Abstract
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.