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Sources and Targets of Trophic Factors in the Avian Locus Coeruleus and Oculomotor System
Advisorvon Bartheld, Chris
Biochemistry and Molecular Biology
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My dissertation focuses on sources and transport routes of neurotrophic factors in the avian nervous system. How trophic signals are transmitted in the nervous system is a key question in neuroscience research. Cells in the nervous system can retrieve trophic signals by two distinct routes. One is through axonal transport (wiring transmission), such as axons, dendrites and synapses; the other is through fluid diffusion (volume transmission), such as extracellular fluid, cerebrospinal fluid, and plasma.In addition, cells in the nervous system can receive trophic signals from multiple sources which contribute to various degrees to the overall trophic maintenance. The importance of different trophic sources can also depend on physiological and pathological conditions. The embryonic chick retina-locus coeruleus system was used as a model system to study both volume and wiring transmission routes of nerve growth factor (NGF). We found that NGF could travel from the retinal ganglion cells to the locus coeruleus (LoC) through a relay in the optic tectum. This is a wiring transmission example. NGF can also travel from the retina to the LoC through cerebrospinal fluid circulation, which is a volume transmission example.The developing chicken oculomotor system was chosen to explore the contributions of different potential sources of insulin-like growth factor I (IGF-I) for extraocular muscles (EOM). IGF-I is a potent myogenic growth factor. The oculomotor system studied in this project contains three components: the superior oblique muscle (an EOM), the trochlear nucleus (cranial nucleus that contains the motoneurons innervating the superior oblique muscle), and the trochlear nerve (myelinated by Schwann cells). The chicken EOM does not contain muscle spindles and proprioceptive afferents and gamma-motor neuron innervation, which makes it a simpler system than the somatic skeletal muscles. Based on real-time PCR data, we found, surprisingly, that Schwann cells express the largest amount of IGF-I mRNA compared with the trochlear nucleus and the superior oblique muscle. Furthermore, in vivo nerve transport studies showed that the trochlear nerve can transport exogenous IGF-I anterogradely to the muscle. Therefore, among multiple potential sources of IGF-I for EOMs, Schwann cells are the most prominent source. In my dissertation, I provide evidence that volume transport and wiring transport co-exist within the avian retina-LoC system. It supports the largely neglected and controversial "volume transmission theory". In addition, I discovered that Schwann cells of the innervating nerve can be the major source of trophic factors for developing EOMs. This is a novel idea in strabismus research, and may contribute to a better understanding of EOM force regulation and its failure in strabismus.