An increasing share of the human population suffers from various neurodegenerative diseases characterized by the loss of neuronal tissue. Understanding the molecular nature of regeneration in organisms that can invoke special programs to replenish lost structures is not only interesting to understand mechanisms of regeneration, but can also be instrumental for devising therapeutic applications for humans. Different from mammals, with only very limited or no existing neurogenic regeneration in adults, the zebrafish possesses a high regeneration capacity in many areas of the central nervous system throughout its entire lifespan. Moreover, the fast development and transparency of zebrafish larvae allow the analysis of regeneration via non-invasive bio-imaging.
In focus of our research is the cerebellum (CB), that is involved in the integration of sensory-motor information, body balance, motor learning, and cognitive behavior. Neurodegenerative diseases affecting the CB include the spinocerebellar ataxia, characterized by severe locomotor symptoms. Furthermore, cerebellar hypoplasia is highly correlated with the autism spectrum disorder. From the evolutionary point of view, the CB is a highly conserved structure, showing the same main cell types and layers, both in zebrafish and mammalians.
Classical studies on degeneration/regeneration are based on local mechanical damage, where the acute injury targets a limited area but -unlike in neurodegenerative diseases- affects several cell types within this region. Moreover, regeneration after mechanical damage can be influenced by compensatory mechanisms of residual cells from the same neuronal population or undesired side effects. Therefore, a non-invasive cell-type specific ablation system would be suitable to study molecular and cellular mechanisms of neuronal regeneration in more detail. For this purpose, the host research group designed the PC-ATTAC system (Purkinje Cell Apoptosis Through Targeted Activation of Caspase by tamoxifen), a new approach that genetically induces cell death specifically of Purkinje cells (PCs), the main output neuron population of the CB. The transgenic PC-ATTAC RFP zebrafish reporter line also allows controlled ablation of PCs at any time point of choice, that enables for example to study the input of aging for the regenerative response. Among the main objectives, we seek for functional deficits in the zebrafish CB as a consequence of PCs depletion, as well as the nature and time course of recovery programs to restore the CB function. Furthermore, we aim to reveal the cellular and molecular processes involved in the regeneration of PCs. Our combination of interdisciplinary methods, cellular and molecular biology, pharmacology, and in vivo imaging, represents a valuable experimental system to gain insight into mechanisms driving the regeneration of a specific neuronal population in the brain.
