Developmental strabismus of sensory origin is a significant public health problem since it affects 2-5% of the infant population. Previously we showed that rearing infant monkeys under conditions of alternate monocular occlusion (AMO) reproduced a sensory strabismus syndrome with large horizontal misalignment, A/V patterns, and Dissociated Vertical Deviation (DVD). An important finding in the previous cycle was that neural factors were responsible for generating cross-axis eye movements that lead to appearance of A/V patterns and DVD. Several lines of evidence including clinical and monkey lesion studies suggest that circuits involving the midline cerebellum are important in binocular control of eye movements including alignment of the eyes. Therefore, in the current cycle, we focus on identifying the actual source for cross-axis movements by performing single cell recording and inactivation studies in the Fastigial Nucleus (FN) and the adjacent Posterior Interposed Nucleus (PIN) of the cerebellum. The experiments are organized into three specific aims.
Specific aim 1 involves neuronal recording in the FN and PIN. The general approach here is to identify neuronal subtypes in each structure and examine neuronal responses for correlation to strabismus angle or cross-axis movements. One of the hypotheses that we are testing is whether neural activity related to the horizontal misalignment is maintained in cells different from those that encode cross-axis movements.
In specific aim 2, we will perform unilateral and bilateral inactivation of the left and right FN and PIN using the GABAA agonist muscimol. The overall goal of these experiments is to determine relative functional contribution of the two target structures in defining properties of strabismus. Several hypotheses that will clarify roles of FN and PIN on one or both sides of the brain and relative contribution towards producing eye misalignment and cross-axis movement role will be tested.
Aim 3 proposes recording from excitatory burst neurons in the paramedian pontine reticular formation to determine whether the pulse signal that drives cross-axis movements is encoded monocularly or binocularly. The strategy here is to use the framework developed via studies of binocular coordination in normal monkeys to address ocularity of drive signals for cross-axis movements. A second theme within all the aims is to compare the AMO model and a more traditionally used model for sensory strabismus, the prism-rearing model. The main goal in performing comparative studies is to validate the AMO model. The AMO and prism-rearing models differ in the type of binocular visual experience during development though they both produce similar behavioral outcomes such as A/V patterns and DVD. Therefore a second outcome is that these comparisons will clarify effect of type of binocular visual experience during development on patterns of activity within oculomotor circuits. Completion of our studies will be of benefit to the understanding and treatment of certain types of strabismus. PROJECT NARRATIVE Ocular misalignment (strabismus) is a developmental disorder that affects a significant number of children born 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 in an animal model to understand the specific problem of A/V-pattern strabismus.
|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|
|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|
|Joshi, Anand C; Das, Vallabh E (2011) Responses of medial rectus motoneurons in monkeys with strabismus. Invest Ophthalmol Vis Sci 52:6697-705|
|Das, Vallabh E; Leigh, R John; Swann, Michelle et al. (2010) Muscimol inactivation caudal to the interstitial nucleus of Cajal induces hemi-seesaw nystagmus. Exp Brain Res 205:405-13|
|Bossong, Heather; Swann, Michelle; Glasser, Adrian et al. (2009) Applicability of infrared photorefraction for measurement of accommodation in awake-behaving normal and strabismic monkeys. Invest Ophthalmol Vis Sci 50:966-73|
|Das, Vallabh E (2009) Alternating fixation and saccade behavior in nonhuman primates with alternating occlusion-induced exotropia. Invest Ophthalmol Vis Sci 50:3703-10|
|Das, Vallabh E (2008) Investigating mechanisms of strabismus in nonhuman primates. J AAPOS 12:324-5|
|Das, Vallabh E; Mustari, Michael J (2007) Correlation of cross-axis eye movements and motoneuron activity in non-human primates with "A" pattern strabismus. Invest Ophthalmol Vis Sci 48:665-74|
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