Solving conflicts: Modulation of choices and actions in the fly.

Lead Research Organisation: University of Birmingham
Department Name: Sch of Biosciences

Abstract

Effective action-selection involves evaluating information from the outside world and our intrinsic needs to select the most appropriate action for each situation. Yet little is known about how external and internal cues are weighed and integrated in the brain to prioritise actions.

This project investigates this fundamental biological problem using the fruit fly Drosophila, an excellent system to investigate the mechanistic basis of behaviour. We will build on our recent knowledge of the key neurons that mediate the choice between feeding and mating (Cheriyamkunnel et. al., Curr.Biol 2021) to characterise the mechanism that integrates modulatory signals to prioritise actions.

Fruit flies have a brain of only 100,000 neurons, most of which have been mapped. Thanks to new genetic tools, single neurons can be manipulated and recorded in Drosophila with a level of temporal, spatial and genetic precision that is not available in any other model organism. With these tools, we can study how cues from the environment and from inside the animal are evaluated in brain circuits to select appropriate actions.

The choice between food or sex is a pretty fundamental one - we have to eat to live and we have to reproduce to pass on our genes to the next generation. We have recently created an assay where food- and sex-deprived flies are confronted with the decision of whether to prioritise feeding or mating. These behaviours cannot be simultaneously displayed in flies, forcing the animal to make a decision and prioritise what to do. Crucially, we know a great deal about the neural basis of courtship and feeding behaviours. Thus, this assay is well suited to identify fundamental principles of action-selection that might apply to other behavioural conflicts and the brains of other organisms.

We discovered that if a male fly is very hungry and sexually aroused, he will choose to eat over courting a female. However, the choice also depends on other factors like the quality of the food on offer and on how hungry and sex deprived the animal is. We found that the neurons that tell the fly to go and eat, or to go and mate are essentially competing with each other. If the need to eat is most urgent, the feeding neurons will take over; if the threat of starvation is less, then the urge to reproduce will win. Further, we found that the presence of a female makes the males eat faster, allowing them to move on to sex very quickly. These findings suggest that conflicting states (e.g. the urge to eat and to reproduce) do not always inhibit each other but may help each other.

Our work provides the unique opportunity to understand how flies integrate sensory cues to make these behavioural choices, and ask what it reveals about the way the brain functions. In this project, we will identify the signals that convey hunger state, as well as the cues that broadcast the presence of a potential mate, to the action-selection centre in the brain. We will study how these signals are integrated in the neurons that steer the animal's actions, making each option more or less attractive. In objective 1, we will define how hunger signals are integrated in the brain to promote feeding over courtship. In objective 2, we will study how the motivation to mate makes the male eat faster, allowing him to quickly move to the female. In objective 3, we will reveal how males determine when to stop a given behaviour (e.g., feeding) to engage in another important task (e.g., mating).

This action-selection is an example of the everyday conflicts animals need to solve but are difficult to tackle in mammals. By studying how the brain makes decisions at a molecular, cellular and circuit level, in a simpler system, we aim to reveal fundamental principles of action-selection that might be common to many species. This knowledge, in turn, will provide insight into how other more complex brains work, like our own.

Technical Summary

When challenged by the choice between essential needs, action-selection can come with a substantial cost. How the brain integrates external context and internal needs to prioritise actions remains poorly understood. We have recently identified the neural circuit node that mediates the choice between feeding and mating in Drosophila (Cheriyamkunnel et. al., Curr.Biol 2021). We showed that antagonism between courtship (P1) neurons and feeding (TyrR) neurons determines the selected behaviour. This provides a unique opportunity to establish how hunger, satiety and sex-related inputs are integrated in the circuit to prioritise actions and modulate behavioural responses. This project has three objectives:

In objective 1, we will decipher how hunger state is integrated in the circuit to prioritise an initial action. We will map hunger-encoding serotonin within the action-selection network by removing serotoninergic receptor function in candidate cells. We will combine two-photon imaging, optogenetics and circuit mapping methods to study how serotonin is represented in the circuit, and how this activity influences behaviour. In objective 2, we will reveal how female sensory cues potentiate feeding responses in males. We found that the presence of a female increases the urgency and commitment to feeding, allowing males to quickly switch to mating. We will use automated tracking, mutagenesis, optogenetics and live imaging methods to study how female sensory cues are integrated in the action-selection circuit node, and how they influence feeding. In objective 3, we will use automated tracking, optogenetics and live imaging methods to study how satiety/hunger cues induce the switch from feeding to mating, and how they modulate the action-selection circuit node.

This research will show how sensory input is integrated with motivational states to modify action-selection and behaviour outputs in conflicting situations, and thus reveal fundamental principles of brain function.

