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Dissecting the neural networks underlying female sexual behavior

Reference	BB/I021817/1
Principal Investigator / Supervisor	Professor Stephen Goodwin
Co-Investigators / Co-Supervisors
Institution	University of Oxford
Department	Physiology Anatomy and Genetics
Funding type	Research
Value (£)	613,645
Status	Completed
Type	Research Grant
Start date	01/04/2012
End date	31/03/2015
Duration	36 months

Abstract

In Drosophila, genes of the sex-determination hierarchy orchestrate sex-specific physiology and neural circuitry. Two transcriptional regulators, fruitless (fru) and doublesex (dsx) establish most aspects of 'maleness' and 'femaleness'. Unlike the male, little is known about the specific neuronal substrates mediating female behaviour. Females appear superficially passive but exhibit subtle behaviours associated with mate choice. We are interested in finding the neural circuits in the female brain that must integrate sensory inputs from the olfactory system, auditory system, and reproductive tract to decide between the alternative actions of acceptance or rejection of the male. Gynandromorph studies mapped a region of the dorsal brain that must be genetically female for a mosaic animal to be receptive; groups of dsx neurons are in fact located in this region. Blocking synaptic transmission of dsx neurons in females disrupts female receptivity. It seems likely that dsx neurons in the brain are involved in female mating decisions, just as homologous neurons are involved in male mating decisions. However, since Fruitless has no action in the female nervous system, any circuits that are actively specified in the female are likely to depend on dsx. To carry out an extensive structure/function analysis of doublesex neurons in the female CNS we have developed a unique set of molecular genetic tools. These reagents will enable us to exploit intersectional methods to genetically dissect dsx neurons into smaller subsets that are anatomically, and functionally, distinct. Our experiments will help to define which neurons participate in specific pre- and post-mating behaviours in the female, allowing us to integrate circuit architecture with underlying cellular and synaptic properties. Future experiments will ask, what activity patterns trigger behaviour, and what activity patterns correlate with behaviour?

Summary

What are the universal genetic, developmental, and neural mechanisms that underlie complex behaviours in any organism? Understanding this requires a model system that is both genetically and behaviourally tractable. Much of the recent progress in understanding how genes can influence behaviour has come from the study of innate behaviours in the fruit fly Drosophila melanogaster. In particular, the elaborate courtship ritual performed by the male fly has provided remarkable insights into how the neural circuitry underlying sexual behaviour - which is largely innate in flies - is built into the nervous system during development, and how this circuitry functions in the adult. While male courtship behaviour has been characterized in great detail, the female role has been largely ignored, thus little is known about the specific neuronal substrates mediating female sexual behaviour. During courtship, females appear superficially passive but exhibit subtle behaviours associated with mate choice. We are interested in finding the neural circuits in the female brain that must integrate her senses, and decide between the alternative actions of acceptance or rejection of the male. We are using molecular-genetic and behavioural approaches in the fruit fly to understand how the female makes her mate choice. The molecular pathways we investigate are highly conserved, and understanding the neuronal events underlying simple behavioural choices, may provide new insights in decision-making in higher animals. In addition to these benefits, understanding behavioural choices has potential commercial and medical relevance, particularly for the development of new approaches for controlling the reproductive or host-seeking behaviours of various agricultural pests and human disease vectors.

Impact Summary

Who will benefit from this research proposal? Discoveries in Drosophila have greatly contributed to our understanding of neuroscience. An unequaled wealth of genetic techniques and strategies has permitted landmark discoveries in nervous system development and function. Such findings have generated and directed many research efforts in vertebrate neuroscience. After 100 years, Drosophila continues to be the choice model system for many neuroscientists. The combinational use of powerful research tools will ensure that this model organism will continue to lead to key discoveries that will impact vertebrate neuroscience. Moreover, working with Drosophila means less use of vertebrate models, saving on housing and husbandry costs as well as ethical considerations. This has long been a goal of the UK Research Councils and of society at large and falls under the aims of the 3Rs programme: replacement, reduction and refinement. We are using the Drosophila nervous system to study behavioural choices of the female during courtship. Because the Drosophila nervous system it is more accessible experimentally and has fewer neurons than vertebrate brains, we believe it will yield insights into the mechanisms of behavioural choice that are much harder to study in higher vertebrates. Moreover, discoveries that contribute to our understanding of pre- and post-mating reproductive behaviours in the female are particularly important to other dipteran insects of medical importance. For example, mosquitoes and mosquito-borne diseases continue to plague mankind throughout the world. Of the critical behaviours that characterise the mosquito life strategy, mating is probably the least understood and most understudied. Yet, as mosquitoes depend on sexual reproduction for species maintenance, this aspect of mosquito biology should receive more attention when seeking new avenues for mosquito control and interventions for mosquito-borne disease. How might individuals, organisations or society benefit from this research? Sexually reproducing species often exhibit gender dimorphisms in behaviours such as courtship, aggression, and parental care. Defining the mechanisms underlying sexual differentiation of the brain and behaviour is one of biology's greatest challenges. Communicating how and why we use model organisms to study these basic mechanisms common to many forms of life is extremely important. S.F.G. has undertaken outreach activities with local schools, particularly during Science Week; presented his lab's work through Café Scientifique (www.cafescientifique.org/), a forum for debating science issues, which is committed to promoting public engagement with science and to making science accountable; and participated in the Channel4 BRITDOC-Festival, which brings together researchers, with some of the UK's foremost documentary filmmakers to exchange ideas and explore the potential for collaborations. This proposal has not only the potential for medically relevant discoveries but will also produce simple, yet provocative experimental paradigms, and discussion groups for teaching school children and undergraduates alike.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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