Neurotrophic agents (peptide growth factors) are essential for the development and maintenance of the nervous system. Evidence for this notion is largely derived from experiments in the peripheral nervous system. Little is known about the effects and functions of neurotrophic peptides in the development and maintenance of circuits within the normal central nervous system. This lack of information is vexing, because neurotrophic factors appear to be involved in pathologic circumstances, e.g. regenerative processes after neuronal injury and neurodegenerative diseases like Alzheimer's. The application's central aim is to develop and apply an in vivo model to test specific functions of trophic factors for neural circuits in the developing and mature brain. The chick embryo's visual system is a particularly useful model for this undertaking because it permits experimental manipulations during embryonic development in vivo. The proposed experiments will focus on two neuronal populations, the isthmo-optic nucleus, a nucleus with transient expression of NGF receptors during target innervation; and the ceruleus complex, a heterogeneous complex of neuronal populations with continued expression of NGF receptors and FGF receptors in the mature brain. The proposed research will determine how changes in the supply of trophic factors (by directly increasing or decreasing their levels in the target, or by pharmacological manipulations of target populations) will affect the formation, stabilization and rewiring of neural projections in the normal brain and following perturbation of neural circuits. Specifically, the proposed experiments will determine which of the neurotrophins supports isthmo-optic neurons, whether this neurotrophin and other target manipulations can stabilize normally transient collateral projections, whether neural activity is necessary for trophic regulations, and whether expression of neurotrophic receptors can be induced in the mature isthmo-optic nucleus. Studies on the ceruleus complex will determine how target specificity develops, how trophic factors influence the development and maintenance of target specificity, transmitter phenotypes and trophic phenotypes, and whether trophic factors have ongoing functions in the regulation of trophic receptors, transmitter phenotypes and target innervation in the mature brain. The proposed experiments will provide new insights into the trophic regulation of neural circuits in the developing brain in vivo, and they will determine how trophic factors may improve the survival, regeneration, and rewiring of lesioned mature neurons in the CNS, properties that are usually restricted to the peripheral nervous system and to the embryonic period of CNS circuits. These studies will help to explore how pathologic neural conditions may be improved by the manipulation of trophic systems.

Project Start
1992-08-01
Project End
1997-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Feng, Cheng-Yuan; Wiggins, Larisa M; von Bartheld, Christopher S (2011) The locus ceruleus responds to signaling molecules obtained from the CSF by transfer through tanycytes. J Neurosci 31:9147-58
Von Bartheld, Christopher S (2004) The terminal nerve and its relation with extrabulbar ""olfactory"" projections: lessons from lampreys and lungfishes. Microsc Res Tech 65:13-24
Wang, XiaoXia; Butowt, Rafal; Vasko, Michael R et al. (2002) Mechanisms of the release of anterogradely transported neurotrophin-3 from axon terminals. J Neurosci 22:931-45
Rind, Howard B; von Bartheld, Christopher S (2002) Anterograde axonal transport of internalized GDNF in sensory and motor neurons. Neuroreport 13:659-64
von Bartheld, C S; Wang, X; Butowt, R (2001) Anterograde axonal transport, transcytosis, and recycling of neurotrophic factors: the concept of trophic currencies in neural networks. Mol Neurobiol 24:1-28
von Bartheld, C S (2001) Tracing with radiolabeled neurotrophins. Methods Mol Biol 169:195-216
von Bartheld, C S; Butowt, R (2000) Expression of neurotrophin-3 (NT-3) and anterograde axonal transport of endogenous NT-3 by retinal ganglion cells in chick embryos. J Neurosci 20:736-48
Anderson, L C; von Bartheld, C S; Byers, M R (1998) NGF depletion reduces ipsilateral and contralateral trigeminal satellite cell reactions after inferior alveolar nerve injury in adult rats. Exp Neurol 150:312-20
Herzog, K H; von Bartheld, C S (1998) Contributions of the optic tectum and the retina as sources of brain-derived neurotrophic factor for retinal ganglion cells in the chick embryo. J Neurosci 18:2891-906
von Bartheld, C S (1998) Radio-iodination of neurotrophins and their delivery in vivo: advantages of membrane filtration and the use of disposable syringes. J Neurosci Methods 79:207-15

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