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

Abstract

Patients with tauopathies present with profoundly different clinical symptoms, even within the same disorder. A central hypothesis in the field, well-supported by biomarker studies and post-mortem pathology, 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, but relating tau load to disrupted behavior — especially before cell death — requires a targeted circuit-level approach. Here we studied two distinct balance behaviors in larval zebrafish expressing a human 0N/4R-tau allele in select populations of evolutionarily-conserved and well-characterized brainstem vestibular circuits. We observed that human tau load predicted the severity of circuit-specific deficits in posture and navigation in the absence of cell death. Targeting expression to either mid- or hindbrain balance neurons recapitulated particular deficits in posture and navigation. By parametrically linking tau load in specific neurons to early behavioral deficits, our work moves beyond cell type to close the gap between pathological and neurological conceptions of tauopathy.