Regeneration of dopaminergic neurons in adult zebrafish depends on immune system activation and differs for distinct populations

Abstract

Adult zebrafish regenerate neurons in their brain, but the extent and variability of this capacity is unclear. Here we ask whether loss of various dopaminergic neuron populations is sufficient to trigger their functional regeneration. Genetic lineage tracing shows that specific diencephalic ependymo-radial glial progenitor cells (ERGs) give rise to new dopaminergic (Th+) neurons. Ablation elicits an immune response, increased proliferation of ERGs and increased addition of new Th+ neurons in populations that constitutively add new neurons, e.g. diencephalic population 5/6. Inhibiting the immune response attenuates neurogenesis to control levels. Boosting the immune response enhances ERG proliferation, but not addition of Th+ neurons. In contrast, in populations in which constitutive neurogenesis is undetectable, e.g. the posterior tuberculum and locus coeruleus, cell replacement and tissue integration are incomplete and transient. This is associated with loss of spinal Th+ axons, as well as permanent deficits in shoaling and reproductive behaviour. Hence, dopaminergic neuron populations in the adult zebrafish brain show vast differences in regenerative capacity that correlate with constitutive addition of neurons and depend on immune system activation.

Inflammation and matrix metalloproteinase 9 (Mmp‐9) regulate photoreceptor regeneration in adult zebrafish

“…In the adult zebrafish, immune suppression using Dex inhibits the production of neural progenitors after a lesion (Caldwell et al, ; Kyritsis et al, ), and we show that treatment with Dex inhibits the proliferation of Müller glia‐derived progenitors. Following a neurotoxic lesion in the retina of the chick, Dex inhibits proliferation of Müller glia‐derived progenitors by activating glucocorticoid receptors on Müller glia (Gallina et al, , ; see also Fischer, Zelinka, Gallina, Scott, & Todd, ).…”

“…To determine if inflammation regulates aspects of photoreceptor regeneration, the glucocorticoid steroid, dexamethasone (Dex), was used to suppress the inflammatory response. A 14‐day pre‐lesion treatment with Dex was chosen (Figure b) based on studies performed by Kyritsis et al (Kyritsis et al, ; see also White et al, ; Tsarouchas et al, ; Caldwell et al, ; Bollaerts et al, ), and here the dose of Dex, route of administration and sizes and ages of animals were matched with Kyritsis et al (). Whereas this lengthy treatment with Dex may affect homeostatic function in all cells (Juszczak & Stankiewicz, ), this treatment in the absence of a lesion does not directly alter constitutive proliferation (Figure S1a; Kyritsis et al, ; White et al, ; Caldwell et al, ), the number of Müller glia or the expression and localization of gfap /Gfap, markers of reactive gliosis (Figure S1b–e).…”

“…Such mechanisms include inflammation. In zebrafish acute inflammation is both necessary and sufficient to induce neuronal regeneration (Caldwell et al, ; Kyritsis et al, ; White et al, ).…”

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

“…This suggests that zebrafish are, perhaps to a certain extent, resistant to Hexb deficiency. In addition, zebrafish, in contrast to mammalian species, can regenerate brain tissue and produce new neurons throughout life (Becker & Becker, ; Becker & Becker, ; Caldwell et al, ; Kizil, Kaslin, Kroehne, & Brand, ).…”

The various routes to functional regeneration in the central nervous system

“…What pathways actually recruit immune cells to the injury site and control their dynamics is a big question that needs to be addressed. Data from many research organisms, especially zebrafish (because of the availability of transgenic lines for different immune cells) has provided interesting insights into the types of immune cells recruited to different types of injuries and their dynamics 31 . The next level is understanding their molecular control in detail.…”