It is becoming increasingly apparent that the molecular machinery that is responsible for the epigenetic regulation of gene expression and maintenance of cell identity has fundamental roles in the development and function of the animal brain. Considering that the disruption of epigenetic processes such as DNA methylation and histone modifications can cause mental retardation, cognitive decline, addiction, and various psychiatric disorders, revealing the mechanistic connection between epigenetics, brain function, and behavior has far- reaching implications not only for neuroscience but also for human health. To better understand how epigenetic processes affect brain function, I will develop and exploit a new model system: the ant Harpegnathos saltator. Ant workers and queens exhibit starkly distinct behaviors without differences in their genetic composition;therefore, by definition, epigenetic mechanisms must contribute to activate and repress caste-specific behaviors in the appropriate individuals. Many of the ants'sophisticated behaviors are predictable, stereotypic within each caste, and often modulated by external cues that can be controlled experimentally, such as social context and chemosensory stimuli. Moreover, unlike Drosophila melanogaster, ants have a fully functional DNA methylation system. For these reasons, ants constitute an ideal experimental system to investigate epigenetics in the brain, especially in the context of social behavior. Among ants, Harpegnathos is particularly suited as a laboratory animal because any worker can, under the proper conditions, be converted into a functional pseudo-queen in a fascinating process that offers a natural experimental paradigm to study epigenetic plasticity in the adult brain and, at the same time, will allow us to develop genetic approaches that are unattainable in most other social insects. The proposed studies consist of a coordinated and ambitious investigation on the molecular mechanisms of caste determination, behavior, and social organization in ants, with particular attention to the regulation of gene expression by epigenetic processes. We will begin from an in-depth characterization of the changes in the brain transcriptome that accompany the behavioral switch from Harpegnathos workers to pseudo-queens. We will identify the gene networks that are responsible for the observed changes in phenotype and dissect the regulatory layer superimposed on these networks, with a focus on known and emerging epigenetic pathways, including DNA methylation, histone modifications, and regulation by noncoding RNAs. To address the functional significance of the genes and pathways identified, we will develop novel genetic tools in Harpegnathos and utilize already established experimental approaches such as RNA interference, pharmacological intervention, hormonal treatments, and manipulation of the social environment. This project will firmly establish Harpegnathos as a model social insect and will lay the foundations to understand at a molecular level the epigenetic regulation of brain function and social behavior.

Public Health Relevance

The regulation of gene expression is controlled by epigenetic pathways that alter the chemical structure of chromosomes (chromatin) and allow for multiple cell identities to arise from a single genome. These pathways are also critical for the brain and their improper functioning can cause mental retardation, cognitive decline, and psychiatric disorders. Because the different castes of social insects, such as ants, display dramatic differences in behavior, all encoded by the same genome, I propose to establish the ant Harpegnathos as an experimental model to study how changes in gene regulation and chromatin structure influence brain function, behavior, and social interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2MH107055-01
Application #
8755972
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (56))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2014-09-16
Project End
2019-09-15
Budget Start
2014-09-16
Budget End
2019-09-15
Support Year
1
Fiscal Year
2014
Total Cost
$2,400,000
Indirect Cost
$900,000
Name
University of Pennsylvania
Department
None
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104