This application outlines a basic research plan that utilizes the fruit fly model organism to illuminate a fundamental molecular mechanism controlling neuroplasticity. Neuroplasticity is a general feature of the nervous system and explains how the adult brain changes over time and in response to heterogeneous external stimuli, including hormones, nutrition, daylight and experience. Defects in neuroplasticity have been associated with multiple mental disorders, including depression, bipolar disorder, and schizophrenia. Understanding the molecular mechanisms controlling neuroplasticity will lead to therapeutic interventions designed to treat and cure these and other mental illnesses. The central hypothesis of this application is that the let- 7-Complex microRNA (miRNA) pathway is a major regulator of neuroplasticity during adulthood as well as development. MiRNAs are a recently discovered class of regulatory RNAs that control the expression of target genes and the let-7-Complex encodes three highly conserved and co-transcribed neural miRNAs, miR-100, let-7 and miR-125. Although many miRNAs are expressed in the adult human brain, there are currently no known examples of miRNAs that are required for brain function in vivo. Based on our novel preliminary data, I propose that the let-7- Complex miRNA pathway regulates at least three aspects of neuroplasticity: synaptic plasticity, neural stem cell plasticity, and axodendritic remodeling. Furthermore, I propose that the let-7- Complex miRNA pathway regulates each of these processes in the same way, by post- transcriptionally modulating the expression of a small group of dosage-sensitive transcription factors that regulate neuronal morphology. To test this model, I will comprehensively characterize the molecular, cellular and behavioral function of let-7-Complex miRNA pathway in the fruit fly, as follows: 1) determine the developmental and post-developmental function of let- 7-Complex miRNAs in the fly mushroom body, 2) relate the molecular, cellular and behavioral requirements of let-7-Complex miRNAs, and 3) identify whether factors that regulate the expression or activity of let-7-Complex miRNAs also modulate neuroplasticity. By illuminating a highly conserved mechanism that controls plasticity during multiple phases of a neuron's life, this project will enable the design of molecular therapies that adjust neuroplasticity and thereby treat multiple mental disorders. Mental illnesses like stress, depression, autism, bipolar disorder and schizophrenia have all been associated with defects in neuroplasticity. In this grant application, I describe experiments designed to identify an underlying mechanism controlling neuroplasticity in the fruit fly, which is a genetically tractable model organism. This mechanism is the post-transcriptional regulation of specific dosage-sensitive transcription factors by let-7-Complex microRNAs. Given the conservation of the let-7-Complex microRNAs, their targets, and their neural expression profiles from flies to humans, I anticipate that this work will illuminate a fundamental epigenetic pathway controlling multiple aspects of neuroplasticity in humans and thereby broadly impact the treatment of mental illness.

Public Health Relevance

Mental illnesses like stress, depression, autism, bipolar disorder and schizophrenia have all been associated with defects in neuroplasticity. In this grant proposal, I describe experiments designed to identify an underlying mechanism controlling neuroplasticity in the fruit fly, which is a genetically tractable model organism. This mechanism is the post-transcriptional regulation of specific dosage-sensitive transcription factors by let-7-Complex microRNAs. Given the conservation of the let-7-Complex microRNAs, their targets, and their neural expression profiles from flies to humans, I anticipate that this work will illuminate a fundamental epigenetic pathway controlling multiple aspects of neuroplasticity in humans and thereby broadly impact the treatment of mental illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH087511-04
Application #
8289642
Study Section
Special Emphasis Panel (ZMH1-ERB-L (06))
Program Officer
Panchision, David M
Project Start
2009-09-23
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$341,488
Indirect Cost
$115,363
Name
Indiana University Bloomington
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Chawla, Geetanjali; Sokol, Nicholas S (2014) ADAR mediates differential expression of polycistronic microRNAs. Nucleic Acids Res 42:5245-55
Luhur, Arthur; Chawla, Geetanjali; Wu, Yen-Chi et al. (2014) Drosha-independent DGCR8/Pasha pathway regulates neuronal morphogenesis. Proc Natl Acad Sci U S A 111:1421-6
Chawla, Geetanjali; Sokol, Nicholas S (2012) Hormonal activation of let-7-C microRNAs via EcR is required for adult Drosophila melanogaster morphology and function. Development 139:1788-97
Chawla, Geetanjali; Sokol, Nicholas S (2011) MicroRNAs in Drosophila development. Int Rev Cell Mol Biol 286:1-65