Publications

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Von Philipsborn A (2023) Courtship Conditioning/Suppression Assays in Drosophila in Cold Spring Harbor Protocols

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Von Philipsborn AC (2023) Female Fly Postmating Behaviors. in Cold Spring Harbor protocols

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Von Philipsborn AC (2023) Measurement of Drosophila Reproductive Behaviors. in Cold Spring Harbor protocols

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Von Philipsborn AC (2023) Probing Acoustic Communication during Fly Reproductive Behaviors. in Cold Spring Harbor protocols

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Von Philipsborn AC (2023) Single-Pair Courtship and Competition Assays in Drosophila. in Cold Spring Harbor protocols

 
Description Board member of FENS-Kavli Network of Excellence
Geographic Reach Europe 
Policy Influence Type Participation in a guidance/advisory committee
URL https://fenskavlinetwork.org/
 
Description FENS-Kavli Netwok of Excellence fellow and board member
Geographic Reach Europe 
Policy Influence Type Participation in a guidance/advisory committee
Impact The multidisciplinary, international network of FENS-Kavli Scholars aims to improve neuroscience in Europe and beyond by enhancing the relationship between science, policy and society, allowing a better understanding of each sector's ambitions, challenges and needs. FKNE Scholars participate in several meetings per year that allow for discussion of a range of topics across Neuroscience as well as challenges and opportunities for European neuroscientists. Since my appointment in September 2021, I have been working alongside different colleagues to develop science outreach activities, and advise policymakers on issues related to neuroscience research, in particular in the face of Brexit (e.g., funding program structures, scientist mobilisation, etc). In addition, we are collectively writing opinion articles and white-paper recommendations to European stakeholders and funding schemes on key issues, including "Environmentally Conscious Science", "Open Science: Practices and Aspirations" and "Diversity and Equity in Neuroscience". During 2022 FENS forum, we will deliver several prizes aimed at celebrating investigators who have shown outstanding examples of mentorship, younger scientists who have delivered excellent PhD theses, and role models who have delivered the advancement of diversity in neuroscience. My involvement in the outlined activities demonstrates that I have identified wellbeing, mentoring and challenges and work to develop solutions.
URL https://fenskavlinetwork.org/portfolio/carolina-rezaval/
 
Description FKNE MENTORING PRIZE 2024
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
URL https://fenskavlinetwork.org/mentoring/fkne-mentoring-prize/
 
Description FKNE PhD Prize
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
URL https://fenskavlinetwork.org/mentoring/fkne-phd-thesis-prize/
 
Description Influence on landscape of European neuroscience policy.
Geographic Reach Europe 
Policy Influence Type Participation in a guidance/advisory committee
Impact see above
 
Description Member of the BBSRC Pool of Experts
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
URL https://www.ukri.org/who-we-are/bbsrc/board-and-panel-membership/
 
Description Organisation of Leadership course
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Policy Influence Type Influenced training of practitioners or researchers
URL https://fenskavlinetwork.org/fkne-leadership-and-soft-skills-online-training-series-for-the-starting...
 
Description How are precise micro-motor movements executed by the CNS to perform complex bimanual tasks in a virtual environment?
Amount £60,036 (GBP)
Funding ID 2266977 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2019 
End 09/2024
 
Description Midlands Integrative Biosciences Training Partnership MIBTP BBSRC PhD fellowship to a student in my lab
Amount £74,488 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2023 
End 09/2027
 
Description Neural Mechanisms of Action-Selection During Sensory Conflict
Amount € 212,933 (EUR)
Funding ID H2020-MSCA-IF-Project ID 101023536 
Organisation Marie Sklodowska-Curie Actions 
Sector Charity/Non Profit
Country Global
Start 08/2022 
End 10/2024
 
Description Neural basis of cost-benefit analysis in flies
Amount £324,945 (GBP)
Funding ID RPG-2023-009 
Organisation The Leverhulme Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2024 
End 01/2027
 
Description Collaboration with Dr Andrew Lin_ University of Sheffield 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution Mate choice is an essential behavioural process with profound consequences in evolution. How do animals choose with whom to mate? How do they evaluate the features of a potential mate to maximise their reproductive success? We're studying how pathogens in?uence mate choice decisions, especially the neural mechanisms underlying the decision-making process.
Collaborator Contribution We have established a collaboration with Dr Andrew Lin to study how infection-related information is processed and integrated in the brain to modulate mating decisions in live imaging experiments. These studies will contribute to an emerging research field that brings together immune system with neuroscience.
Impact not yet
Start Year 2020
 
Description Collaboration with Dr Andrew Lin_ University of Sheffield 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution Mate choice is an essential behavioural process with profound consequences in evolution. How do animals choose with whom to mate? How do they evaluate the features of a potential mate to maximise their reproductive success? We're studying how pathogens in?uence mate choice decisions, especially the neural mechanisms underlying the decision-making process.
Collaborator Contribution We have established a collaboration with Dr Andrew Lin to study how infection-related information is processed and integrated in the brain to modulate mating decisions in live imaging experiments. These studies will contribute to an emerging research field that brings together immune system with neuroscience.
Impact not yet
Start Year 2020
 
