MicroRNA is a recently characterized class of small, non-coding, RNA that repress mRNA translation. Work over the past several years has revealed important roles for microRNA in a vast array of developmental and disease-related processes. Within the developing mammalian central nervous system, results from dicer null mice support a role for microRNAs in neuronal morphogenesis and neuronal survival. However, relatively little is known about how neuronal activity regulates microRNA expression patterns in the mature nervous system and, importantly, whether microRNA regulate neuronal plasticity and cell viability. Based on recent work by a number of investigators, and on the preliminary data reported here, we propose that microRNA plays a key role in activity-dependent structural plasticity in the mature nervous system. To test this hypothesis we have assembled a novel set of genetically modified mouse models, and an array of genetic and functional screening assays.
In Aim 1, we propose to utilize the Solexa deep sequence method to examine activity-dependent expression of non-coding RNA in the hippocampus. We will also examine the contribution of transcriptional networks that underlie activity-dependent neuronal plasticity and perform a series of experiments to identify functionally relevant microRNA targets.
In Aim 2 we propose to determine the contribution of microRNA to adult neuronal structural plasticity and neuroprotection. To this end, we will employ an inducible form of Cre-recombinase to disrupt Dicer expression. The effects on both physiological and pathophysiological levels of neuronal activity will be examined.
In Aim 3, we propose to determine the role of the microRNA-132 locus in activity-induced structural remodeling in vivo. A combination of knockout and tet-inducible microRNA mouse strains will be used to test this question. The data generated here should provide a wealth of new insights regarding how neuronal activity sculpts microRNA expression patterns, and, in turn, how these changes affect key aspects of neuronal plasticity and pathology.

Public Health Relevance

microRNAs are small molecules that act as potent silencers of protein expression. With respect to brain health, dysregulation of microRNAs expression has been suggested to contribute to a number of neurological disorders, including Down syndrome, Rett syndrome and schizophrenia. In this proposal, our goal is to provide the first comprehensive examination of how neuronal activity regulates microRNA expression in the adult mammalian central nervous system and, in turn, how microRNA regulates key aspects of neuronal plasticity and pathology. These data should provide a framework to begin to develop therapeutic approaches designed to regulate microRNA expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS066345-03
Application #
8325141
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Riddle, Robert D
Project Start
2010-09-15
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$384,441
Indirect Cost
$78,222
Name
Ohio State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Aten, Sydney; Hansen, Katelin F; Hoyt, Kari R et al. (2016) The miR-132/212 locus: a complex regulator of neuronal plasticity, gene expression and cognition. RNA Dis 3:
Karelina, K; Liu, Y; Alzate-Correa, D et al. (2015) Mitogen and stress-activated kinases 1/2 regulate ischemia-induced hippocampal progenitor cell proliferation and neurogenesis. Neuroscience 285:292-302
Hansen, Katelin F; Sakamoto, Kensuke; Pelz, Carl et al. (2014) Profiling status epilepticus-induced changes in hippocampal RNA expression using high-throughput RNA sequencing. Sci Rep 4:6930
Karelina, Kate; Alzate-Correa, Diego; Obrietan, Karl (2014) Ribosomal S6 kinase regulates ischemia-induced progenitor cell proliferation in the adult mouse hippocampus. Exp Neurol 253:72-81
Cao, Ruifeng; Butcher, Greg Q; Karelina, Kate et al. (2013) Mitogen- and stress-activated protein kinase 1 modulates photic entrainment of the suprachiasmatic circadian clock. Eur J Neurosci 37:130-40
Hansen, Katelin F; Obrietan, Karl (2013) MicroRNA as therapeutic targets for treatment of depression. Neuropsychiatr Dis Treat 9:1011-21
Hansen, Katelin F; Karelina, Kate; Sakamoto, Kensuke et al. (2013) miRNA-132: a dynamic regulator of cognitive capacity. Brain Struct Funct 218:817-31
Sakamoto, Kensuke; Norona, Frances E; Alzate-Correa, Diego et al. (2013) Clock and light regulation of the CREB coactivator CRTC1 in the suprachiasmatic circadian clock. J Neurosci 33:9021-7
Lesiak, Adam; Pelz, Carl; Ando, Hideaki et al. (2013) A genome-wide screen of CREB occupancy identifies the RhoA inhibitors Par6C and Rnd3 as regulators of BDNF-induced synaptogenesis. PLoS One 8:e64658

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