METHYL-CPG BINDING PROTEINS MEDIATE OCTOPAMINERGIC REGULATION OF COMPLEX BEHAVIORAL TRAITS

An organism’s survivability in the natural world is contingent to its ability to respond rapidly and appropriately to various cues and challenges in its physical and social environment. The dynamicity of various environmental and social factors necessitates plasticity in morphological, physiological and behavioral systems – both at the level of an individual organism and that of a species. For more than century, natural selection of existing genetic variation in populations has helped us understand such plasticity across generations. However, recent years have seen a re-emergence of somewhat contentious quasi-Lamarckian framework with which organisms can reliably transmit acquired traits to subsequent generations in response to changes in external conditions. Whether or not it can be categorized as such, a stable transgenerational transmission of acquired alterations in epigenetic code, including methylation patterns and small RNA molecules, associated with behavioral and physiological, and I use the term here loosely, ‘adaptations’ for up to three generations has indeed been demonstrated in a number of species. The focus on methyl-binding proteins in this dissertation is guided by a motivation to advance our understanding of such epigenetic systems in one of the most extensively used model systems in biological and biomedical research – Drosophila. In contrast to the vast body of literature on the genetics, physiology, ecology, and neurobiology of Drosophila, methylation and methylation-associated processes represent one of the few relatively unexplored territories in this system. This certainly hasn’t been for the lack of trying (see section 1.8). Consistent with their role in other species, Drosophila MBD proteins have been implicated in dynamic regulation of chromatin architecture and spatiotemporal regulation of gene expression. However, methylationdependence of their functions and their contribution to the overall organismal behavior remains equivocal. In this dissertation, I explore the role of the conserved methyl-CpG binding (MBD) proteins in the regulation of octopaminergic (OA) systems that are associated with a number of critical behaviors such as aggression, courtship, feeding, locomotion, sleep, and learning and memory. In chapter II, I, along with my colleagues, demonstrate functional conservation of human and Drosophila MBD-containing proteins. We show – (a) that a well-characterized human protein – MeCP2 – can regulate amine neuron output in Drosophila through MBD domain, (b) that endogenous MBD proteins in Drosophila regulate OA sleep circuitry in a manner similar to human MeCP2, and (c) that human and Drosophila MBD proteins may share a select few genomic binding sites on larval polytene chromosomes. In chapter III, we describe a novel function of these chromatin modifiers in the regulation of social behaviors, including aggression and courtship. Returning to the issue of methylation, we demonstrate an interaction effect between induced-DNA hypermethylation and MBD-function in context of aggression and intermale courtship. Species – and sex–specific behaviors such as courtship and aggression rely on an organism’s ability to reliably discriminate between species, sexes and social hierarchy of interacting partners, and adjust to the dynamic shifts in sensory and behavioral feedback cues. At the level of an individual organism, such behavioral flexibility is often achieved by modulating the strength and directionality of neural network outputs which endows a limited biological circuit the capacity to generate variable outputs and adds richness to the repertoire of behaviors it can display (Marder, 2012). The role of MBD proteins discussed in this dissertation highlights a mechanism that couples chromatin remodeling and OA neuromodulation in context-dependent decision-making processes