Studying epigenetic pathways in brain function and social behavior using ants

描述（由申请人提供）：越来越明显的是，负责基因表达的表观遗传调控和细胞身份维持的分子机制在动物大脑的发育和功能中起着重要作用。考虑到表观遗传过程如DNA甲基化和组蛋白修饰的破坏可导致智力迟钝，认知能力下降，成瘾和各种精神疾病，揭示表观遗传，脑功能和行为之间的机制联系不仅对神经科学而且对人类健康具有深远的意义。为了更好地理解表观遗传过程如何影响大脑功能，我将开发和利用一个新的模型系统：蚂蚁Harpegnathos saltator。工蚁和蚁后表现出截然不同的行为，没有基因组成的差异；因此，根据定义，表观遗传机制必须有助于激活和抑制适当个体的种姓特异性行为。蚂蚁的许多复杂行为是可预测的，在每个等级中都是刻板的，并且经常受到可以通过实验控制的外部线索的调节，例如社会背景和化学感觉刺激。此外，与黑腹果蝇不同，蚂蚁有一个功能齐全的DNA甲基化系统。由于这些原因，蚂蚁构成了研究大脑表观遗传学的理想实验系统，特别是在社会行为的背景下。在蚂蚁中，Harpegnathos特别适合作为实验动物，因为在适当的条件下，任何工蚁都可以在一个迷人的过程中转化为功能性的伪蚁后，这为研究成人大脑的表观遗传可塑性提供了一个自然的实验范例，同时，将使我们能够开发出大多数其他群居昆虫无法实现的遗传方法。这些研究包括对蚂蚁种姓决定、行为和社会组织的分子机制进行协调和雄心勃勃的调查，特别关注表观遗传过程对基因表达的调节。我们将从深入表征大脑转录组的变化开始，这些变化伴随着从Harpegnathos工蜂到伪皇后的行为转变。我们将确定负责观察到的表型变化的基因网络，并剖析叠加在这些网络上的调控层，重点关注已知和新兴的表观遗传途径，包括DNA甲基化，组蛋白修饰和非编码rna的调控。为了确定基因和途径的功能意义，我们将在Harpegnathos中开发新的遗传工具，并利用已经建立的实验方法，如RNA干扰，药物干预，激素治疗和社会环境操纵。该项目将牢固确立Harpegnathos作为一种模式群居昆虫的地位，并为从分子水平上理解脑功能和社会行为的表观遗传调控奠定基础。

DESCRIPTION (provided by applicant): 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.