Kenta Asahina - US grants

PROJECT SUMMARY To engage in productive social interactions, an animal must modulate its behavior based on the current situa- tion. Neural and genetic factors regulating homeostatic behaviors (e.g., feeding and sleeping) have been well studied, but the genetic mechanisms by which social behaviors are adjusted remain largely unexplored. Social behaviors are intrinsically more complex than homeostatic behaviors, because in a social context an animal must take into account its own internal state (e.g., hunger, arousal), as well as the reactions and perceived in- tentions of the other individual. Understanding how behavior-related neural circuits are modulated in these con- texts may shed light on human neural disorders that compromise patients' ability to interact with others (e.g., schizophrenia and autism). To identify genetic elements that correlate with behavioral phenotypes, genome- wide association studies have been performed involving patients with psychiatric disorders or animal models. Results from these approaches have been difficult to interpret, however, because: (1) most identified mutations had a small effect, 2) causality between mutation and behavioral phenotype often could not be established, and 3) mutations generally did not involve neuromodulators and neurohormonal systems known to control these processes. To develop more direct approaches for tackling this problem, researchers have turned to Drosophila melanogaster, which exhibits a rich repertoire of stereotypical social behaviors. The Drosophila sys- tem allows for precise genetic alterations, and the labeling and functional manipulation of specific cell types, making it an attractive model for studying how genes control behavioral choice by affecting specific neuronal populations. Research into fly agonistic behavior has been particularly informative, as specific neurons ex- pressing the neuropeptide tachykinin, which functions as a neuromodulator, have been shown to promote ag- gression. However, elements that dampen aggression levels have not been found. Using an RNAi screening approach, five genes that negatively regulate aggression were identified. Proposed research aims to elucidate the molecular mechanisms by which these genes control the intensity of agonistic interactions. These genes encode: (1) the neuropeptide FMRFamide, which may function as a neuromodulator to suppress agonistic be- havior, (2 and 3) PKA-R2 and nervy, which act downstream of G-protein coupled receptors and therefore may regulate signaling of aggression-promoting neuromodulators such as tachykinin, (4) TBPH, a transcriptional repressor implicated in neurodegenerative diseases, and (5) Gr21a, a CO2 co-receptor. Finally, interplay be- tween these negative regulators of aggression and known aggression promoters will be studied. As previous work on the genetics of Drosophila aggression has consistently identified genes that regulate mammalian ag- gression, the proposed project promises to illuminate genetic and neuronal networks that dynamically regulate agonistic interaction across animal phyla. Such knowledge will fill critical gap in our understanding about how genes influence social behaviors through specific neurons and circuits.

PROJECT SUMMARY Neuropeptides play important roles in modulating neural circuits that process olfactory and gustatory infor- mation. This modulation generally functions to align an animal's internal state (e.g., levels of arousal, or food status) with behavioral responses to sensory stimuli (e.g., pheromones or food-associated odorants). Although the neuropeptidergic modulation of specific sensory neurons has been described, the molecular and cellular mechanisms by which neuropeptides affect central chemosensory circuits are unknown. The long-term goal is to characterize the neuropeptidergic modulation of chemosensory circuits by deconstructing this physiological process into clearly defined, behaviorally relevant molecular and neuronal events. Importantly, altered chemosensation in humans is often associated with certain types of mental disorders, and characterizing at a molecular level the neuropeptidergic modulation of chemosensation is a fundamental first step toward under- standing and improving treatments for these disorders. The Drosophila model system offers an excellent plat- form for these studies, because neuropeptidergic systems can be precisely manipulated and the effects on well-characterized circuits mediating chemosensation-induced behaviors, such as male aggressive behavior, can be measured. Initial experiments will focus on the neuropeptide tachykinin, with the central hypothesis that neuropeptides act locally to affect a specific population of neurons to modulate chemosensory information rele- vant to male agonistic behavior. The three specific aims, each based on preliminary success, are to: 1) charac- terize the neuropeptidergic circuit that modulates pheromone-induced male agonistic behavior, 2) characterize synergies between neuropeptides and co-released neurotransmitters, and 3) elucidate the cellular basis of in- teractions among three neuropeptide (tachykinin, neuropeptide F and FMRFamide) that each modulate male agonistic behavior (a chemosensation-guided behavior). In Aim 1, neurons expressing the tachykinin receptor (Takr86C) will be morphologically characterized, and those receiving synaptic input from aggression-promoting tachykininergic neurons will be identified via photo-activatable GFP-assisted neuronal tracing and in vivo cal- cium imaging. In Aim 2, interactions between tachykinin and the co-expressed neurotransmitter acetylcholine will be characterized. Peptide or transmitter release will be independently blocked in relevant cells, and effects on downstream neuronal activity and behavior will be analyzed. In Aim 3, anatomical and physiological rela- tionships between neurons expressing tachykinin, neuropeptide F, or FMRFamide will be established, leading to a better understanding of how these three neuropeptides synergistically affect a pheromone-processing neu- ral circuit. Together, the research proposed here will uncover the genetic and cellular mechanisms by which neuropeptides physiologically affect chemosensory circuits to modulate behavior. Such knowledge will provide a fundamental understanding of how smell and taste perception is centrally controlled, and how dysfunction of this process may lead to non-adaptive responses to environmental cues.