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.