Dopaminergic neurons regenerate following chemogenetic ablation in the olfactory bulb of adult Zebrafish (Danio rerio)

Abstract

Adult zebrafish have the ability to regenerate cells of the central nervous system. However, few neuronal regeneration studies in adult zebrafish addressed their ability to regenerate specific types of neurons following cell specific ablation. We show here that treatment of transgenic Tg( dat:CFP-NTR ) adult zebrafish with the prodrug metronidazole (Mtz) according to our administration regimen predominantly ablates dopamine (DA) neurons within the olfactory bulb (OB) of adult fish. Loss of DA neurons was accompanied by an impaired olfaction phenotype, as early as 1-week post-treatment, in which fish were unable to sense the presence of the repulsive stimulus cadaverine. The olfactory impairment was reversed within 45 days and coincided with the recovery of DA neuron counts in the OB. A multi-label pulse-chase analysis with BrdU and EdU over the first seventeen days-post Mtz exposure showed that newly formed DA neurons were recruited within the first nine days following exposure and led to functional and morphological recovery of the OB.

Cerebroventricular Microinjections of MPTP on Adult Zebrafish Induces Dopaminergic Neuronal Death, Mitochondrial Fragmentation, and Sensorimotor Impairments

“…With the telencephalic and olfactory regions being two epicenters, in the zebrafish brain, that modulate behavior, this impact can be explained by the drastic decreases in eGFP+ cells residing within the OBs and telencephalon in MPTP-injected zebrafish. These effects are greater than those observed in our group's previous work from Godoy et al (2020), that used a chemogenetic approach to ablate dopaminergic neurons. The phenotypes observed in this study were transient as all motor and sensory functions were restored following a 2-week recovery period.…”

The Promise of the Zebrafish Model for Parkinson’s Disease: Today’s Science and Tomorrow’s Treatment

“…Apart from that, zebrafish possess the natural ability to perform regeneration and neurogenesis for the replacement of cell injury or cell death( Gemberling et al, 2013 ; Barbosa and Ninkovic, 2016 ). For example, the dopaminergic neuronal population in the olfactory bulb of adult zebrafish was regenerated to the normal level within 45 days of post-ablation ( Godoy et al, 2020 ). This ability has brought some difficulties to PD studies because it makes the establishment of a PD model more challenging.…”

“…It is a well-known fact that anatomically, zebrafish relate closer to humans compared to its invertebrate counterparts, C. elegans and D. melanogaster. Not just that, between zebrafish and humans, Barbazuk et al, 2000;Njiwa et al, 2004;Ali et al, 2011;Kalueff and Cachat, 2011;Avdesh et al, 2012;Gilbert et al, 2013;Howe et al, 2013;Hoo et al, 2016;D'Amora and Giordani, 2018 Arslan and Edmondson, 2010;Ali et al, 2011;Goldsmith and Jobin, 2012;Fierro et al, 2013;Gemberling et al, 2013;Lardelli, 2014;Stewart et al, 2014;Barbosa and Ninkovic, 2016;Saleem and Kannan, 2018;Marques et al, 2019;Godoy et al, 2020 relies similar quantifiable behaviors and pathophysiology. From its first official announcement as a model organism in 1998 until recently, extensive studies involving zebrafish have led to the mapping of its dopaminergic nervous system (Tay et al, 2011).…”

Pharmacogenetic and whole-brain activity analyses uncover integration of distinct molecular and circuit programs that drive learning

“…Our opposing results underscore the complex roles that dopamine plays in regulating acoustic startle sensitivity and habituation. Additionally, we note that chemogenetic ablation was restricted to Th1-positive dopamine neurons, and that this approach is chronic, in contrast to our transient pharmacological inhibition, and eliminates dopaminergic neurons while potentially having no immediate effect on neurotransmitter levels 39 . Given these differences, it is perhaps not surprising that these approaches yield somewhat differing results.…”