Oculomotor Abnormalities in a Sheep (Ovis aries) Model of Huntington’s Disease: Towards a Biomarker for Assessing Therapeutic Efficacy

Abstract

Background: Huntington’s disease (HD) is characterized by a loss of control of motor function that causes the presence of abnormal eye movements at early stages. Objective: To determine if, compared to normal sheep, HD sheep have abnormal eye movements. Methods: We measured eye movements in a transgenic sheep (Ovis aries) model of HD using a purpose-built, head-mounted sheep oculometer. This allows us to measure saccades without the need for either behavioral training or head fixation. At the age of testing (6 years old), the HD sheep were pre-manifest. We used 21 sheep (11 HD, 10 normal). Results: We found small but significant differences in eye movements between normal (control) and HD sheep during vestibular ocular reflex (VOR)- and vestibular post-rotational nystagmus (PRN)-based tests. Conclusions: Two measures were identified that could distinguish normal from HD sheep; the number of PRN oscillations when tested in the dark and the gain (eye movement to head movement ratio) during the VOR when tested in the light. To our knowledge, this is the first study in which eye movements have been quantified in sheep. It demonstrates the feasibility of measuring and quantifying human-relevant eye movements in this species. The HD-relevant deficits show that even in ‘premanifest’ sheep there are measurable signs of neurological dysfunction that are characterized by loss of control of eye movements.