Final Report Summary - SENSORINEURAL (Elaboration and refinement of sensorineural dendritic architecture)
The main aim of the SENSORINEURAL research project was to study sensory perception and integration, using the zebrafish as experimental system. We concentrated on the anatomically discrete but functionally sophisticated mechanosensory organ of the lateral line, which the fish uses to evaluate water currents and orient itself in space. This sensory system is analogous to the human inner ear. We have characterized the mechanisms by which the neurons associated to the lateral line elaborate and remodel sensory circuits, and how the peripheral mechanoreceptors, called hair cells, regenerate and re-innervate after damage to maintain life-long function.
We begun by hypothesizing that genome-encoded and activity-dependent mechanisms combine to govern the ability of sensory neurons to maintain an appropriate innervation of the hair cells and represent them in the brain. Moreover, that axonal arborizations of sensory neurons are highly dynamic and that they are modulated by the number, orientation and activity of the hair cells. In addition, we postulated that the ascending sensory pathway constructs two separate neural maps -a somatotopic map that informs the central nervous system about the spatial distribution of peripheral receptors, and a polarity map that conveys information about the orientation of the mechanical stimuli along the main body axes of the animal. Both neural maps may converge along the ascending pathway and integrated by higher-order neurons in the central nervous system. To test these hypotheses we used a combination of forward- and reverse-genetic approaches, pharmacology, high-end optical live imaging, electrophysiology and optogenetics.
We resolved a long-stading problem of how bilateral mechanoreception in the peripheral organs is established and maintained. We discovered that compartmentalized intercellular communication governs the directional regeneration of hair cells because it controls the generation of stem-cell derived hair-cell progenitors. We also discovered a novel process that we termed “planar cell inversions” whereby sibling hair cells invert positions immediately after progenitor division. We also found that the peripheral organs can regenerate hair cells after recurrent severe injuries and in adulthood. Moreover, they can reverse transient imbalances of intercellular signaling that result in defective organ proportions during repair. Our results revealed inextinguishable hair-cell regeneration in the lateral line, and suggest that the sensory epithelia are formed by plastic territories that are maintained by continuous intercellular communication.
In parallel, we studied hair-cell innervation. Our findings revealed a conceptually novel paradigm of synaptic selectivity, in which collective neuronal behaviour impart coherent patterns of innervation in a non-deterministic manner. These results further advanced our fundamental understanding of how patterns of connectivity are maintained in a constantly remodeling sensory circuit. Finally, we have devised a novel method based on optogenetic manipulation of cAMP to promote the regeneration of refractory sensory axons.