The overall goal of research in our laboratory is to investigate the post-natal development of the ocular motor system in normal monkeys and monkeys reared under conditions to induce developmental problems such as ocular misalignment (strabismus). Strabismus of sensory origin is a significant public health problem since it affects 2-5% of the infant population. Previously we have shown, in an animal model for strabismus, that a slow vergence eye movement pathway involving projections from the midline cerebellar nuclei to the supraoculomotor area and thereafter the medial rectus motoneurons in the oculomotor nucleus partially drives the steady state misalignment. In the present investigation of strabismus mechanisms, we propose to investigate the neural basis for three strabismus properties - 1) eye misalignment, 2) fixation instability and 3) fixation-switch. Each o these strabismus properties implicates an important oculomotor control structure, the Superior Colliculus (SC), and our plan is to couple behavioral studies with neurophysiological investigation of SC contributions. The experiments are organized into three specific aims.
In specific aim 1, we propose single unit recording studies and muscimol inactivation studies in the rostral SC with the goal of determining contribution of the rostral SC in defining state of eye misalignment. The motivation for these studies is that human clinical and animal neural recording and lesion studies suggest that the rostral SC is important in control of slow vergence movements including alignment of the eyes.
In aim 2, we propose single-unit recording studies and muscimol inactivation studies of the rostral SC to determine its role in fixation instability, problem frequently associated with strabismus and amblyopia. The motivation for these experiments is that studies in normal monkeys have proposed a framework where balanced activity across the two rostral colliculi promotes fixation.
In aim 3, we propose single unit recording studies of neurons in the caudal SC to determine their role in fixation-switch (alternating saccade) behavior frequently observed in humans and monkeys with strabismus. We propose to test a framework wherein fixation-switch behavior is driven via the same neural mechanisms that drive target selection in normal monkeys. Studies will be performed in juvenile rhesus monkeys previously induced with a sensory form of strabismus by rearing them under special viewing conditions (optical prism rearing) for the first four months of their life. In summary, each of the specific aims in this project is likely to significantly advance our understanding of strabismus mechanisms and neural circuitry and has the potential to eventually help guide the development of rationally based therapies.

Public Health Relevance

Ocular misalignment (strabismus) is a developmental disorder that affects a significant number of children born every year in the United States and around the world. A better understanding of neural mechanisms that are affected in the different forms of strabismus will help develop rationally based therapy. This particular project will combine various physiological methods and behavior investigation in an animal model to investigate neural correlates to oculomotor disruptions in strabismus including eye misalignment, fixation instability and fixation-switch behavior.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY015312-09A1
Application #
8961813
Study Section
Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section (SPC)
Program Officer
Araj, Houmam H
Project Start
2004-02-01
Project End
2017-09-29
Budget Start
2015-09-30
Budget End
2017-09-29
Support Year
9
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Houston
Department
Type
Schools of Optometry/Opht Tech
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204
Joshi, Anand C; Agaoglu, Mehmet N; Das, Vallabh E (2017) Comparison of Naso-temporal Asymmetry During Monocular Smooth Pursuit, Optokinetic Nystagmus, and Ocular Following Response in Strabismic Monkeys. Strabismus 25:47-55
Upadhyaya, Suraj; Meng, Hui; Das, Vallabh E (2017) Electrical stimulation of superior colliculus affects strabismus angle in monkey models for strabismus. J Neurophysiol 117:1281-1292
Das, Vallabh E (2016) Strabismus and the Oculomotor System: Insights from Macaque Models. Annu Rev Vis Sci 2:37-59
Pirdankar, Onkar H; Das, Vallabh E (2016) Influence of Target Parameters on Fixation Stability in Normal and Strabismic Monkeys. Invest Ophthalmol Vis Sci 57:1087-95
Agaoglu, Sevda; Agaoglu, Mehmet N; Das, Vallabh E (2015) Motion Information via the Nonfixating Eye Can Drive Optokinetic Nystagmus in Strabismus. Invest Ophthalmol Vis Sci 56:6423-32
Agaoglu, Mehmet N; LeSage, Stephanie K; Joshi, Anand C et al. (2014) Spatial patterns of fixation-switch behavior in strabismic monkeys. Invest Ophthalmol Vis Sci 55:1259-68
Joshi, Anand C; Das, Vallabh E (2013) Muscimol inactivation of caudal fastigial nucleus and posterior interposed nucleus in monkeys with strabismus. J Neurophysiol 110:1882-91
Das, Vallabh E (2012) Responses of cells in the midbrain near-response area in monkeys with strabismus. Invest Ophthalmol Vis Sci 53:3858-64
Ono, Seiji; Das, Vallabh E; Mustari, Michael J (2012) Conjugate adaptation of smooth pursuit during monocular viewing in strabismic monkeys with exotropia. Invest Ophthalmol Vis Sci 53:2038-45
Das, Vallabh E (2011) Cells in the supraoculomotor area in monkeys with strabismus show activity related to the strabismus angle. Ann N Y Acad Sci 1233:85-90

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