouse. After brain damage, numerous cells, mainly neurons, die. This process is followed by the activation and recruitment of microglial and other immune cells (leukocytes) in parallel to OPCs. Then an astrogliosis process occurs in mice, while RGCs become reactive and proliferative in zebrafish. Proliferation in the neurogenic niches peak at day 7 after damage in both models. Note that the cellular response on the contralateral side is not shown for zebrafish and rodent. In zebrafish and rodent, the first row shows cell death, microglial recruitment, and activation. In zebrafish, the second-row highlights the hypertrophy of RGC processes, the neurogenic injury-induced proliferation as well oligodendrocytes/OPCs response. In rodents, the second row shows astrogliosis, neurogenic proliferation along the SVZ and oligodendrocytes/OPCs response. Note that in zebrafish oligodendrocytes/OPCs accumulate close to the lesion site without increasing their number; dpl: day(s) post lesion, hpl: hour(s) post lesion.

Figure 4

Resting and activated microglia under injured and uninjured (control) conditions in the telencephalon of zebrafish. Confocal microscopy showing quiescent (resting) microglia (left panel) and ameboid (activated) microglia (right panel) in the adult zebrafish telencephalon. There is an obvious change in the shape of the microglia between injured and uninjured tissue, illustrated by the mpeg:mcherry transgenic fish line, which labels microglia in the central nervous system. Arrows show the resting morphology of microglia cells (left panel) the ameboid shape of activated microglia at 1dpl (right panel). Bar: 18 μm.