Tau load in select brainstem neurons predicts the severity and nature of balance deficits in the absence of cell death

Patients with tauopathies present with profoundly different clinical symptoms 1 , even within the same disorder 2 . A central hypothesis in the field, well-supported by biomarker studies 3,4 and post-mortem pathology 5–7 , is that clinical heterogeneity reflects differential degeneration of vulnerable neuronal populations responsible for specific neurological functions. Recent work has revealed mechanisms underlying susceptibility of particular cell types 8–10 , but relating tau load to disrupted behavior — es- pecially before cell death — requires a targeted circuit-level approach. Here we studied two distinct balance behaviors in larval zebrafish 11 expressing a human 0N/4R-tau allele 12 in select populations of evolutionarily-conserved and well-characterized brainstem vestibular circuits 13,14 . We observed that human tau load predicted the severity of circuit-specific deficits in posture and navigation in the ab- sence of cell death. Targeting expression to either mid- or hindbrain balance neurons recapitulated these particular deficits in posture and navigation. By parametrically linking tau load in specific neu- rons to early behavioral deficits, our work moves beyond cell type to close the gap between pathological and neurological conceptions of tauopathy.