The purpose of this research is to study the ontogeny of oculomotor neuron physiology and behavior by exploiting the developmental genetics of zebrafish. To achieve this objective, we will investigate the physiology and genetic specification of four neuronal subtypes that contribute to the production of horizontal and torsional eye movement. The proposed research will focus on quantifiable behaviors and physiological properties of oculomotor neurons and circuits to explore the role of Hox paralog group 4 genes (hoxa4a, Hoxb4a, hoxc4a, hoxd4a) in the patterning and differentiation of three nuclei specific for horizontal eye motion that originate from hindbrain rhombomeres 7 and 8. The first nucleus, PNI, performs a neural integration to provide an eye position signal essential for horizontal fixation and vestibuloocular reflex performance. The second, VNI, encodes eye velocity and provides the major input signal to the vestibulocerebellum, and thus is instrumental in all oculomotor plasticity paradigms. A third nucleus, the inferior olive (IO), provides climbing fiber input to the cerebellum necessary for eye movement stability. In addition, the physiology and development of the tangential nucleus (TAN) will be studied. TAN is responsible for gravitoinertial compensatory eye reflexes and develops in rhombomere 5 under control of Hox paralog group 3 genes. Otolith-induced torsional eye motion will provide an assay for cross-regulatory effects between Hox4 and Hox3 genes.
The first aim of the project will characterize the electrophysiology, morphology, and behavior of identified hindbrain oculomotor neurons endogenously labeled with reporter proteins driven by specific Hox gene regulatory sequences.
The second aim will use targeted misexpression of each Hox4 paralog to produce changes in neuronal structure / function and eye movements (as documented in Aim 1) to test the contributions of Hox4 genes to specification of PNI, VNI, IO and TAN neurons.
The third aim will use perturbation of retinoic acid-sensitive regulatory pathways to manipulate hindbrain segmentation and neuronal specification to identify additional genes required for origin, migration and function of the four oculomotor nuclei. Disruptions in the genetic regulatory cascades specifying these oculomotor subgroups will be directly linked to morphological and electrophysiological alterations in their task specific neural networks as reflected in behavioral sequelae. The overall objective of the proposed work is to analyze oculomotor neurons and behaviors that have been functionally conserved throughout vertebrate evolution to establish a basis for understanding the developmental genetic underpinnings of human oculomotor behavior and eye movement disorders. ? ? ?
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