Abstract
Disorientation is an early symptom of dementia, suggesting impairments in neural circuits responsible for head direction signaling. The anterodorsal thalamic nucleus (ADn) exhibits early and selective vulnerability to pathological misfolded forms of tau (ptau), a major hallmark of Alzheimer's disease and ageing. The ADn contains a high density of head direction (HD) cells; their disruption may contribute to spatial disorientation. To test this, we virally expressed human tau in the ADn of adult mice. HD-ptau mice were defined by ptau+ cells in the ADn and ptau+ axon terminals in postsynaptic target regions. Despite being able to learn spatial memory tasks, HD-ptau mice exhibited increased looping behavior during spatial learning and made a greater number of head turns during memory recall, consistent with disorientation. Using in vivo extracellular recordings, we identified ptau-expressing ADn cells and found that ADn cells from HD-ptau mice had reduced directionality and altered burst firing. These data suggest that ptau alters HD signaling, leading to impairments in spatial orientation.