Description Collaboration with Lisa Scheunemann- Freie Universität Berlin 
Organisation Free University of Berlin
Country Germany 
Sector Academic/University 
PI Contribution Joint development of technology to image neurons in live flies-
Collaborator Contribution Joint development of technology to image neurons in live flies-
Impact Manuscript in preparation-
Start Year 2022
 
Description Collaboration with Marta Moita, Champalimaud Foundation, Lisbon, Portugal 
Organisation Champalimaud Foundation
Department Champalimaud Centre for the Unknown
Country Portugal 
Sector Academic/University 
PI Contribution In the context of this grant, we are identifying neurons involved in the choice between survival and reproduction in Drosophila. We're currently dissecting the neural mechanisms underlying this action-selection.
Collaborator Contribution We have established a collaboration with Dr Marta Moita to use state of the art technology to deliver a threat in our behavioural paradigm. My post doc spent 10 days in Dr Moita's lab to learn how to use their software and behavioural set up and we're now setting it up here.
Impact not yet
Start Year 2019
 
Description A talk or presentation - Taster lecture for prospective university students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A taster lecture was organized for prospective university students, providing them with an insightful glimpse into academic life and specific subject areas. The purpose of the presentation was to offer a preview of the university experience and highlight the exciting opportunities available within the chosen field of study.

During the lecture, I aimed to engage the students with captivating content, showcasing the depth and relevance of our research in neuroscience. The talk aimed to spark interest, encourage questions, and help students make informed decisions about their academic pursuits.

As a result, the taster lecture generated enthusiastic discussions among the attendees, addressing their queries and concerns. Prospective students gained valuable insights into the curriculum, research opportunities, and potential career paths within the field. The positive impact of the presentation was reflected in increased interest and engagement among the students, as reported by the university's admissions team.
Year(s) Of Engagement Activity 2023
 
Description Invited lecturer Master in Life Science, ENS 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Master in Life Science, ENS
Invited lecturer. 2nd year of Master around sexual differentiation in brain function
IBENS institute in Paris.
Year(s) Of Engagement Activity 2023
URL https://www.enseignement.biologie.ens.fr/spip.php?article215&lang=fr
 
Description Offer Holder Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact During the Offer Holder Visit Day, two taster lectures were conducted to enthuse prospective university students about the exciting research opportunities available within the academic community. The purpose of these lectures was to provide offer holders with a glimpse into the engaging and innovative research taking place at the university, fostering enthusiasm and imagination about potential contributions they could make as future students.

The taster lectures aimed to showcase the vibrant research environment, spark curiosity, and help offer holders envision their role in the university's academic landscape. Following the lectures, interactive discussions were encouraged, allowing students to ask questions and engage with faculty members or experts.

While specific outcomes may vary, it is anticipated that the taster lectures will leave a positive impact on the offer holders, influencing their decision-making process and increasing their enthusiasm for joining the university. This engagement may manifest in heightened interest in related subject areas, increased inquiries about research opportunities, and a deeper understanding of the university's academic culture. Feedback and observations from participants could further provide insights into the effectiveness of the taster lectures in achieving their intended purpose.
Year(s) Of Engagement Activity 2023
 
Description Pint of Science Festival talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact From fruit flies to decision-making masters: unravelling the secrets of the brain, one tiny brain at a time! Laurie Cazalé-Debat, a postdoc in my lab, shares her exciting science with the public at Pint of Science Festival.
Year(s) Of Engagement Activity 2023
URL https://pintofscience.co.uk/event/a-journey-into-the-mind
 
Description Science engagement at Brain Awareness Week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The lab's dedication to science outreach was on full display during the Brain Awareness Week, as we shared the awe-inspiring wonders of the fruit fly brain with the wider public.

Brain Awareness Week is upon us again! This year, our researchers will be present at the Midlands Arts Centre (MAC) on Saturday 18th March to engage with the public through a variety of 'brainy' activities, crafts and conversations! Take a look below to find out more on what will be on offer. The event is free to attend, thanks to funding from the Federation of European Neuroscience Societies

'Looking into the brain of a fly to understand our own'

Come and discover with us the amazing brain of the fruit-fly Drosophila and why and how it is pushing research boundaries. We are scientists from the University of Birmingham using the fruit-fly to understand how the brain is formed, how it changes throughout life, how it works, how it enables us to make our daily life decisions, as well as what happens in brain disease and how we can learn to promote regeneration and repair. There will be displays demonstrating how we use fruit-fly genetics to address those questions, investigate cell biology and neural circuits in the brain. We'll show how fruit-flies enable us to link genes, neural circuits, brain health, disease and behaviour. We will show you a large fly and fly brain that will open your eyes to genetics and how the brain is built. We will teach you how to make your own fly brain! Come to talk to scientists and ask any questions you may be curious about!
Year(s) Of Engagement Activity 2023
URL https://www.birmingham.ac.uk/research/centre-for-human-brain-health/events/2023/brain-awareness-week...