Sarm1 is dispensable for mechanosensory-motor transformations in zebrafish.

Sarm1 is an evolutionary conserved protein that is essential for Wallerian axon degeneration. Sarm1 has emerged as a therapeutic target to treat neuropathies derived from metabolic or chemical stress and physical injury of axons. Yet, the full repertoire of consequences of inhibiting Sarm1 remains unknown. Here we show that loss of Sarm1 in zebrafish does not affect the sensorimotor transformations that underlie rheotaxis. In addition, Sarm1 deficit accelerates the re-growth of regenerating axons. These data indicate that systemic inhibition of Sarm1 is a viable therapeutic option compatible with sustained nervous system function.

A neuronal blueprint for directional mechanosensation in larval zebrafish.

Animals have a remarkable ability to use local cues to orient in space in the absence of a panoramic fixed reference frame. Here we use the mechanosensory lateral line in larval zebrafish to understand rheotaxis, an innate oriented swimming evoked by water currents. We generated a comprehensive light-microscopy cell-resolution projectome of lateralis afferent neurons (LANs) and used clustering techniques for morphological classification. We find surprising structural constancy among LANs. Laser-mediated microlesions indicate that precise topographic mapping of lateral-line receptors is not essential for rheotaxis. Recording neuronal-activity during controlled mechanical stimulation of neuromasts reveals unequal representation of water-flow direction in the hindbrain. We explored potential circuit architectures constrained by anatomical and functional data to suggest a parsimonious model under which the integration of lateralized signals transmitted by direction-selective LANs underlies the encoding of water-flow direction in the brain. These data provide a new framework to understand how animals use local mechanical cues to orient in space.

Converging axons collectively initiate and maintain synaptic selectivity in a constantly remodeling sensory organ.

Sensory receptors are the functional link between the environment and the brain. The repair of sensory organs enables animals to continuously detect environmental stimuli. However, receptor cell turnover can affect sensory acuity by changing neural connectivity patterns. In zebrafish, two to four postsynaptic lateralis afferent axons converge into individual peripheral mechanosensory organs called neuromasts, which contain hair cell receptors of opposing planar polarity. Yet, each axon exclusively synapses with hair cells of identical polarity during development and regeneration to transmit unidirectional mechanical signals to the brain. The mechanism that governs this exceptionally accurate and resilient synaptic selectivity remains unknown. We show here that converging axons are mutually dependent for polarity-selective connectivity. If rendered solitary, these axons establish simultaneous functional synapses with hair cells of opposing polarities to transmit bidirectional mechanical signals. Remarkably, nonselectivity by solitary axons can be corrected upon the reintroduction of additional axons. Collectively, our results suggest that lateralis synaptogenesis is intrinsically nonselective and that interaxonal interactions continuously rectify mismatched synapses. This dynamic organization of neural connectivity may represent a general solution to maintain coherent synaptic transmission from sensory organs undergoing frequent variations in the number and spatial distribution of receptor cells.