Neurofibromatosis Type 1 (NF1) is a common genetic disorder. Besides physical abnormalities, up to 60% of children with NF1 exhibit cognitive problems including learning defects, attention deficit hyperactivity disorder, and difficulty with visuo-spatial tasks, e.g. judgment of line orientation (JLO). Animal models with mutations in the neurofibromin (NF1) gene also show cognitive deficits. Two NF1-dependent intracellular pathways regulate learning and long term memory (LTM) in flies. The carboxy terminus of the NF1 protein stimulates an adenylyl cyclase (AC) that raises cAMP levels and protein kinase A (PKA) activity required for learning. The central GAP domain of NF1 deactivates Ras to decrease activity in downstream mitogen activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K) pathways required for LTM. Pharmacological inhibitors exist for these pathways, including some drugs approved for use in humans for other indications. We hypothesize that compounds targeting the AC/PKA or MAPK/PI3K pathways will have modulating effects on cognitive ability, specifically learning and/or attention. In this study, three FDA approved compounds, lovastatin, rolipram, and rapamycin, were each fed to flies overnight before behavioral testing in one of three cognitive assessment assays. We developed a simplified olfactory learning apparatus, and a flight simulator with a novel collection of components.
Olfactory learning is a common and robust learning assay used for Drosophila. Visual learning and attention were assayed using a flight simulator containing visual cues. Effects of the drugs were also monitored at the biochemical level. Drosophila NF1 mutants are known to have impaired olfactory learning but we are the first to test for defects in visual learning or attention-like behavior. These studies are the first to identify deficits in visual learning and attention-like behavior in NF1 mutant flies. Treatment with these drugs did not change the behavior or biochemical markers of NF1 mutants. The visual learning ability of control flies was impaired after treatment, indicating that the drugs were able to affect relevant cognitive pathways. Future studies of Drosophila learning and attention-like behavior should facilitate the identification of novel therapeutics for humans suffering from NF1-associated cognitive deficits.
|Advisor:||Hannan, Frances, Stanton, Patric K.|
|Commitee:||Fried, Victor, Olson, Susan, Pfleger, Cathie|
|School:||New York Medical College|
|School Location:||United States -- New York|
|Source:||DAI-B 74/08(E), Dissertation Abstracts International|
|Subjects:||Neurosciences, Pharmacology, Behavioral Sciences, Cognitive psychology|
|Keywords:||Attention, Behavior, Cognitive impairments, Learning deficits, Neurofibromatosis Type 1, Olfactory, Visual|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be