Full visual function depends on the coordinated action of vision and eye movements. We must direct our line of sight on an object of interest so that it will be imaged on the fovea of each eye. Furthermore, to achieve maximum visual acuity and depth perception, we must be able to hold our eyes steady on a stationary or moving target. These important capabilities require appropriate postnatal visual and oculomotor experience. The visual and oculomotor systems are immature at birth and sensitive to injury in both monkeys and humans. When synergistic interactions between visual and oculomotor systems are impaired early in life, strabismus (eye misalignment) and loss of visual function (e.g., amblyopia, stereopsis) occur. These disorders, which affect at least 3% of children born in the United States, are permanent and difficult to treat. Human infantile strabismus syndrome is comprised of impaired gaze-holding, eye misalignment and abnormal smooth pursuit and saccadic eye movement coordination. We have developed effective animal models for studying the development of the visual and oculomotor systems by raising infant monkeys (Macaca mulatta) with either surgical or prism induced strabismus. Our non-human primate model of infantile esotropia syndrome allows us to examine neural mechanisms associated with impaired visual-oculomotor function in strabismus. Our studies are directed at understanding the role of cortical-cortical and cortical-brainstem circuits essential for normal visual-oculomotor function and how these circuits are compromised in disease. During the previous finding cycle, we demonstrated that the pretectal nucleus of the optic tract (NOT) was a likely locus for a common gaze-holding disorder (latent nystagmus) associated with infantile esotropia syndrome. Our current studies indicate that alteration in visual and eye movement signals in the medial superior temporal (MST) area may contribute to defective smooth pursuit of strabismic subjects. Our proposed studies address a significant problem in visual-oculomotor development related to strabismus and development of the cortical smooth pursuit system in health and disease. Our studies are hypothesis driven and use behavioral, single unit recording and modeling approaches to examine the potential role of neurons in MST, frontal eye fields (FEF) and their brainstem targets in normal and pathological smooth pursuit eye movements. Completion of our studies will provide important perspectives that could lead to improved diagnosis and treatment options for developmental disorders affecting vision and eye movements in children. In addition, the strabismic monkey provides important opportunities to uncover fundamental neural mechanisms associated with plasticity in the visual-oculomotor systems.

Public Health Relevance

Human infantile strabismus syndrome is a common problem affecting at least 3% of children born in the United States. The abnormal gaze-holding, eye misalignment and asymmetric eye movements of infantile strabismus impair vision. We have developed effective animal models (Macaca mulatta) for studying development of visual and oculomotor behavior and the underlying neural mechanisms associated with strabismus. Our research is important for improving understanding of clinically important disorders effecting children and developing new treatment options.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY006069-26
Application #
8111854
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (03))
Program Officer
Araj, Houmam H
Project Start
1990-09-30
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
26
Fiscal Year
2011
Total Cost
$374,220
Indirect Cost
Name
University of Washington
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bakst, Leah; Fleuriet, Jérome; Mustari, Michael J (2017) FEFsem neuronal response during combined volitional and reflexive pursuit. J Vis 17:13
Walton, Mark M G; Mustari, Michael J (2017) Comparison of three models of saccade disconjugacy in strabismus. J Neurophysiol 118:3175-3193
McMillan, A; Mustari, M; Horn, A (2017) Identification of secondary vestibulo-ocular neurons in human based on their histochemical characteristics found in monkey. J Neurol 264:583-585
McLoon, Linda K; Christiansen, Stephen P; Ghose, Geoffrey M et al. (2016) Improvement of Eye Alignment in Adult Strabismic Monkeys by Sustained IGF-1 Treatment. Invest Ophthalmol Vis Sci 57:6070-6078
Ono, Seiji; Mustari, Michael J (2016) Response properties of MST parafoveal neurons during smooth pursuit adaptation. J Neurophysiol 116:210-7
Fleuriet, Jérome; Walton, Mark M G; Ono, Seiji et al. (2016) Electrical Microstimulation of the Superior Colliculus in Strabismic Monkeys. Invest Ophthalmol Vis Sci 57:3168-80
Willoughby, Christy L; Fleuriet, Jérome; Walton, Mark M et al. (2015) Adaptability of the Immature Ocular Motor Control System: Unilateral IGF-1 Medial Rectus Treatment. Invest Ophthalmol Vis Sci 56:3484-96
Walton, Mark M G; Mustari, Michael J; Willoughby, Christy L et al. (2015) Abnormal activity of neurons in abducens nucleus of strabismic monkeys. Invest Ophthalmol Vis Sci 56:10-9
Tang, Xiaofang; Büttner-Ennever, Jean A; Mustari, Michael J et al. (2015) Internal organization of medial rectus and inferior rectus muscle neurons in the C group of the oculomotor nucleus in monkey. J Comp Neurol 523:1809-23
Willoughby, Christy L; Fleuriet, Jérome; Walton, Mark M et al. (2015) Adaptation of slow myofibers: the effect of sustained BDNF treatment of extraocular muscles in infant nonhuman primates. Invest Ophthalmol Vis Sci 56:3467-83

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