After lesioning the frog optic nerve, regeneration occurs and retinal ganglion cells (RGCs) reconnect to their targets. Even so, approximately 50% of the retinal ganglion cells die, compared to mammals where almost all do so. Application of neurotrophins such as brain-derived neurotrophic factor (BDNF) can largely prevent this cell death. However, although these factors are known to have potent effects on axonal growth, branching and synapse formation during development, very little is known about how they will affect regrowing axons during regeneration and reconnection to the target. Before neurotrophins can be used therapeutically to increase ganglion cell survival it is important that these potential effects on target reconnection are understood. The following aims should help in that understanding, and will contribute to our long-term goal of elucidating the molecular requirements for achieving complete and accurate regeneration of the optic pathway. In the first aim, we will test the hypothesis that axonally-applied BDNF increases the speed of axonal regeneration. This will be tested using assays of axonal growth with immunohistochemical markers, and by investigating whether blockers of the Erk and PI3K signaling pathways slow axonal regeneration. In the second aim, we will test the hypothesis that BDNF is synthesized in the tectum, and that increasing tectal BDNF levels promotes RGC branching and synapse formation and modulates the refinement of the retinotopic projection during regeneration. In the third aim, we will investigate how the levels and patterns of visual activity affect the synthesis of BDNF by regenerating frog RGCs, and whether these changes in BDNF synthesis in RGCs in turn affect the refinement of the regenerating retinal projection. This research will help our understanding of the molecular pathways involved in the regrowth and reconnection of regenerating nerve cells in the central nervous system.

Public Health Relevance

Relevance This research will help our understanding of the molecular pathways involved in the regrowth and reconnection of regenerating nerve cells in the central nervous system. This basic knowledge will increase our understanding of the molecular mechanisms involved in the formation and modulation of synaptic connections during regeneration. It will also have the potential to contribute towards improved therapeutic methods to promote recovery after injury and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
5SC3GM093869-04
Application #
8519473
Study Section
Special Emphasis Panel (ZGM1-MBRS-5 (NP))
Program Officer
Krasnewich, Donna M
Project Start
2010-09-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$107,477
Indirect Cost
$35,826
Name
University of Puerto Rico Med Sciences
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
948108063
City
San Juan
State
PR
Country
United States
Zip Code
00936