An animal's nervous system endows it with the ability to react to its environment and to learn from its experiences. How specific molecules within cells of the nervous system are changed by an animal's experience is not well understood. A powerful model organism, C. elegans, will be used to study the genetic basis for plasticity of behavior. The central dogma that DNA, the cell's genetic material, makes an intermediate RNA which then makes protein has been expanded recently to include regulation of protein synthesis by RNA. This study will add another layer of regulation to the dogma by showing that RNA can also modify the DNA itself. To test the hypothesis that small RNAs can modify the activity of neurons to change an organism's behavior, C. elegans that lack key RNA or chromatin molecules will be examined. The prediction is that animals lacking the small RNAs or specific DNA binding proteins will not be able to alter their behavior and will be unable to learn from experience. This would indicate that there is feedback through which small RNAs regulate DNA that encodes genes needed for learning and complex behaviors. This work will provide training opportunities for a postdoctoral scholar, a recent graduate and an undergraduate student and will generate valuable data and reagents to share with the scientific community.
Our work focuses on the olfactory sensory neurons of the nematode, C. elegans since they provide a physiologically relevant odor seeking behavior that is both robust and malleable. For example, the C. elegans is inherently attracted to specific odors that are thought to signal a food source. If, however, the animal experiences those piquant odors while it is starving, it will learn to ignore them. This change in the animal's behavior toward the odor from attraction to indifference results from changes within the sensory neuron itself and by examining in detail the molecular and cell biological processes that underlie the change, we have discovered that olfactory experience causes long lasting changes to the genetic material within the neuron. These changes are mediated by a previously unanticipated class of molecules termed small RNAs. The central dogma of modern biology is that the cell's genetic material, DNA, makes RNA and that RNA then makes protein and proteins carry out all the functions that makes a cell work. Surprisingly, we have found that RNA made by the cell's DNA is used by the cell to turn off the DNA sequence (gene) from which the RNA was made. This feedback loop is an elegant way of turning off genes that make RNA. Indeed, we found that the odor signal amplifies this feedback loop by causing more of these small RNAs to be made and by activating repressive DNA binding proteins so that the DNA is completely silenced. Thus, an environmental stimulus can turn off the cohort of genes it induces by altering the small RNA mediated repression of these genes. This is one means by which homeostasis is maintained within a cell. Our results have implications for all of biology in that it could shed light onto how all types of cells maintain homeostasis in the face of stimulation. Using small RNAs and their regulation by activity any cell with an organism that is stimulated over a period of time would be able to ignore this non-informative stimuli and thereby adapt to the stimulation. This adaptation protects retinal cells in the eye from degeneration and may play a role in limiting hyperproliferation in cancer and myocaridal hypertropy. Beyond biology, understanding how cells maintain homeostasis could allow engineers to utilize or construct similar feedback loops in building self regulating self replicating machines as is proposed in nanotechnology. Further, in terms of behavioral sciences, the negative feedback loop is likely to act in the context of addiction and normal learning. It is possible that understanding this feed back loop and how it is altered by experience could enhance behavioral manipulations in humans to maximize learning and minimize the ill effects of exposure to addictive substances.
