Regeneration of Dopaminergic Neurons in Adult Zebrafish Depends on Immune System Activation and Differs for Distinct Populations

Abstract

Adult zebrafish, in contrast to mammals, regenerate neurons in their brain, but the extent and variability of this capacity is unclear. Here we ask whether the loss of various dopaminergic neuron populations is sufficient to trigger their functional regeneration. Both sexes of zebrafish were analyzed. Genetic lineage tracing shows that specific diencephalic ependymo-radial glial (ERG) progenitor cells give rise to new dopaminergic [tyrosine hydroxylase-positive (TH ϩ)] neurons. Ablation elicits an immune response, increased proliferation of ERG progenitor cells, and increased addition of new TH ϩ 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 ϩ neurons. In contrast, in populations in which constitutive neurogenesis is undetectable (e.g., the posterior tuberculum and locus ceruleus), cell replacement and tissue integration are incomplete and transient. This is associated with a loss of spinal TH ϩ axons, as well as permanent deficits in shoaling and reproductive behavior. 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.

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, ).…”

Dynamic cell interactions allow spinal cord regeneration in zebrafish

“…Dopamine [22] and serotonin [23] derived from descending axons, as well as Ctgf, derived from reactive ERGs and other cells [12], also promote regenerative neurogenesis. ERGs react to immune signals with enhanced neurogenesis in the larval spinal cord [24] and other CNS regions of adults [25,26]. In summary, ERGs support regeneration by integrating a multitude of developmental and regeneration-specific signals to produce new neurons and growth-promoting astroglial-like cells.…”

“…Using dexamethasone to inhibit the immune reaction led to reduced regeneration of neurons in the injured larval spinal cord [24]. Similarly, neuronal regeneration after stab lesion of the telencephalon [26] and ablation of dopaminergic neurons [25] in the diencephalon of adult zebrafish can also be suppressed by dexamethasone. The leukotriene C4 has been identified as possible signalling molecule from the microglial cells [26].…”

Dendrimer-targeted immunosuppression of microglia reactivity super-accelerates photoreceptor regeneration kinetics in the zebrafish retina

“…Broadly, nanoparticle-based modulation of immune system responses to neuronal cell death may represent a generalizable strategy for enhancing neural stem cell activity. However, accelerated regenerative processes in zebrafish do not necessarily equate to improved functional recovery (43,44) nor to enhanced regenerative capacities in mammals. Additional studies will be required to test how accelerated retinal cell regeneration correlates to the recovery of visual deficits and to assess targeted immunomodulation in mammalian retinal degeneration models.…”