title: New approaches on the role of the Mauthner neuron
Creators: name: Hecker, Alexander
Publisher: name: University of Bayreuth
Year: 2020
Subjects: subject: Mauthner neuron
subject: neuronal regeneration
subject: homeostasis
subject: laser ablation
subject: 500

description: For decades the giant Mauthner (M-) cell has been the model neuron for different fields of neuroscience. For instance examining the M-cell enabled important breakthroughs in understanding synaptic plasticity or electrical transmission. However, despite numerous groundbreaking studies the question of the M-cell’s ultimate function for the whole organism remains unanswered. The M-cell is the largest neuron in the vertebrate brain and it is thought to play a major role in the vital escape response of most fish and larval amphibians. Yet ablation has repeatedly failed to eliminate all rapid escapes, suggesting that those escapes can equally well be mediated by other smaller neurons. This, however, raises the question, why animals should keep such a giant and costly neuron if the exact same behavior can be triggered by smaller neurons. Here, I ablated the M-cell but – in contrast to previous studies – checked not only for the absence of the M-cell soma but also for the absence of its giant axon. By doing this, I showed that rapid escapes completely vanished. Moreover, because I simultaneously monitored soma and axon state as well as the escape performance, I demonstrated that the M-axon alone can be recruited to initiate rapid escapes even in the absence of the soma. This result suggests a simple solution concerning the role of the M-cell: the M-axon can mediate rapid escapes even in the absence of the soma, but once the entire M-cell (i.e. soma and axon) is actually gone, all rapid escapes vanish. I then managed to raise zebrafish, whose M-cells I ablated during larval stages and showed that even adult zebrafish cannot compensate the loss of the M-cell. Lastly, I affirmed the critical role of the M-cell for enhancing the biological fitness and showed that M-cells are substantial for the escape success in the presence of a relevant predator. The survival-relevant role of the M-cell that I established inevitably raised another important issue that was addressed by previous reports: Why is the M-cell among the very few CNS neurons in fish that is not able to regenerate? For such an important neuron it would be crucial to utilize a rapid regeneration program, that smaller neurons of their CNS obviously contain. I therefore injured the M-axon at different distances to its soma and showed that the M-cell is capable of rapid axon regeneration using an injury distance-dependent switch: If the axon was injured distantly to its soma, the M-axon did not regenerate at all. In contrast, an injury more proximal to the soma triggered rapid and robust regeneration. Moreover, after proximal injury even behavioral functionality was restored within less than ten days. The system I found here therefore opens new avenues to investigate vertebrate CNS injury and repair by exploiting the intrinsic switch that decides if regeneration occurs or not. Finally, I used the giant size and easy accessibility of the M-cell to investigate how M-cells manage extrinsic manipulations (i.e. distinct temperature drop). Such an important neuron should possess mechanisms that allow homeostatic plasticity, a process that maintains functionality of neuronal circuits even in the presence of ongoing perturbations. I showed that cooled zebrafish larvae are able to rapidly compensate the temperature impact on the escape latency. This makes sense because zebrafish larvae have temperature-independent predators. I therefore confirmed the importance of such rapid latency recovery directly in relevant predator-prey experiments. Further, the M-cell simultaneously restored the post-response Ca2+-influx, which was surprisingly tightly linked to escape latency. I then used pharmaceuticals that inhibit NMDA receptors, CaMKII as well as gap junctions and showed that recovery of latency depends on key mechanisms of homeostatic signaling (i.e. NMDA receptors and CaMKII) that directly affect electrical transmission (through gap junctions) and ultimately escape latency. I present the first link between a survival-relevant behavioral homeostasis and homeostatic processes within a single neuron. This suggests that the M-cell can ‘measure’ drastic extrinsic changes through post-response Ca2+-influxes to initiate rapid adaptation. Summed up, I established a survival-critical role of the M-cell. If the M-cell is lost, the escape performance is forever impaired. I showed that an intrinsic and injury distance-dependent switch decides if the M-axon will regenerate or not after spinal cord injury. Lastly, I demonstrated that behavioral homeostasis is mapped to properties of a single cell that initiate homeostatic signaling. I therefore present groundbreaking findings that not only solved issues discussed in Mauthner cell research since decades but also will have an impact on future studies in neuroethology, spinal cord repair and neuroplasticity all by manipulating one individual neuron.